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
Q16873	P23443	0	phosphorylation	down-regulates activity	0.2	Here, we identified Ser(36) as the major p70S6k phosphorylation site, along with a low frequency site at Thr(40), using an in vitro phosphorylation assay combined with mass spectrometry. Cellular LTC4S activity is suppressed by PKC-mediated phosphorylation, and recently a downstream p70S6k was shown to play an important role in this process.	SIGNOR-277256
P22681	P04626	1	ubiquitination	down-regulates quantity by destabilization	0.601	Ligand binding to EGFR also leads to rapid internalization and proteosomal/lysosomal degradation of the receptors. This process results in a dramatic downregulation of both total and cell surface receptors. EGF-induced degradation of EGFR is thought to be initiated by phosphorylation of tyrosine 1045 of the receptor followed by binding of Cbl adaptor proteins and ubiquitination of the receptor. Internalized EGFR is transported to early endosomes where receptor-ligand complexes are sorted for either degradation or recycling to the cell surface.	SIGNOR-30794
P61764	Q9ULB1	2	binding	up-regulates activity	0.527	We propose that all these neurexin complexes can interact with Munc18. Both Mint1 and Mint2 could function as direct adaptors of Munc18 to neurexins, whereas Mint1 in addition could recruit Munc18 to CASK-neurexin (Fig. 5 B).	SIGNOR-264040
P55017	Q9UEW8	0	phosphorylation	down-regulates activity	0.484	SPAK directly phosphorylates NCC and its effects on NCC are universally associated with phosphorylation\|This adds to the evidence that SPAK-mediated phosphorylation acts primarily to increase activity of individual cotransporters without affecting the amount of NCC on the surface\| the kinase (SPAK) that phosphorylates NCC at T53	SIGNOR-264623
Q14469	P15172	1	transcriptional regulation	down-regulates activity	0.294	Notch signaling up-regulated HES1 mRNA expression within 1 h and subsequently reduced expression of MyoD mRNA	SIGNOR-243181
Q8WYK2	P05412	2	binding	down-regulates activity	0.607	JDP2 dimerizes with other AP-1 proteins such as activating transcription factor-2 (ATF2) and Jun to repress transcription from promoters that contain a cyclic AMP-responsive element (CRE).	SIGNOR-226398
Q13464	Q9UPT6	1	phosphorylation	up-regulates	0.332	Identification of rock1 as an upstream activator of the jip-3 to jnk signaling axis in response to uvb damage. phosphorylation of jip-3 by rock1 was crucial for the recruitment of jnk. Inhibition of the activity of rock1 in keratinocytes resulted in decreased activation of the jnk pathway and thus a reduction in apoptosis.	SIGNOR-134588
P63000	Q9P107	0	gtpase-activating protein	down-regulates activity	0.445	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-260506
P04626	P49327	1	phosphorylation	up-regulates activity	0.442	Conversely, HER2 directly phosphorylates and activates FASN, while it also promotes FASN gene expression ( xref ; xref ).\|Conversely, HER2 directly phosphorylates and activates FASN, while it also promotes FASN gene expression.	SIGNOR-278399
P27361	Q07869	1	phosphorylation	up-regulates activity	0.601	We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution.	SIGNOR-249474
P27361	Q14247	1	phosphorylation	up-regulates	0.422	Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement.	SIGNOR-165212
P24941	P23470	0	dephosphorylation	down-regulates activity	0.298	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-254695
Q9Y2X7	P19174	2	binding	up-regulates	0.557	Git1 interaction with plcgamma is required for plcgamma activation based on inhibition of tyrosine phosphorylation	SIGNOR-118454
P21754	Q5JUK2	0	transcriptional regulation	up-regulates quantity by expression	0.378	Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters.	SIGNOR-266078
