GleghornLab/Signor_3class · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels int64 0 2	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
P53041	Q99683	1	dephosphorylation	down-regulates activity	0.597	After exposure of cells to H2O2, ASK1 is transiently activated by autophosphorylation at Thr845. The protein then associates with PP5 (protein serine/threonine phosphatase 5), which inactivates ASK1 by dephosphorylation of Thr845.	SIGNOR-248540
Q15369	Q02539	1	phosphorylation	up-regulates	0.2	Our results also show the potential function of p-tefb phosphorylation of h1, namely, to increase h1 dissociation from actively transcribed dna. P-tefb preferentially phosphorylates the ser-183 phosphorylation site of histone h1.1	SIGNOR-166120
O14965	Q15398	1	phosphorylation	up-regulates quantity by stabilization	0.751	Phosphorylation and stabilization of HURP by Aurora-A. Four phosphorylated residues were identified, namely, HURP-S627, -S725, -S757, and -S830, with 65% amino acid sequence coverage. we propose here that Aurora-A may phosphorylate HURP and this probably attenuates the negative impact of cdk1 phosphorylation and by inhibiting subsequent proteasome activity and this will generate a longer HURP half-life.	SIGNOR-262651
P06400	P00519	2	binding	down-regulates	0.57	A domain in the c-terminus of rb, outside of the a/b pocket, binds to the atp-binding lobe of the c-abl tyrosine kinase, resulting in kinase inhibition.	SIGNOR-37139
P48729	Q6IE81	1	phosphorylation	down-regulates activity	0.277	We demonstrate that the destruction complex component casein kinase 1α (CK1α) phosphorylates Jade-1 at a conserved SLS motif and reduces the ability of Jade-1 to inhibit β-catenin signaling.	SIGNOR-273618
Q15831	P28482	0	phosphorylation	down-regulates activity	0.402	Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK.	SIGNOR-209876
Q06124	Q14511	1	dephosphorylation	down-regulates activity	0.488	In this study we demonstrated that SHP-2 inhibits tyrosine phosphorylation of Cas-L, and negatively regulates the cell migration induced by Cas-L.\|These results show that both SH2 domains of SHP-2 are necessary for the interaction with Cas-L.\nIn this study we demonstrated that SHP-2 inhibits tyrosine phosphorylation of Cas-L, and negatively regulates the cell migration induced by Cas-L. Furthermore, our data raise the possibility that Cas-L is a direct substrate for SHP-2, although SHP-2 may inhibit Cas-L phosphorylation indirectly by regulating kinase activity.	SIGNOR-277083
Q9UHA4	P85298	2	binding	up-regulates activity	0.252	Furthermore, we identify that BPGAP1 (a BCH domain-containing, Cdc42GAP-like Rho GTPase-activating protein) promotes MEK partner 1 (MP1)-induced ERK activation on late endosome through scaffolding MP1/MEK1 complex. This regulatory function requires phosphorylation of BPGAP1 by JNK at its C terminal tail (Ser424) to unlock its autoinhibitory conformation.	SIGNOR-275551
Q969R2	P49841	0	phosphorylation	up-regulates activity	0.2	CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.\|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes.	SIGNOR-264874
P11362	O15530	1	phosphorylation	up-regulates activity	0.2	Y105 phosphorylation of PKM2, which is involved in FGFR1-regulated PDHK1 expression, appears to be an upstream event that precedes FGFR1-dependent phosphorylation and activation of PDHK1 in cancer cell metabolism.	SIGNOR-279174
Q8NFG4	P08238	2	binding	up-regulates quantity by stabilization	0.2	Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it is regulated by co-chaperones. Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. FNIPs decelerate the chaperone cycle, facilitating FLCN interaction with Hsp90, consequently ensuring FLCN stability.	SIGNOR-261418
P17252	P38936	1	phosphorylation	up-regulates activity	0.375	Binding of calmodulin to the carboxy-terminal region of p21 induces nuclear accumulation via inhibition of protein kinase c-mediated phosphorylation of ser153\| When phosphorylated at Ser153, p21 is located at the cytoplasm and disrupts stress fibers.	SIGNOR-139302
Q13131	Q13363	1	phosphorylation	down-regulates	0.2	We found that an activated amp-activated protein kinase (ampk) phosphorylates ctbp1 on ser-158 upon metabolic stresses. Moreover, ampk-mediated phosphorylation of ctbp1 (s158) attenuates the repressive function of ctbp1	SIGNOR-200250
P31749	P51617	1	phosphorylation	down-regulates activity	0.386	CaMKKc and Akt overexpression increases IRAK1 phosphorylation at Thr100, and point mutation of this site abrogates the inhibitory effect of Akt on IRAK1-mediated NF-kappaB activation.	SIGNOR-252551
O43765	P11441	2	binding	up-regulates activity	0.577	USP13 and gp78 control ubiquitination of Ubl4A.These data suggest that USP13 and gp78 play antagonizing roles in regulation of Ubl4A ubiquitination: While gp78 assembles ubiquitin chains on Ubl4A, USP13 antagonizes this activity to limit Ubl4A ubiquitination.Ubiquitination of Ubl4A preferentially occurs on Lys48. We identify the Bag6 cofactor Ubl4A as a shared substrate of gp78 and USP13. USP13 depletion is associated with hyper-ubiquitination of Ubl4A and altered interaction between the Bag6 complex and its co-chaperone SGTA. Because the interaction of Ubl4A with SGTA is mediated by positively-charged residues in Ubl4A including Lys48 (Chartron et al., 2012; Xu et al., 2012), which happens to be the major ubiquitination site, the simplest model to explain reduced Bag6-SGTA interaction in USP13 knockdown cells is that ubiquitin conjugates on Ubl4A sterically hinder SGTA binding.	SIGNOR-272858
Q8NHY2	Q13330	2	polyubiquitination	down-regulates quantity by destabilization	0.2	Here we report that MTA1 is an ubiquitinated protein and targeted by the RING-finger E3 ubiquitin-protein ligase constitutive photomorphogenesis protein 1 (COP1) for degradation via the ubiquitin-proteasome pathway.	SIGNOR-271891
O14905	P02708	2	binding	up-regulates	0.2	We identified five wnts (wnt9a, wnt9b, wnt10b, wnt11, and wnt16) that are able to stimulate achr clustering, of which wnt9a and wnt11 are expressed abundantly in developing muscles.	SIGNOR-195978
P25874	P37231	0	transcriptional regulation	up-regulates quantity by expression	0.533	NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma\|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog,	SIGNOR-263985
P63096	Q9H228	2	binding	up-regulates activity	0.492	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256676
P27361	Q9NYA1	1	phosphorylation	up-regulates	0.601	Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation.	SIGNOR-118550
Q15797	O43318	0	phosphorylation	up-regulates activity	0.373	This analysis showed that phosphorylation of Smad1 at the C-terminal serines S463 and S465 was increased by co-expression of constitutively active TAK1.	SIGNOR-279419