Q08211	P52948	2	binding	up-regulates activity	0.356	Here we report on the identification of the DExH/D-box helicase DHX9 as an intranuclear Nup98 binding partner. Various results, including in vitro assays, show that the FG/GLFG region of Nup98 binds to N- and C-terminal regions of DHX9 in an RNA facilitated manner. Importantly, binding of Nup98 stimulates the ATPase activity of DHX9, and a transcriptional reporter assay suggests Nup98 supports DHX9-stimulated transcription.	SIGNOR-260954
P31749	Q15173	0	dephosphorylation	down-regulates	0.661	Activation of pp2a is the intermediate step between the abeta-ceramide cascade and the subsequent inactivation of akt.	SIGNOR-252615
P35226	P68400	0	phosphorylation	down-regulates quantity by destabilization	0.269	Here we report that CK2α, a nuclear serine threonine kinase, phosphorylates BMI1 at Serine 110 as determined by in-vitro/ex-vivo kinase assay and mass spectrometry. e-expression of the phosphorylatable but not non-phosphorylatable BMI1 rescued clonal growth in endogenous BMI1 silenced cancer cells leading us to speculate that CK2α-mediated phosphorylation stabilizes BMI1 and promotes its oncogenic function.	SIGNOR-277345
P11912	Q9NRF2	0	dephosphorylation	down-regulates activity	0.2	SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK.	SIGNOR-268457
O15552	P30679	2	binding	up-regulates activity	0.404	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-257276
P51617	Q01638	2	binding	up-regulates activity	0.604	As shown in Figure 3D, MyD88, IRAK, IRAK4, and TRAF6 are all recruited to ST2 upon IL-33 stimulation.	SIGNOR-277706
Q9Y243	Q01860	1	phosphorylation	up-regulates quantity by stabilization	0.257	Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG.	SIGNOR-242107
Q16665	P49841	0	phosphorylation	down-regulates activity	0.332	Glycogen synthase kinase 3 \u03b2 (GSK3\u03b2) phosphorylates HIF-1\u03b1 at three serine residues (Ser-551, Ser-555, and Ser-589) located within its oxygen-dependent degradation domain (ODDD) [12] (Figure 5). Phosphorylation at these residues by GSK3\u03b2 enhances HIF-1\u03b1 degradation in a pVHL-independent manner, resulting in suppression of the HIF-1 activity [12,13].\|Phosphorylation at these residues by GSK3beta enhances HIF-1alpha degradation in a pVHL independent manner, resulting in suppression of the HIF-1 activity , ].	SIGNOR-278294
P52597	Q96JP5	0	ubiquitination	down-regulates quantity	0.2	Collectively, our results indicate that ZFP91 polyubiquitinated hnRNP F at Lys 185.\|We found that silencing ZFP91 increased hnRNP F protein levels, but not hnRNP F mRNA levels, while ectopically expressing ZFP91 decreased hnRNP F protein levels, but not hnRNP F mRNA levels.	SIGNOR-278802
Q13131	Q9UQL6	1	phosphorylation	down-regulates	0.341	Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs)	SIGNOR-176479
O14746	Q9UHC7	0	polyubiquitination	down-regulates quantity by destabilization	0.475	MKRN1 functions as an E3 ubiquitin-ligase for hTERT in vitro and in vivo. Furthermore, we have used the yeast two-hybrid method to identify a novel RING finger gene (MKRN1) encoding an E3 ligase that mediates ubiquitination of hTERT. Overexpression of MKRN1 in telomerase-positive cells promotes the degradation of hTERT and decreases telomerase activity and subsequently telomere length.	SIGNOR-271529
Q14004	P22674	2	binding	up-regulates activity	0.271	Cyclin O promotes lung cancer progression and cetuximab resistance via cell cycle regulation and CDK13 interaction\|CCNO promoted tumor cell proliferation and survival in vivo via CDK13\|	SIGNOR-275618
P49841	P46531	1	phosphorylation	up-regulates	0.463	Here, we observed that gsk3beta was able to bind and phosphorylate notch1ic in vitro, and attenuation of gsk3beta activity reduced phosphorylation of notchic in vivo.Functionally, ligand-activated signaling through the endogenous notch1 receptor was reduced in gsk3beta fibroblasts, implying a positive role for gsk3beta in mammalian notch signaling.	SIGNOR-90608