O96017	Q13263	1	phosphorylation	down-regulates activity	0.411	In particular, Chk2 phosphorylates KAP1 on Ser473 decreasing the interaction between KAP1 and HP1 proteins: this post translational modification promotes HP1\u03b2 mobilization and the reorganization of chromatin structure favoring the repair of DNA breaks inside heterochromatin [ , ].\|Of note, phosphorylation of S473 by Chk2 decreases the interaction between KAP1 and HP1 proteins and is necessary for HP1\u03b2 mobilization, a key event for DNA repair in the heterochromatin [ - ].	SIGNOR-279730
P01111	Q9Y397	0	palmitoylation	up-regulates activity	0.404	Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein.	SIGNOR-261355
Q9UBN7	P49841	0	phosphorylation	up-regulates activity	0.381	GSK3beta was found to co-localize with HDAC6 in hippocampal neurons, and inhibition of GSK3beta resulted in decreased binding of antibody to phosphoserine-22, a potential GSK3beta phosphorylation site in HDAC6.\|This suggests that GSK3\u03b2 may directly phosphorylate HDAC6 at this site, although further work with purified proteins is needed to determine whether this is the case.\|The fact that HDAC6 is the predominant cytoplasmic deacetylase in neurons suggests that GSK3beta dependent phosphorylation may enhance HDAC6 activity, resulting in a decrease in acetylation of tubulin and an inhibition of both mitochondrial motility and the transport of other kinesin-1 dependent cargoes.	SIGNOR-278941
Q06609	Q8NFZ0	2	binding	up-regulates activity	0.2	The F-box DNA helicase 1 (FBH1) is a 3'-5' DNA helicase with a putative function as a negative regulator of HR. It is the only known DNA helicase to contain an F-box, suggesting that one of its functions is to act as a ubiquitin ligase as part of an SCF (SKP1, CUL1 and F-box) complex. Here we report that the central player in HR, RAD51, is ubiquitylated by the SCF(FBH1) complex. Expression of an ubiquitylation-resistant form of RAD51 in human cells leads to hyperrecombination, as well as several phenotypes indicative of an altered response to DNA replication stress. However, K58/64R RAD51 was ubiquitylated much less efficiently by FBH1 in vitro than was wild-type (WT) RAD51 (Fig. 1d), confirming that the primary sites of modification by FBH1 on RAD51 are K58 and K64.	SIGNOR-272451
Q12834	Q96GD4	0	phosphorylation	down-regulates activity	0.767	When SAC is active, Aurora kinase B (AurkB) phosphorylates and inactivates CDC20, to prevent the activation of anaphase promoting complex and cyclosome (APC/C).\|When SAC is active, Aurora kinase B (AurkB) phosphorylates and inactivates CDC20, to prevent the activation of anaphase-promoting complex/cyclosome (APC/C) (Hagting et al., xref ; Nasmyth, xref ; Ruchaud et al., xref ).	SIGNOR-280190
Q8WYL5	P23528	1	dephosphorylation	up-regulates activity	0.786	Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.\|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH).	SIGNOR-248762
Q9Y5X3	P11717	2	binding	down-regulates quantity	0.569	Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures.	SIGNOR-269442
P98155	Q8WY64	0	ubiquitination	down-regulates quantity by destabilization	0.698	Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation.	SIGNOR-271487
Q06330	Q14469	2	transcriptional regulation	up-regulates quantity	0.6	ligand-induced Notch signaling up-regulated HES1 mRNA expression within 1h and subsequently reduced expression of MyoD mRNA	SIGNOR-243178
P06396	P12931	0	phosphorylation	up-regulates	0.572	Identification of tyr438 as the major in vitro c-src phosphorylation site in human gelsolin recently	SIGNOR-67014
P20382	Q99705	2	binding	up-regulates	0.713	Here we show that the 353-amino-acid human orphan g-protein-coupled receptor slc-1 expressed in hek293 cells binds mch with sub-nanomolar affinity, and is stimulated by mch to mobilize intracellular ca2+ and reduce forskolin-elevated cyclic amp levels.	SIGNOR-69517
Q8TDX7	Q8TD19	0	phosphorylation	up-regulates activity	0.715	Nercc1 catalyzes the phosphorylation of nek6 (ser206) and the equivalent site on nek7 (ser195), resulting in a 20-25-fold activation of nek6/7 kinase activity	SIGNOR-103030
P50148	Q96RI0	2	binding	up-regulates activity	0.385	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257370
Q15303	Q00535	0	phosphorylation	up-regulates activity	0.278	Cdk5 Promotes ErbB4 and PI3-Kinase Activity In Vivo.\|Cdk5 phosphorylates ErbB4 at T1152, situated in close proximity to the PI3-kinase-binding site (Y1056), and in turn promotes ErbB4 tyrosine phosphorylation.	SIGNOR-278436
P49841	Q05397	0	phosphorylation	up-regulates activity	0.365	Inhibition of FAK by its small molecule inhibitor attenuated IL-33-induced tyrosine 216 phosphorylation of GSK3beta in a both time- and dose dependent manner (XREF_FIG).\|The current study indicates that FAK activated GSK3beta modulates ST2L internalization and signaling.	SIGNOR-278986
Q13873	P12643	2	binding	up-regulates	0.8	Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor.	SIGNOR-33425
P10636	P30153	0	dephosphorylation	down-regulates	0.2	Galpha12 directly interacts with pp2a: evidence for galpha12-stimulated pp2a phosphatase activity and dephosphorylation of microtubule-associated protein, tau.	SIGNOR-130136
Q05397	P16234	0	phosphorylation	up-regulates activity	0.429	Focal adhesion kinase (FAK) has a crucial role in integration of signals from integrins and growth factor receptors. In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor Met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate FAK on Tyr194 in the FERM domain (band 4.1 and ezrin/radixin/moesin homology domain). Upon binding to Met or phosphoinositides, FAK may undergo conformational changes, which renders Tyr194 accessible for phosphorylation. Substitution of Tyr194 with Phe significantly suppresses the activation of FAK by Met.	SIGNOR-259400
P61586	Q12774	0	guanine nucleotide exchange factor	up-regulates activity	0.617	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260533
Q96PU5	Q13114	1	ubiquitination	up-regulates activity	0.27	Nedd4l promotes TRAF3 to interact with cIAP1/2 and HECTD3.\|Ubiquitination of TRAF3 by Nedd4l promotes interaction of TRAF3 with proteins such as cIAP1/2, HECTD3, and TBK1.	SIGNOR-278587
P15884	Q9UBE8	0	phosphorylation	down-regulates	0.2	Whereas lef-1 and tcf-4 phosphorylation by nlk (nemo-like kinase) leads to less lef/tcf/beta-catenin complex binding to dna and to lef-1/tcf-4 degradation	SIGNOR-24147
P00533	Q86U44	0	transcriptional regulation	up-regulates quantity by expression	0.331	Here we find that METTL3 promotes translation of certain mRNAs including epidermal growth factor receptor (EGFR) and the Hippo pathway effector TAZ in human cancer cells.	SIGNOR-265954
Q6ZN04	O95149	1	polyubiquitination	down-regulates quantity by destabilization	0.556	HOTAIR associates with E3 ubiquitin ligases bearing RNA-binding domains, Dzip3 and Mex3b, as well as with their respective ubiquitination substrates, Ataxin-1 and Snurportin-1. In this manner, HOTAIR facilitates the ubiquitination of Ataxin-1 by Dzip3 and Snurportin-1 by Mex3b in cells and in vitro, and accelerates their degradation.	SIGNOR-272079
P23470	O75553	1	dephosphorylation	down-regulates activity	0.2	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254697
P05186	P10636	1	dephosphorylation	down-regulates activity	0.2	TNAP dephosphorylates overphosphorylated tau once it is released upon neuronal death.	SIGNOR-277097
P27361	O75582	1	phosphorylation	up-regulates	0.585	In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758.	SIGNOR-131379
O15169	O15169	2	binding	up-regulates activity	0.2	The axin dix domain has a novel structural fold largely composed of beta-strands that engage in head-to-tail self-interaction to form filaments in the crystal	SIGNOR-155218
P53350	Q8TAP6	2	binding	down-regulates activity	0.433	Here, we found that centrosomal protein of 76 kDa (Cep76), previously shown to restrain centriole amplification, interacts with cyclin-dependent kinase 2 (CDK2) and is a bona fide substrate of this kinase. Cep76 is preferentially phosphorylated by cyclin A/CDK2 at a single site S83, and this event is crucial to suppress centriole amplification in S phase. Mechanistically, Cep76 phosphorylation inhibits activation of polo-like kinase 1 (Plk1), thereby blocking premature centriole disengagement and subsequent amplification.	SIGNOR-262731
O43791	Q27J81	2	binding	down-regulates activity	0.2	SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. It revealed that INF2 was ubiquitinated at least at 7 lysine residues (Fig 2I). Interestingly, 5 of 7 ubiquitin attachment sites are localized in a short stretch of sequence (amino acids 612–682) within the FH2 domain of INF2 (Fig 2J).	SIGNOR-272798
Q9UNW8	O95837	2	binding	up-regulates activity	0.407	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257396
Q15797	O43541	2	transcriptional regulation	up-regulates quantity	0.579	Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation	SIGNOR-268935
Q99717	Q9HCE7	0	ubiquitination	down-regulates	0.769	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps.	SIGNOR-195663
P22415	O14672	1	transcriptional regulation	up-regulates quantity by expression	0.27	The promoter region of ADAM10 contains several transcription factor binding sites that can stimulate its transcription. These include binding sites for transcription factors SP1 and USF, and the spliced form of the X-box binding protein (XBP)-1 as well as a retinoic acid-responsive element	SIGNOR-259837
Q13131	Q9BU19	1	phosphorylation	down-regulates	0.2	Arebp is phosphorylated at ser(470) by ampk. Phosphorylation reduces the dna-binding activity of arebp.	SIGNOR-150590
Q9P289	P15311	1	phosphorylation	up-regulates	0.2	Activation of ezrin is mediated by initial pip2 binding and subsequent phosphorylation of threonine 567. Mst4 phosphorylates the regulatory t567 residue of ezrin.	SIGNOR-185563
O95251	P06493	0	phosphorylation	up-regulates	0.355	Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate.	SIGNOR-160747
P40763	Q13882	0	phosphorylation	up-regulates activity	0.622	29 PTK6 promotes activating phosphorylation of STAT3 at tyrosine residue 705.\|STAT3 has been shown to promote tumor initiation of different tumor types, including those of the gastrointestinal tract and skin, and PTK6 was previously shown to promote STAT3 activation and tumorigenesis in mouse models of colon and skin cancer.	SIGNOR-278346
Q96J02	O15519	1	ubiquitination	down-regulates quantity	0.614	Depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch, which specifically ubiquitinates c-FLIP and induces its proteasomal degradation.	SIGNOR-245307
P07948	Q9UK17	1	phosphorylation	up-regulates activity	0.2	These results indicate that Y108 (for Src-family kinases) and Y136 (for EGFR kinase) are involved in the tyrosine phosphorylation of hKv4.3 channels.	SIGNOR-276395
Q8IW41	O43524	1	phosphorylation	up-regulates activity	0.475	Analysis of mutant alleles of FoxO3a showed that MK5 phosphorylated FoxO3a predominantly at S215, but that mutation of four of the identified sites was required to essentially abolish phosphorylation of FoxO3a by MK5 (\u201c4A\u201d) ( Figure\u00a04 C and data not shown).\|MK5 phosphorylates and activates the transcription factor FoxO3a and potentially other FoxO factors.	SIGNOR-279469
P10915	P09238	0	cleavage	down-regulates quantity by destabilization	0.323	Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix.	SIGNOR-256332
Q16619	P40189	2	binding	up-regulates	0.627	In the cos-7 cell line demonstrate that gp130-gp190 heterocomplex formation is essential for ct-1 signaling	SIGNOR-46509
P28223	P63096	2	binding	up-regulates activity	0.349	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256742
Q07817	O60260	0	ubiquitination	down-regulates quantity by destabilization	0.2	In cells, we found BCL-XL levels were reduced by overexpression of PARK2, but this catalytic activity was blocked by the proteasome inhibitor MG132, suggesting degradation of BCL-XL protein by PARK2 is dependent on the proteasome system (XREF_FIG A).\|PARK2 directly binds to and ubiquitinates BCL-XL.	SIGNOR-278661
P09471	P55085	2	binding	up-regulates activity	0.2	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257144
P29274	P09471	2	binding	up-regulates activity	0.301	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257239
P49768	P05129	0	phosphorylation	up-regulates activity	0.2	A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis.	SIGNOR-249238
P19793	Q07869	2	binding	up-regulates	0.597	Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology	SIGNOR-105345
Q15796	Q9GZV5	2	binding	up-regulates	0.593	Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal.	SIGNOR-169835
O14920	O95999	1	phosphorylation	up-regulates activity	0.772	Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling.	SIGNOR-276292
P22413	P06213	2	binding	down-regulates activity	0.388	Plasma cell membrane glycoprotein-1 (PC-1) inhibits insulin receptor (IR) tyrosine kinase activity and subsequent cellular signaling. PC-1 may inhibit the IR by interacting directly with a specific region in the IR alpha-subunit.	SIGNOR-252190
P17612	P09917	1	phosphorylation	down-regulates activity	0.335	These results indicate that PKA phosphorylates 5-LO on Ser-523, which inhibits the catalytic activity of 5-LO and reduces cellular LT generation.	SIGNOR-264410
Q13535	Q00987	1	phosphorylation	down-regulates activity	0.522	We found that a major kinase responsible for s407 phosphorylation is atrs407 phosphorylation of mdm2 by atr reduces mdm2-dependent export of p53 from nuclei to cytoplasm.	SIGNOR-119546
Q9HC77	Q9NYY3	0	phosphorylation	up-regulates	0.579	Plk2 phosphorylates the s589 and s595 residues of cpap in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle.	SIGNOR-165999
P28335	P08754	2	binding	up-regulates activity	0.28	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256877