O75382	Q5VSY0	1	polyubiquitination	down-regulates quantity by destabilization	0.248	Here we identify the RING finger-containing protein TRIM3 as a specific E3 ubiquitin ligase for the PSD scaffold GKAP/SAPAP1. Present in PSD fractions from rat brain, TRIM3 stimulates ubiquitination and proteasome-dependent degradation of GKAP, and induces the loss of GKAP and associated scaffold Shank1 from postsynaptic sites.	SIGNOR-271959
P53805	Q08209	2	binding	down-regulates activity	0.633	MCIP proteins can bind to and inhibit calcineurin, a calcium/calmodulin-regulated serine/threonine protein phosphatase that is activated during cardiac hypertrophy and failure	SIGNOR-252025
P15172	P84022	2	binding	down-regulates activity	0.731	We show that the TGF-beta intracellular effector Smad3, but not Smad2, mediates the inhibition of myogenic differentiation in MyoD-expressing C3H10T1/2 cells and C2C12 myoblasts by repressing the activity of the MyoD family of transcriptional factors.	SIGNOR-252071
Q9UKT8	P35548	2	binding	down-regulates quantity by destabilization	0.2	Mechanistic studies revealed that MSX2 is a new substrate of SCFFBXW2 E3 ubiquitin ligase. Taken together, our combined results showed that MSX2 is a substrate of the SCFFBXW2 E3 ligase, which ubiquitylates it and targets it for proteasome degradation.	SIGNOR-272259
O60500	P06241	0	phosphorylation	up-regulates activity	0.738	Fyn directly bound Nephrin via its SH3 domain, and Fyn directly phosphorylated Nephrin.\|Similar to Fyn deletion, simultaneous deletion of Fyn and Yes reduced Nephrin phosphorylating activity.	SIGNOR-279523
Q5S007	O00429	1	phosphorylation	up-regulates activity	0.568	LRRK2 G2019S directly bound to and phosphorylated Drp1 at Threonine595, whereas P110 treatment abolished this phosphorylation.Threonine595 phosphorylation of Drp1 by LRRK2 G2019S is required for Drp1-mediated mitochondrial fragmentation and excessive autophagy	SIGNOR-276495
P08581	P08047	0	transcriptional regulation	up-regulates quantity by expression	0.319	Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region.	SIGNOR-241490
Q8N0W4	Q9ULB1	2	binding	up-regulates activity	0.77	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.\|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264145
Q15139	O75628	1	phosphorylation	up-regulates activity	0.356	We found that activation of protein kinase D1, a protein kinase downstream of α(1)-adrenergic signaling, leads to direct phosphorylation of Rem1 at Ser18. This results in an increase of the channel activity and plasma membrane expression observed by using a combination of electrophysiology, live cell confocal microscopy, and immunohistochemistry in heterologous expression system and neonatal cardiomyocytes.	SIGNOR-273832
Q07820	Q7Z6Z7	0	ubiquitination	down-regulates quantity by destabilization	0.502	Mule was identified as Mcl-1 ubiquitin ligase E3 to promote Mcl-1 degradation via the proteasomal pathway [46]. We found that knockdown of Mule (Fig. 4C) but not β-TRCP or FBXW7 (data not shown) prevented Mcl-1 downregulation caused by PKCη depletion.	SIGNOR-261909
P35367	P50148	2	binding	up-regulates activity	0.428	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-257376
P49137	P09917	1	phosphorylation	up-regulates activity	0.546	Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2). when stimulated with only exogenous arachidonic acid, activity for the S271A mutant was significantly lower as compared with wild type 5-LO.	SIGNOR-250143
P22681	P06213	2	ubiquitination	down-regulates	0.528	Aps couples c-cbl to theinsulinreceptor, resulting in ubiquitination of theinsulinreceptor	SIGNOR-109688
P61254	Q00987	0	ubiquitination	down-regulates quantity by destabilization	0.498	In addition, Mdm2 ubiquitylates L26, leading to its proteasome-mediated degradation.\|We now report that Mdm2 regulates p53 levels also by targeting ribosomal protein L26.	SIGNOR-278828
O43193	P50148	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-257016
P28482	Q9BUB5	1	phosphorylation	up-regulates	0.594	We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity toward a substrate, eukaryotic initiation factor-4e (eif-4e).	SIGNOR-48298