P41968	O95837	2	binding	up-regulates activity	0.25	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257298
P09619	P20936	2	binding	up-regulates	0.58	The gtpase activating protein (gap) of ras binds only to beta-receptors / we have previously shown that the binding site for gtpase activating protein of ras (rasgap) in the pdgf beta-receptor, tyr771, is phosphorylated to a much lower extent in the heterodimeric configuration of pdgf alpha- and beta-receptors, compared to the pdgf beta-receptor homodimer. / the decreased recruitment of the rasgap to the receptor leads to prolonged activation of the ras/map kinase pathway	SIGNOR-115843
Q15750	O43541	2	binding	down-regulates	0.568	Smad6 interacts with tak1 and tab1, and smad7 with tab1. The interaction of i-smads with tak1 and/or tab1 implies that several mechanisms exist underlying the repression of the tak1-p38 kinase pathway by i-smads.	SIGNOR-112642
P40424	Q96AQ6	2	binding	down-regulates activity	0.331	This protein that we have termed hematopoietic PBX-interacting protein (HPIP) is mainly localized in the cytosol and in small amounts in the nucleus. The region of PBX that interacts with HPIP includes both the homeodomain and immediate N-terminal flanking sequences. Strikingly, electrophoretic mobility shift assays revealed that HPIP inhibits the ability of PBX-HOX heterodimers to bind to target sequences.	SIGNOR-273666
O60674	Q92858	1	phosphorylation	up-regulates quantity	0.339	We discovered tyrosine 78 of Atoh1 is phosphorylated by a Jak2-mediated pathway only in tumor-initiating cells and in human SHH-type medulloblastoma. Phosphorylation of tyrosine 78 stabilizes Atoh1, increases Atoh1’s transcriptional activity, and is independent of canonical Jak2 signaling.	SIGNOR-262201
P14618	Q92519	0	phosphorylation	up-regulates activity	0.2	This study demonstrated that TRIB2, not a "pseudokinase", has the kinase activity to directly phosphorylate PKM2 at serine 37 in cancer cells.	SIGNOR-275431
Q8TCY5	Q01718	2	binding	up-regulates activity	0.76	We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling.We have previously identified MRAP as an accessory protein for MC2R, required for receptor trafficking to the cell surface and the formation of a functional MC2R. Here we have identified MRAP2 as a homologue of MRAP. Like MRAP, MRAP2 is able to support MC2R cell-surface expression, producing a functional ACTH-responsive receptor.	SIGNOR-252360
O94826	Q13627	0	phosphorylation	up-regulates activity	0.2	Phosphorylation of TOM70 Ser91 by DYRK1A stimulates interaction of TOM70 with the core TOM translocase.	SIGNOR-279994
P06493	Q9UI09	1	phosphorylation	up-regulates activity	0.2	Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.\|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation	SIGNOR-275587
O15169	O15105	2	binding	down-regulates	0.712	Here, we show that axin activates tgf-beta signaling by forming a multimeric complex consisting of smad7 and ubiquitin e3 ligase arkadia.	SIGNOR-145851
Q96S42	Q8NER5	2	binding	up-regulates activity	0.636	Human activin receptor-like kinase 7 (ALK7), a type I receptor for Nodal. activation of the Nodal-ALK7 signaling pathway leads to induction of apoptosis and inhibition of cell proliferation.	SIGNOR-251936
Q9H257	Q9BVG3	0	ubiquitination	up-regulates activity	0.51	Importantly, using in vitro ubiquitination assays with purified proteins, we verified that CARD9 is directly ubiquitinated by TRIM62 at residue K125; this ubiquitination is dependent on the ligase activity of TRIM62 and does not occur in CARD9 Delta11 (XREF_FIG).	SIGNOR-278552
Q9UBB4	P53350	0	phosphorylation	down-regulates	0.353	Phosphorylation of ataxin-10 by polo-like kinase 1 is required for cytokinesis. Plk1 phosphorylates ataxin-10 at s77 and t82 in vitro. we found that ataxin-10 is ubiquitinated, and is subject to proteasome-dependent degradation, which is delayed in the 2a mutant. We propose a model in which plk1 phosphorylation of ataxin-10 influences its degradation and cytokinesis	SIGNOR-176122
P23458	Q9HBE5	2	binding	up-regulates	0.628	Retroviral-mediated transduction of wild-type gamma c into xscid jt cells restored function to the il-21r, as shown by il-21-induced tyrosine phosphorylation of jak1 and jak3, and downstream activation of stat5	SIGNOR-90266
P46531	Q86Y01	0	ubiquitination	up-regulates activity	0.781	The human Deltex (DTX1) gene encodes a cytoplasmic protein that functions as a positive regulator of the Notch signaling pathway.	SIGNOR-85942
O15530	O15530	2	phosphorylation	down-regulates quantity by destabilization	0.2	PDK1 kinase activity is negatively regulated by binding to 14-3-3 through the PDK1 autophosphorylation site Ser-241. PDK1 binds to 14-3-3 in vivo and in vitro through the residues surrounding the autophosphorylation site Ser-241 and that the association is achieved only when Ser-241 has been phosphorylated	SIGNOR-250077
Q9P2K8	P56192	1	phosphorylation	down-regulates	0.2	Here we demonstrate that aimp3 is released from mrs by uv irradiation-induced stress. Dissociation was induced by phosphorylation of mrs at ser662 by general control nonrepressed-2 (gcn2) following uv irradiation. Substitution of ser662 to asp (s662d) induced a conformational change in mrs and significantly reduced its interaction with aimp3. This mutant possessed significantly reduced mrs catalytic activity because of loss of trna(met) binding, resulting in down-regulation of global translation.	SIGNOR-177648
P99999	P31751	0	phosphorylation	down-regulates activity	0.293	Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain.	SIGNOR-277236
Q9GZV5	Q15796	2	binding	up-regulates	0.593	Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal.	SIGNOR-169835
O43561	P42336	2	binding	up-regulates activity	0.414	By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively.	SIGNOR-246065
Q96CW1	P00533	1	relocalization	down-regulates	0.524	The removal of the epidermal growth factor receptor (egfr) from the cell surface by endocytosis is triggered by receptor activation, but many facets of egfr trafficking remain unresolvedthe ap-2 complex is involved in the internalization of activated egfr.	SIGNOR-185124
O00429	P16298	0	dephosphorylation	up-regulates activity	0.278	When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis.	SIGNOR-248361
P01106	Q01850	2	binding	up-regulates activity	0.498	Here we find that cdr2 is cell cycle regulated in tumor cells with protein levels peaking in mitosis. As cells exit mitosis, cdr2 is ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) and rapidly degraded by the proteasome. Previously we showed that cdr2 binds to the oncogene c-myc, and here we extend this observation to show that cdr2 and c-myc interact to synergistically regulate c-myc-dependent transcription during passage through mitosis.	SIGNOR-252000
Q9H3N8	P08754	2	binding	up-regulates activity	0.435	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256815