P34972	P09471	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-256979
P00519	O60674	1	phosphorylation	up-regulates activity	0.41	Jak2 peptide substrate studies indicated that the Bcr-Abl and Abl tyrosine kinases specifically phosphorylated Y1007 of Jak2 but only poorly phosphorylated Y1008. Phosphorylation of Y1007 of Jak2 is known to be critical for its tyrosine kinase activation.	SIGNOR-245365
P40763	Q16539	0	phosphorylation	up-regulates	0.621	All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below).	SIGNOR-154783
Q86WV6	P35813	0	dephosphorylation	down-regulates activity	0.2	Collectively, our findings suggest that the overexpression of PPM1A antagonizes the STING- and TBK1-induced type I interferon signaling pathway.\|First, PPM1A directly dephosphorylated STING, likely via its S358 site (Figs.\|Moreover, our study demonstrates that while TBK1 enhances STING aggregation in a kinase activity-dependent manner, PPM1A suppresses STING aggregation by dephosphorylating both STING and TBK1.	SIGNOR-276958
P00533	O14965	0	phosphorylation	up-regulates activity	0.393	Because AURKA associated with EGFR, we next investigated whether AURKA phosphorylates EGFR at Thr654 and Ser1046.\|Protein phosphorylation profiling using an in situ proximity ligation assay: phosphorylation of AURKA-elicited EGFR-Thr654 and EGFR-Ser1046 in lung cancer cells.	SIGNOR-279589
Q9GZU7	Q15797	1	dephosphorylation	down-regulates	0.498	In human cells, rnai-mediated depletion of scp1 and scp2 increases the extent and duration of smad1 phosphorylation in response to bmp, the transcriptional action of smad1, and the strength of endogenous bmp gene responses. The present identification of the scp family as smad c-terminal phosphatases sheds light on the events that attenuate smad signaling and reveals unexpected links to the essential phosphatases that control rna polymerase ii in eukaryotes.	SIGNOR-148396
Q86UX7	P05556	2	binding	up-regulates activity	0.386	Mechanistically, Kindlin-3 can directly bind to regions of beta-integrin tails distinct from those of Talin and trigger integrin activation. We have therefore identified Kindlin-3 as a novel and essential element for platelet integrin activation in hemostasis and thrombosis\|Kindlin-3 was also able to interact with the wild-type beta1 and beta3 integrin tails (Fig. 3c), in the presence and absence of Talin1 (Supplementary Fig. 3 online), and the F3 subdomain of Kindlin-3 was sufficient for this interaction and this interaction occurred in a direct manner	SIGNOR-266065
P27986	P68400	0	phosphorylation	up-regulates activity	0.246	Protein kinase CK2 phosphorylates p85α on Ser608 when p85α is free but not when it is complexed with p110α.	SIGNOR-276005
O95837	Q15391	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-257210
P68400	P53539	1	phosphorylation	up-regulates	0.2	Our findings indicate that ck2 activation increases deltafosb's transactivation potential, while ck2 inhibition decreases it. Further, we show that preventing ser27 phosphorylation by mutating the site to ala results in a significant decrease in deltafosb transactivation	SIGNOR-152403
P00519	Q05209	0	dephosphorylation	down-regulates activity	0.439	Several experiments suggest that the pest-type ptps negatively regulate c-abl activity: c-abl was hyperphosphorylated in ptp-pest-deficient cells dephosphorylation of c-abl by pest-type ptp represents a novel mechanism by which c-abl activity is regulated.	SIGNOR-235568
Q14247	P28482	0	phosphorylation	up-regulates	0.467	Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement.	SIGNOR-165200
P08581	P22681	0	ubiquitination	down-regulates quantity by destabilization	0.732	Tyrosine y1001, which when phosphorylated upon met activation, is involved in cbl recruitment, allowing receptor ubiquitination and down regulation	SIGNOR-185680
P43405	P68366	1	phosphorylation	up-regulates activity	0.33	Syk, Activated by Cross-linking the B-cell Antigen Receptor, Localizes to the Cytosol Where It Interacts with and Phosphorylates alpha-Tubulin on Tyrosine	SIGNOR-246626
Q9UQE7	Q9BW11	2	binding	down-regulates activity	0.296	We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive eects of Mad proteins on c-myc functions.	SIGNOR-241281
P45985	P45985	2	phosphorylation	up-regulates activity	0.2	Ser221 and, to a lesser extent, Thr225 in MKK4 as necessary sites for basal and MEKK-induced autophosphorylation and activation of MKK4.	SIGNOR-251420
P00519	Q15139	1	phosphorylation	up-regulates	0.339	By using a phospho-specific antibody, we show that abl directly phosphorylates pkd at tyr(463) in vitro, and in cells phosphorylation of this site is sufficient to mediate full activation of pkd	SIGNOR-99255
Q9H1D0	P05771	0	phosphorylation	down-regulates activity	0.2	This regulation requires PKC(betaII) and defined phosphorylation sites within the ARD and the C-terminus. Both regulatory sites act synergistically to constitute a novel mechanism by which ATP stabilizes channel activity and acts as a metabolic switch for Ca(2+) influx. Decreases in ATP concentration or activation of PKC(betaII) disable regulation of the channels by ATP, rendering them more susceptible to inactivation and rundown and preventing Ca(2+) overload.	SIGNOR-276265
Q9UDY8	Q9BXL7	2	binding	up-regulates	0.805	The carboxy-terminal part of the bcl10 card and a short stretch of 13 amino acids following the card are required for constitutive binding to malt1.	SIGNOR-167393
P12931	Q14247	1	phosphorylation	down-regulates activity	0.801	Erk phosphorylation and a mimicking S405,418D double mutation enhanced cortactin binding and activation of N-WASP. In contrast, Src phosphorylation inhibited the ability of cortactin previously phosphorylated by Erk, and that of S405,418D double mutant cortactin, to bind and activate N-WASP. Furthermore, Y-->D mutation of three tyrosine residues targeted by Src (Y421, Y466, and Y482) inhibited the ability of S405,418D cortactin to activate N-WASP.	SIGNOR-246513
P57059	P49841	0	phosphorylation	up-regulates activity	0.2	Glycogen synthase kinase-3beta (GSK-3beta) phosphorylates Ser/Thr residues located at the fourth position ahead of the pre-phosphorylated Ser/Thr residues, and inhibitors of GSK-3beta reduce the phosphorylation at Thr182. The results of an in vitro reconstitution assay also indicate that GSK-3beta could be the SIK1 kinase. However, overexpression and knockdown of GSK-3beta in LKB1-defective HeLa cells suggests that GSK-3beta alone may not be able to phosphorylate or activate SIK1, indicating that LKB1 may play a crucial role by phosphorylating SIK1 at Thr182, possibly as an initiator of the autophosphorylation cascade, and GSK-3beta may phosphorylate SIK1 at Thr182 by recognizing the priming-autophosphorylation at Ser186 in cultured cells.	SIGNOR-279742
P05556	O75365	0	dephosphorylation	down-regulates activity	0.527	In this study, we demonstrate that PRL-3 directly binds to integrin \u03b21 and dephosphorylates integrin \u03b21-Y783, a key residue for integrin \u03b21 function [ ].\|These results indicate that PRL-3 dephosphorylates integrin \u03b21 in vitro and in vivo.	SIGNOR-277050
O95997	P28482	0	phosphorylation	up-regulates	0.353	Pttg is phosphorylated in vitro on ser(162) by map kinase and this phosphorylation site plays an essential role in pttg transactivation function.	SIGNOR-79515
P63096	Q9H1C0	2	binding	up-regulates activity	0.415	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-256718
P98170	O43464	2	binding	down-regulates	0.709	Here we report that a serine protease called htra2/omi is released from mitochondria and inhibits the function of xiap by direct binding in a similar way to diablo.	SIGNOR-110834
P15907	P20273	1	glycosylation	down-regulates activity	0.471	CD22-ligand interaction is regulated by the activity of a b-galactoside a2,6- sialyltransferase that can inactivate CD22-mediated binding by sialylating the CD22 receptor itself. These observations suggest that N-linked glycosylation sites on the CD22 molecule may play a role in the regulation of CD22-mediated adhesion.	SIGNOR-261741