P53041

Q99683

1

dephosphorylation

down-regulates activity

0.597

After exposure of cells to H2O2, ASK1 is transiently activated by autophosphorylation at Thr845. The protein then associates with PP5 (protein serine/threonine phosphatase 5), which inactivates ASK1 by dephosphorylation of Thr845.

SIGNOR-248540

Q15369

Q02539

1

phosphorylation

up-regulates

0.2

Our results also show the potential function of p-tefb phosphorylation of h1, namely, to increase h1 dissociation from actively transcribed dna. P-tefb preferentially phosphorylates the ser-183 phosphorylation site of histone h1.1

SIGNOR-166120

O14965

Q15398

1

phosphorylation

up-regulates quantity by stabilization

0.751

Phosphorylation and stabilization of HURP by Aurora-A. Four phosphorylated residues were identified, namely, HURP-S627, -S725, -S757, and -S830, with 65% amino acid sequence coverage. we propose here that Aurora-A may phosphorylate HURP and this probably attenuates the negative impact of cdk1 phosphorylation and by inhibiting subsequent proteasome activity and this will generate a longer HURP half-life.

SIGNOR-262651

P06400

P00519

2

binding

down-regulates

0.57

A domain in the c-terminus of rb, outside of the a/b pocket, binds to the atp-binding lobe of the c-abl tyrosine kinase, resulting in kinase inhibition.

SIGNOR-37139

P48729

Q6IE81

1

phosphorylation

down-regulates activity

0.277

We demonstrate that the destruction complex component casein kinase 1α (CK1α) phosphorylates Jade-1 at a conserved SLS motif and reduces the ability of Jade-1 to inhibit β-catenin signaling.

SIGNOR-273618

Q15831

P28482

0

phosphorylation

down-regulates activity

0.402

Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK.

SIGNOR-209876

Q06124

Q14511

1

dephosphorylation

down-regulates activity

0.488

In this study we demonstrated that SHP-2 inhibits tyrosine phosphorylation of Cas-L, and negatively regulates the cell migration induced by Cas-L.|These results show that both SH2 domains of SHP-2 are necessary for the interaction with Cas-L.\nIn this study we demonstrated that SHP-2 inhibits tyrosine phosphorylation of Cas-L, and negatively regulates the cell migration induced by Cas-L. Furthermore, our data raise the possibility that Cas-L is a direct substrate for SHP-2, although SHP-2 may inhibit Cas-L phosphorylation indirectly by regulating kinase activity.

SIGNOR-277083

Q9UHA4

P85298

2

binding

up-regulates activity

0.252

Furthermore, we identify that BPGAP1 (a BCH domain-containing, Cdc42GAP-like Rho GTPase-activating protein) promotes MEK partner 1 (MP1)-induced ERK activation on late endosome through scaffolding MP1/MEK1 complex. This regulatory function requires phosphorylation of BPGAP1 by JNK at its C terminal tail (Ser424) to unlock its autoinhibitory conformation.

SIGNOR-275551

Q969R2

P49841

0

phosphorylation

up-regulates activity

0.2

CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes.

SIGNOR-264874

P11362

O15530

1

phosphorylation

up-regulates activity

0.2

Y105 phosphorylation of PKM2, which is involved in FGFR1-regulated PDHK1 expression, appears to be an upstream event that precedes FGFR1-dependent phosphorylation and activation of PDHK1 in cancer cell metabolism.

SIGNOR-279174

Q8NFG4

P08238

2

binding

up-regulates quantity by stabilization

0.2

Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it is regulated by co-chaperones. Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. FNIPs decelerate the chaperone cycle, facilitating FLCN interaction with Hsp90, consequently ensuring FLCN stability.

SIGNOR-261418

P17252

P38936

1

phosphorylation

up-regulates activity

0.375

Binding of calmodulin to the carboxy-terminal region of p21 induces nuclear accumulation via inhibition of protein kinase c-mediated phosphorylation of ser153| When phosphorylated at Ser153, p21 is located at the cytoplasm and disrupts stress fibers.

SIGNOR-139302

Q13131

Q13363

1

phosphorylation

down-regulates

0.2

We found that an activated amp-activated protein kinase (ampk) phosphorylates ctbp1 on ser-158 upon metabolic stresses. Moreover, ampk-mediated phosphorylation of ctbp1 (s158) attenuates the repressive function of ctbp1

SIGNOR-200250

P31749

P51617

1

phosphorylation

down-regulates activity

0.386

CaMKKc and Akt overexpression increases IRAK1 phosphorylation at Thr100, and point mutation of this site abrogates the inhibitory effect of Akt on IRAK1-mediated NF-kappaB activation.

SIGNOR-252551

O43765

P11441

2

binding

up-regulates activity

0.577

USP13 and gp78 control ubiquitination of Ubl4A.These data suggest that USP13 and gp78 play antagonizing roles in regulation of Ubl4A ubiquitination: While gp78 assembles ubiquitin chains on Ubl4A, USP13 antagonizes this activity to limit Ubl4A ubiquitination.Ubiquitination of Ubl4A preferentially occurs on Lys48. We identify the Bag6 cofactor Ubl4A as a shared substrate of gp78 and USP13. USP13 depletion is associated with hyper-ubiquitination of Ubl4A and altered interaction between the Bag6 complex and its co-chaperone SGTA. Because the interaction of Ubl4A with SGTA is mediated by positively-charged residues in Ubl4A including Lys48 (Chartron et al., 2012; Xu et al., 2012), which happens to be the major ubiquitination site, the simplest model to explain reduced Bag6-SGTA interaction in USP13 knockdown cells is that ubiquitin conjugates on Ubl4A sterically hinder SGTA binding.

SIGNOR-272858

Q8NHY2

Q13330

2

polyubiquitination

down-regulates quantity by destabilization

0.2

Here we report that MTA1 is an ubiquitinated protein and targeted by the RING-finger E3 ubiquitin-protein ligase constitutive photomorphogenesis protein 1 (COP1) for degradation via the ubiquitin-proteasome pathway.

SIGNOR-271891

O14905

P02708

2

binding

up-regulates

0.2

We identified five wnts (wnt9a, wnt9b, wnt10b, wnt11, and wnt16) that are able to stimulate achr clustering, of which wnt9a and wnt11 are expressed abundantly in developing muscles.

SIGNOR-195978

P25874

P37231

0

transcriptional regulation

up-regulates quantity by expression

0.533

NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog,

SIGNOR-263985

P63096

Q9H228

2

binding

up-regulates activity

0.492

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-256676

P27361

Q9NYA1

1

phosphorylation

up-regulates

0.601

Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation.

SIGNOR-118550

Q15797

O43318

0

phosphorylation

up-regulates activity

0.373

This analysis showed that phosphorylation of Smad1 at the C-terminal serines S463 and S465 was increased by co-expression of constitutively active TAK1.