Q9Y5F6	Q9Y5I2	2	binding	up-regulates activity	0.2	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265705
Q9UQL6	Q15139	0	phosphorylation	down-regulates activity	0.516	Here, we demonstrate that signaling by protein kinase C (PKC) is sufficient and, in some cases, necessary to drive nuclear export of class II HDAC5 in cardiomyocytes.	SIGNOR-249270
P31751	P98177	1	phosphorylation	down-regulates activity	0.606	FOXO4 transcription factor, also referred to AFX, contains three putative phosphorylation motif sites for protein kinase B (PKB), Thr32, Ser197, and Ser262, and it is proposed that phosphorylated FOXO4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression.[...]These results indicate that phosphorylation at Thr32 and Ser197 is indispensable, whereas that at Ser262 is not critical, for regulation of the nuclear localization and transcriptional activity of FOXO4	SIGNOR-248055
Q9Y572	P09622	1	phosphorylation	up-regulates activity	0.2	Here, we show that RIP3 activates the pyruvate dehydrogenase complex (PDC, also known as PDH), the rate-limiting enzyme linking glycolysis to aerobic respiration, by directly phosphorylating the PDC E3 subunit (PDC-E3) on T135.	SIGNOR-266372
O94989	P60953	1	guanine nucleotide exchange factor	up-regulates activity	0.556	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-260541
P84022	Q6ZNA4	0	ubiquitination	down-regulates activity	0.654	Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblasts. Arkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling.	SIGNOR-235388
P30518	P01185	2	binding	up-regulates	0.738	We report here the cloning of a complementary dna encoding the hepatic v1a arginine vasopressin receptor. The liver cdna encodes a protein with seven putative transmembrane domains, which binds arginine vasopressin.	SIGNOR-20185
O95644	P05112	1	transcriptional regulation	up-regulates quantity by expression	0.549	Recombinant NFAT1 can mediate transcription of the interleukin-2, interleukin-4, tumor necrosis factor alpha, and granulocyte-macrophage colony-stimulating factor promoters in T cells, suggesting that NFAT1 contributes to the CsA-sensitive transcription of these genes during the immune response.	SIGNOR-254498
Q13315	Q8TAQ5	1	phosphorylation	down-regulates activity	0.459	These results indicate that Apak is a genuine substrate of ATM kinase. Apak phosphorylation on Ser 68 is critical for p53-mediated apoptosis. in response to DNA damage, ATM is rapidly activated by autophosphorylation and mediates p53 activation through disruption of the Apak–p53 complex by phosphorylating Apak on Ser 68.	SIGNOR-273513
P62745	O14757	0	phosphorylation	up-regulates activity	0.328	We identified that Thr173 and Thr175 of RhoB was phosphorylated by Chk1 using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) (Supplementary Fig.\u00a06f).	SIGNOR-279727
Q9NQ66	O14641	0	null	up-regulates activity	0.268	Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin	SIGNOR-258979
Q9Y5B0	P06493	1	dephosphorylation	down-regulates activity	0.333	Thus, Fcp1 coordinates Cdk1 and Gwl inactivation to derepress PP2A-B55, generating a dephosphorylation switch that drives mitosis progression.\|We can not exclude that, in addition to S90 and S453, other Cdk1 phosphorylation sites in Gwl are dephosphorylated by Fcp1; nevertheless, assaying S67-Ensa kinase activity of V5-GwlS90A and V5-GwlS453A mutant proteins, isolated from transfected and prometaphase arrested HeLa cells, revealed that both mutants had significantly reduced S67-Ensa kinase activity compared to V5-GwlWT (XREF_FIG).\|We show here that activation of PP2A-B55, a major mitosis exit phosphatase, required the phosphatase Fcp1 downstream Cdk1 inactivation in human cells.	SIGNOR-277141