SIGNOR-279419

O96017

Q13263

1

phosphorylation

down-regulates activity

0.411

In particular, Chk2 phosphorylates KAP1 on Ser473 decreasing the interaction between KAP1 and HP1 proteins: this post translational modification promotes HP1\u03b2 mobilization and the reorganization of chromatin structure favoring the repair of DNA breaks inside heterochromatin [ , ].|Of note, phosphorylation of S473 by Chk2 decreases the interaction between KAP1 and HP1 proteins and is necessary for HP1\u03b2 mobilization, a key event for DNA repair in the heterochromatin [ - ].

SIGNOR-279730

P01111

Q9Y397

0

palmitoylation

up-regulates activity

0.404

Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein.

SIGNOR-261355

Q9UBN7

P49841

0

phosphorylation

up-regulates activity

0.381

GSK3beta was found to co-localize with HDAC6 in hippocampal neurons, and inhibition of GSK3beta resulted in decreased binding of antibody to phosphoserine-22, a potential GSK3beta phosphorylation site in HDAC6.|This suggests that GSK3\u03b2 may directly phosphorylate HDAC6 at this site, although further work with purified proteins is needed to determine whether this is the case.|The fact that HDAC6 is the predominant cytoplasmic deacetylase in neurons suggests that GSK3beta dependent phosphorylation may enhance HDAC6 activity, resulting in a decrease in acetylation of tubulin and an inhibition of both mitochondrial motility and the transport of other kinesin-1 dependent cargoes.

SIGNOR-278941

Q06609

Q8NFZ0

2

binding

up-regulates activity

0.2

The F-box DNA helicase 1 (FBH1) is a 3'-5' DNA helicase with a putative function as a negative regulator of HR. It is the only known DNA helicase to contain an F-box, suggesting that one of its functions is to act as a ubiquitin ligase as part of an SCF (SKP1, CUL1 and F-box) complex. Here we report that the central player in HR, RAD51, is ubiquitylated by the SCF(FBH1) complex. Expression of an ubiquitylation-resistant form of RAD51 in human cells leads to hyperrecombination, as well as several phenotypes indicative of an altered response to DNA replication stress. However, K58/64R RAD51 was ubiquitylated much less efficiently by FBH1 in vitro than was wild-type (WT) RAD51 (Fig. 1d), confirming that the primary sites of modification by FBH1 on RAD51 are K58 and K64.

SIGNOR-272451

Q12834

Q96GD4

0

phosphorylation

down-regulates activity

0.767

When SAC is active, Aurora kinase B (AurkB) phosphorylates and inactivates CDC20, to prevent the activation of anaphase promoting complex and cyclosome (APC/C).|When SAC is active, Aurora kinase B (AurkB) phosphorylates and inactivates CDC20, to prevent the activation of anaphase-promoting complex/cyclosome (APC/C) (Hagting et al., xref ; Nasmyth, xref ; Ruchaud et al., xref ).

SIGNOR-280190

Q8WYL5

P23528

1

dephosphorylation

up-regulates activity

0.786

Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH).

SIGNOR-248762

Q9Y5X3

P11717

2

binding

down-regulates quantity

0.569

Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures.

SIGNOR-269442

P98155

Q8WY64

0

ubiquitination

down-regulates quantity by destabilization

0.698

Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation.

SIGNOR-271487

Q06330

Q14469

2

transcriptional regulation

up-regulates quantity

0.6

ligand-induced Notch signaling up-regulated HES1 mRNA expression within 1h and subsequently reduced expression of MyoD mRNA

SIGNOR-243178

P06396

P12931

0

phosphorylation

up-regulates

0.572

Identification of tyr438 as the major in vitro c-src phosphorylation site in human gelsolin recently

SIGNOR-67014

P20382

Q99705

2

binding

up-regulates

0.713

Here we show that the 353-amino-acid human orphan g-protein-coupled receptor slc-1 expressed in hek293 cells binds mch with sub-nanomolar affinity, and is stimulated by mch to mobilize intracellular ca2+ and reduce forskolin-elevated cyclic amp levels.

SIGNOR-69517

Q8TDX7

Q8TD19

0

phosphorylation

up-regulates activity

0.715

Nercc1 catalyzes the phosphorylation of nek6 (ser206) and the equivalent site on nek7 (ser195), resulting in a 20-25-fold activation of nek6/7 kinase activity

SIGNOR-103030

P50148

Q96RI0

2

binding

up-regulates activity

0.385

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-257370

Q15303

Q00535

0

phosphorylation

up-regulates activity

0.278

Cdk5 Promotes ErbB4 and PI3-Kinase Activity In Vivo.|Cdk5 phosphorylates ErbB4 at T1152, situated in close proximity to the PI3-kinase-binding site (Y1056), and in turn promotes ErbB4 tyrosine phosphorylation.

SIGNOR-278436

P49841

Q05397

0

phosphorylation

up-regulates activity

0.365

Inhibition of FAK by its small molecule inhibitor attenuated IL-33-induced tyrosine 216 phosphorylation of GSK3beta in a both time- and dose dependent manner (XREF_FIG).|The current study indicates that FAK activated GSK3beta modulates ST2L internalization and signaling.

SIGNOR-278986

Q13873

P12643

2

binding

up-regulates

0.8

Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor.

SIGNOR-33425

P10636

P30153

0

dephosphorylation

down-regulates

0.2

Galpha12 directly interacts with pp2a: evidence for galpha12-stimulated pp2a phosphatase activity and dephosphorylation of microtubule-associated protein, tau.

SIGNOR-130136

Q05397

P16234

0

phosphorylation

up-regulates activity

0.429

Focal adhesion kinase (FAK) has a crucial role in integration of signals from integrins and growth factor receptors. In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor Met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate FAK on Tyr194 in the FERM domain (band 4.1 and ezrin/radixin/moesin homology domain). Upon binding to Met or phosphoinositides, FAK may undergo conformational changes, which renders Tyr194 accessible for phosphorylation. Substitution of Tyr194 with Phe significantly suppresses the activation of FAK by Met.

SIGNOR-259400

P61586

Q12774

0

guanine nucleotide exchange factor

up-regulates activity

0.617

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260533

Q96PU5

Q13114

1

ubiquitination

up-regulates activity

0.27

Nedd4l promotes TRAF3 to interact with cIAP1/2 and HECTD3.|Ubiquitination of TRAF3 by Nedd4l promotes interaction of TRAF3 with proteins such as cIAP1/2, HECTD3, and TBK1.

SIGNOR-278587

P15884

Q9UBE8

0

phosphorylation

down-regulates

0.2

Whereas lef-1 and tcf-4 phosphorylation by nlk (nemo-like kinase) leads to less lef/tcf/beta-catenin complex binding to dna and to lef-1/tcf-4 degradation

SIGNOR-24147

P00533

Q86U44

0

transcriptional regulation

up-regulates quantity by expression

0.331

Here we find that METTL3 promotes translation of certain mRNAs including epidermal growth factor receptor (EGFR) and the Hippo pathway effector TAZ in human cancer cells.

SIGNOR-265954

Q6ZN04

O95149

1

polyubiquitination

down-regulates quantity by destabilization

0.556

HOTAIR associates with E3 ubiquitin ligases bearing RNA-binding domains, Dzip3 and Mex3b, as well as with their respective ubiquitination substrates, Ataxin-1 and Snurportin-1. In this manner, HOTAIR facilitates the ubiquitination of Ataxin-1 by Dzip3 and Snurportin-1 by Mex3b in cells and in vitro, and accelerates their degradation.

SIGNOR-272079

P23470

O75553

1

dephosphorylation

down-regulates activity

0.2

PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.

SIGNOR-254697

P05186

P10636

1

dephosphorylation

down-regulates activity

0.2

TNAP dephosphorylates overphosphorylated tau once it is released upon neuronal death.

SIGNOR-277097

P27361

O75582

1

phosphorylation

up-regulates

0.585

In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758.

SIGNOR-131379

O15169

2

binding

up-regulates activity

0.2

The axin dix domain has a novel structural fold largely composed of beta-strands that engage in head-to-tail self-interaction to form filaments in the crystal

SIGNOR-155218

P53350

Q8TAP6

2

binding

down-regulates activity

0.433

Here, we found that centrosomal protein of 76 kDa (Cep76), previously shown to restrain centriole amplification, interacts with cyclin-dependent kinase 2 (CDK2) and is a bona fide substrate of this kinase. Cep76 is preferentially phosphorylated by cyclin A/CDK2 at a single site S83, and this event is crucial to suppress centriole amplification in S phase. Mechanistically, Cep76 phosphorylation inhibits activation of polo-like kinase 1 (Plk1), thereby blocking premature centriole disengagement and subsequent amplification.

SIGNOR-262731

O43791

Q27J81

2

binding

down-regulates activity

0.2

SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. It revealed that INF2 was ubiquitinated at least at 7 lysine residues (Fig 2I). Interestingly, 5 of 7 ubiquitin attachment sites are localized in a short stretch of sequence (amino acids 612–682) within the FH2 domain of INF2 (Fig 2J).

SIGNOR-272798

Q9UNW8

O95837

2

binding

up-regulates activity

0.407

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-257396

Q15797

O43541

2

transcriptional regulation

up-regulates quantity

0.579

Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation

SIGNOR-268935

Q99717

Q9HCE7

0

ubiquitination

down-regulates

0.769

Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps.

SIGNOR-195663

P22415

O14672

1

transcriptional regulation

up-regulates quantity by expression

0.27

The promoter region of ADAM10 contains several transcription factor binding sites that can stimulate its transcription. These include binding sites for transcription factors SP1 and USF, and the spliced form of the X-box binding protein (XBP)-1 as well as a retinoic acid-responsive element

SIGNOR-259837

Q13131

Q9BU19

1

phosphorylation

down-regulates

0.2

Arebp is phosphorylated at ser(470) by ampk. Phosphorylation reduces the dna-binding activity of arebp.

SIGNOR-150590

Q9P289

P15311

1

phosphorylation

up-regulates

0.2

Activation of ezrin is mediated by initial pip2 binding and subsequent phosphorylation of threonine 567. Mst4 phosphorylates the regulatory t567 residue of ezrin.

SIGNOR-185563

O95251

P06493

0

phosphorylation

up-regulates

0.355

Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate.

SIGNOR-160747

P40763

Q13882

0

phosphorylation

up-regulates activity

0.622

29 PTK6 promotes activating phosphorylation of STAT3 at tyrosine residue 705.|STAT3 has been shown to promote tumor initiation of different tumor types, including those of the gastrointestinal tract and skin, and PTK6 was previously shown to promote STAT3 activation and tumorigenesis in mouse models of colon and skin cancer.

SIGNOR-278346

Q96J02

O15519

1

ubiquitination

down-regulates quantity

0.614

Depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch, which specifically ubiquitinates c-FLIP and induces its proteasomal degradation.

SIGNOR-245307

P07948

Q9UK17

1

phosphorylation

up-regulates activity

0.2

These results indicate that Y108 (for Src-family kinases) and Y136 (for EGFR kinase) are involved in the tyrosine phosphorylation of hKv4.3 channels.

SIGNOR-276395

Q8IW41

O43524

1

phosphorylation

up-regulates activity

0.475

Analysis of mutant alleles of FoxO3a showed that MK5 phosphorylated FoxO3a predominantly at S215, but that mutation of four of the identified sites was required to essentially abolish phosphorylation of FoxO3a by MK5 (\u201c4A\u201d) ( Figure\u00a04 C and data not shown).|MK5 phosphorylates and activates the transcription factor FoxO3a and potentially other FoxO factors.

SIGNOR-279469

P10915

P09238

0

cleavage

down-regulates quantity by destabilization

0.323

Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix.

SIGNOR-256332

Q16619

P40189

2

binding

up-regulates

0.627

In the cos-7 cell line demonstrate that gp130-gp190 heterocomplex formation is essential for ct-1 signaling

SIGNOR-46509

P28223

P63096

2

binding

up-regulates activity

0.349

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-256742

Q07817

O60260

0

ubiquitination

down-regulates quantity by destabilization

0.2

In cells, we found BCL-XL levels were reduced by overexpression of PARK2, but this catalytic activity was blocked by the proteasome inhibitor MG132, suggesting degradation of BCL-XL protein by PARK2 is dependent on the proteasome system (XREF_FIG A).|PARK2 directly binds to and ubiquitinates BCL-XL.

SIGNOR-278661

P09471

P55085

2

binding

up-regulates activity

0.2

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-257144

P29274

P09471

2

binding

up-regulates activity

0.301

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-257239

P49768

P05129

0

phosphorylation

up-regulates activity

0.2

A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis.

SIGNOR-249238

P19793

Q07869

2

binding

up-regulates

0.597

Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology

SIGNOR-105345

Q15796

Q9GZV5

2

binding

up-regulates

0.593

Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal.

SIGNOR-169835

O14920

O95999

1

phosphorylation

up-regulates activity

0.772

Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling.

SIGNOR-276292

P22413

P06213

2

binding

down-regulates activity

0.388

Plasma cell membrane glycoprotein-1 (PC-1) inhibits insulin receptor (IR) tyrosine kinase activity and subsequent cellular signaling. PC-1 may inhibit the IR by interacting directly with a specific region in the IR alpha-subunit.

SIGNOR-252190

P17612

P09917

1

phosphorylation

down-regulates activity

0.335

These results indicate that PKA phosphorylates 5-LO on Ser-523, which inhibits the catalytic activity of 5-LO and reduces cellular LT generation.

SIGNOR-264410

Q13535

Q00987

1

phosphorylation

down-regulates activity

0.522

We found that a major kinase responsible for s407 phosphorylation is atrs407 phosphorylation of mdm2 by atr reduces mdm2-dependent export of p53 from nuclei to cytoplasm.

SIGNOR-119546

Q9HC77

Q9NYY3

0

phosphorylation

up-regulates

0.579

Plk2 phosphorylates the s589 and s595 residues of cpap in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle.