Q05655	P49715	1	phosphorylation	down-regulates quantity by destabilization	0.2	We next demonstrated by immunoprecipitation that IL-32\u03b2 interacted with PKC\u03b4 and C/EBP\u03b1, thereby mediating C/EBP\u03b1 Ser-21 phosphorylation by PKC\u03b4.	SIGNOR-279427
Q96RI0	P19086	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-257312
P02730	P43405	0	phosphorylation	up-regulates	0.451	Our findings suggest that, upon phosphorylation by p72syk, y8 and y21 act as docking sites for the sh2 domain of lyn, which subsequently phosphorylates band 3 at additional secondary sites.	SIGNOR-80792
Q96J02	O43353	2	binding	up-regulates activity	0.528	ITCH preferentially binds to RIPK2, promoting its K63-linked ubiquitination while simultaneously protecting YAP protein levels and maintaining its nuclear localization in CRC cells.	SIGNOR-280458
Q8N6P7	P29597	2	binding	up-regulates	0.542	Il-22 activates jak1 and tyk2	SIGNOR-90165
P38405	P35348	2	binding	up-regulates activity	0.278	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-256955
Q9Y4P8	Q8TEV9	0	transcriptional regulation	up-regulates quantity	0.271	Global mRNA expression analysis revealed that SMCR8 regulates transcription of several other autophagy genes including WIPI2	SIGNOR-252028
P06241	Q9NPH5	1	phosphorylation	down-regulates activity	0.271	We found that direct phosphorylation of tyrosine 566 on NOX4 was critical for this FYN-mediated negative regulation.	SIGNOR-277273
P09238	O00755	0	transcriptional regulation	up-regulates quantity by expression	0.2	We first proved that Wnt7a activated the canonical Wnt pathway through direct regulation of the MMP10 gene.	SIGNOR-278867
P19429	P67775	0	dephosphorylation	down-regulates	0.401	The major phosphatase thought to dephosphorylate ctni and phospholamban is type 2a protein phosphatase (pp2a) [61]. Activation of pp2a and ensuing dephosphorylation of regulatory proteins is involved in the anti-adrenergic effects of adenosine and muscarinic receptor activation see also fig2.	SIGNOR-134601
P52630	P23470	0	dephosphorylation	up-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-254728
Q02410	Q9ULB1	2	binding	up-regulates activity	0.667	Mint1 and Mint2 Interact with the Cytoplasmic Domain of Neurexin I. The interaction of Mint1 with neurexins is mediated by its PDZ domains and allows the formation of mixed CASK-Mint complexes. Both CASK and Mint1 can bind directly to neurexins and to each other. Therefore, the assembly of various multimeric complexes could proceed as CASK could be indirectly recruited to neurexin-bound Mint1 and vice versa.	SIGNOR-264038
P09622	Q9Y572	0	phosphorylation	up-regulates activity	0.2	Here, we show that RIP3 activates the pyruvate dehydrogenase complex (PDC, also known as PDH), the rate-limiting enzyme linking glycolysis to aerobic respiration, by directly phosphorylating the PDC E3 subunit (PDC-E3) on T135.	SIGNOR-266372
Q9C026	P50552	1	ubiquitination	down-regulates quantity	0.345	TRIM9 ubiquitinates VASP but not Mena or EVL.\|Thus TRIM9 negatively regulates VASP localization to filopodia tips, whereas netrin promotes VASP tip localization.	SIGNOR-278580
P08047	P23511	2	binding	up-regulates activity	0.617	Our results further confirm the important transactivating role for NF-Y for the CBS-1b promoter, via its synergism with Sp1. While differential phosphorylation of Sp1 likely contributes to binding to multiple GC-/GT-boxes in the CBS-1b and promoter activation [16], NF-Y is clearly necessary for a maximal activation response.	SIGNOR-254816
P98170	P31751	0	phosphorylation	up-regulates	0.42	Here, we demonstrate that akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin. Moreover, autoubiquitination of xiap is also inhibited by akt.	SIGNOR-119492
P47901	P50148	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-257264
P03372	P51948	0	phosphorylation	up-regulates activity	0.397	Human Estrogen Receptor α Is Phosphorylated at Serine 118 In Vivo by Cdk7	SIGNOR-260837
P63096	P34972	2	binding	up-regulates activity	0.468	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-256700