SIGNOR-165999

P28335

P08754

2

binding

up-regulates activity

0.28

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-256877

P41968

O95837

2

binding

up-regulates activity

0.25

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-257298

P09619

P20936

2

binding

up-regulates

0.58

The gtpase activating protein (gap) of ras binds only to beta-receptors / we have previously shown that the binding site for gtpase activating protein of ras (rasgap) in the pdgf beta-receptor, tyr771, is phosphorylated to a much lower extent in the heterodimeric configuration of pdgf alpha- and beta-receptors, compared to the pdgf beta-receptor homodimer. / the decreased recruitment of the rasgap to the receptor leads to prolonged activation of the ras/map kinase pathway

SIGNOR-115843

Q15750

O43541

2

binding

down-regulates

0.568

Smad6 interacts with tak1 and tab1, and smad7 with tab1. The interaction of i-smads with tak1 and/or tab1 implies that several mechanisms exist underlying the repression of the tak1-p38 kinase pathway by i-smads.

SIGNOR-112642

P40424

Q96AQ6

2

binding

down-regulates activity

0.331

This protein that we have termed hematopoietic PBX-interacting protein (HPIP) is mainly localized in the cytosol and in small amounts in the nucleus. The region of PBX that interacts with HPIP includes both the homeodomain and immediate N-terminal flanking sequences. Strikingly, electrophoretic mobility shift assays revealed that HPIP inhibits the ability of PBX-HOX heterodimers to bind to target sequences.

SIGNOR-273666

O60674

Q92858

1

phosphorylation

up-regulates quantity

0.339

We discovered tyrosine 78 of Atoh1 is phosphorylated by a Jak2-mediated pathway only in tumor-initiating cells and in human SHH-type medulloblastoma. Phosphorylation of tyrosine 78 stabilizes Atoh1, increases Atoh1’s transcriptional activity, and is independent of canonical Jak2 signaling.

SIGNOR-262201

P14618

Q92519

0

phosphorylation

up-regulates activity

0.2

This study demonstrated that TRIB2, not a "pseudokinase", has the kinase activity to directly phosphorylate PKM2 at serine 37 in cancer cells.

SIGNOR-275431

Q8TCY5

Q01718

2

binding

up-regulates activity

0.76

We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling.We have previously identified MRAP as an accessory protein for MC2R, required for receptor trafficking to the cell surface and the formation of a functional MC2R. Here we have identified MRAP2 as a homologue of MRAP. Like MRAP, MRAP2 is able to support MC2R cell-surface expression, producing a functional ACTH-responsive receptor.

SIGNOR-252360

O94826

Q13627

0

phosphorylation

up-regulates activity

0.2

Phosphorylation of TOM70 Ser91 by DYRK1A stimulates interaction of TOM70 with the core TOM translocase.

SIGNOR-279994

P06493

Q9UI09

1

phosphorylation

up-regulates activity

0.2

Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation

SIGNOR-275587

O15169

O15105

2

binding

down-regulates

0.712

Here, we show that axin activates tgf-beta signaling by forming a multimeric complex consisting of smad7 and ubiquitin e3 ligase arkadia.

SIGNOR-145851

Q96S42

Q8NER5

2

binding

up-regulates activity

0.636

Human activin receptor-like kinase 7 (ALK7), a type I receptor for Nodal. activation of the Nodal-ALK7 signaling pathway leads to induction of apoptosis and inhibition of cell proliferation.

SIGNOR-251936

Q9H257

Q9BVG3

0

ubiquitination

up-regulates activity

0.51

Importantly, using in vitro ubiquitination assays with purified proteins, we verified that CARD9 is directly ubiquitinated by TRIM62 at residue K125; this ubiquitination is dependent on the ligase activity of TRIM62 and does not occur in CARD9 Delta11 (XREF_FIG).

SIGNOR-278552

Q9UBB4

P53350

0

phosphorylation

down-regulates

0.353

Phosphorylation of ataxin-10 by polo-like kinase 1 is required for cytokinesis. Plk1 phosphorylates ataxin-10 at s77 and t82 in vitro. we found that ataxin-10 is ubiquitinated, and is subject to proteasome-dependent degradation, which is delayed in the 2a mutant. We propose a model in which plk1 phosphorylation of ataxin-10 influences its degradation and cytokinesis

SIGNOR-176122

P23458

Q9HBE5

2

binding

up-regulates

0.628

Retroviral-mediated transduction of wild-type gamma c into xscid jt cells restored function to the il-21r, as shown by il-21-induced tyrosine phosphorylation of jak1 and jak3, and downstream activation of stat5

SIGNOR-90266

P46531

Q86Y01

0

ubiquitination

up-regulates activity

0.781

The human Deltex (DTX1) gene encodes a cytoplasmic protein that functions as a positive regulator of the Notch signaling pathway.

SIGNOR-85942

O15530

2

phosphorylation

down-regulates quantity by destabilization

0.2

PDK1 kinase activity is negatively regulated by binding to 14-3-3 through the PDK1 autophosphorylation site Ser-241. PDK1 binds to 14-3-3 in vivo and in vitro through the residues surrounding the autophosphorylation site Ser-241 and that the association is achieved only when Ser-241 has been phosphorylated

SIGNOR-250077

Q9P2K8

P56192

1

phosphorylation

down-regulates

0.2

Here we demonstrate that aimp3 is released from mrs by uv irradiation-induced stress. Dissociation was induced by phosphorylation of mrs at ser662 by general control nonrepressed-2 (gcn2) following uv irradiation. Substitution of ser662 to asp (s662d) induced a conformational change in mrs and significantly reduced its interaction with aimp3. This mutant possessed significantly reduced mrs catalytic activity because of loss of trna(met) binding, resulting in down-regulation of global translation.

SIGNOR-177648

P99999

P31751

0

phosphorylation

down-regulates activity

0.293

Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain.

SIGNOR-277236

Q9GZV5

Q15796

2

binding

up-regulates

0.593

Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal.

SIGNOR-169835

O43561

P42336

2

binding

up-regulates activity

0.414

By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively.

SIGNOR-246065

Q96CW1

P00533

1

relocalization

down-regulates

0.524

The removal of the epidermal growth factor receptor (egfr) from the cell surface by endocytosis is triggered by receptor activation, but many facets of egfr trafficking remain unresolvedthe ap-2 complex is involved in the internalization of activated egfr.

SIGNOR-185124

O00429

P16298

0

dephosphorylation

up-regulates activity

0.278

When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis.

SIGNOR-248361

P01106

Q01850

2

binding

up-regulates activity

0.498

Here we find that cdr2 is cell cycle regulated in tumor cells with protein levels peaking in mitosis. As cells exit mitosis, cdr2 is ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) and rapidly degraded by the proteasome. Previously we showed that cdr2 binds to the oncogene c-myc, and here we extend this observation to show that cdr2 and c-myc interact to synergistically regulate c-myc-dependent transcription during passage through mitosis.

SIGNOR-252000

Q9H3N8

P08754

2

binding

up-regulates activity

0.435

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-256815