Q16873

P23443

0

phosphorylation

down-regulates activity

0.2

Here, we identified Ser(36) as the major p70S6k phosphorylation site, along with a low frequency site at Thr(40), using an in vitro phosphorylation assay combined with mass spectrometry. Cellular LTC4S activity is suppressed by PKC-mediated phosphorylation, and recently a downstream p70S6k was shown to play an important role in this process.

SIGNOR-277256

P22681

P04626

1

ubiquitination

down-regulates quantity by destabilization

0.601

Ligand binding to EGFR also leads to rapid internalization and proteosomal/lysosomal degradation of the receptors. This process results in a dramatic downregulation of both total and cell surface receptors. EGF-induced degradation of EGFR is thought to be initiated by phosphorylation of tyrosine 1045 of the receptor followed by binding of Cbl adaptor proteins and ubiquitination of the receptor. Internalized EGFR is transported to early endosomes where receptor-ligand complexes are sorted for either degradation or recycling to the cell surface.

SIGNOR-30794

P61764

Q9ULB1

2

binding

up-regulates activity

0.527

We propose that all these neurexin complexes can interact with Munc18. Both Mint1 and Mint2 could function as direct adaptors of Munc18 to neurexins, whereas Mint1 in addition could recruit Munc18 to CASK-neurexin (Fig. 5 B).

SIGNOR-264040

P55017

Q9UEW8

0

phosphorylation

down-regulates activity

0.484

SPAK directly phosphorylates NCC and its effects on NCC are universally associated with phosphorylation|This adds to the evidence that SPAK-mediated phosphorylation acts primarily to increase activity of individual cotransporters without affecting the amount of NCC on the surface| the kinase (SPAK) that phosphorylates NCC at T53

SIGNOR-264623

Q14469

P15172

1

transcriptional regulation

down-regulates activity

0.294

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

SIGNOR-243181

Q8WYK2

P05412

2

binding

down-regulates activity

0.607

JDP2 dimerizes with other AP-1 proteins such as activating transcription factor-2 (ATF2) and Jun to repress transcription from promoters that contain a cyclic AMP-responsive element (CRE).

SIGNOR-226398

Q13464

Q9UPT6

1

phosphorylation

up-regulates

0.332

Identification of rock1 as an upstream activator of the jip-3 to jnk signaling axis in response to uvb damage. phosphorylation of jip-3 by rock1 was crucial for the recruitment of jnk. Inhibition of the activity of rock1 in keratinocytes resulted in decreased activation of the jnk pathway and thus a reduction in apoptosis.

SIGNOR-134588

P63000

Q9P107

0

gtpase-activating protein

down-regulates activity

0.445

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-260506

P04626

P49327

1

phosphorylation

up-regulates activity

0.442

Conversely, HER2 directly phosphorylates and activates FASN, while it also promotes FASN gene expression ( xref ; xref ).|Conversely, HER2 directly phosphorylates and activates FASN, while it also promotes FASN gene expression.

SIGNOR-278399

P27361

Q07869

1

phosphorylation

up-regulates activity

0.601

We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution.

SIGNOR-249474

P27361

Q14247

1

phosphorylation

up-regulates

0.422

Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement.

SIGNOR-165212

P24941

P23470

0

dephosphorylation

down-regulates activity

0.298

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-254695

Q9Y2X7

P19174

2

binding

up-regulates

0.557

Git1 interaction with plcgamma is required for plcgamma activation based on inhibition of tyrosine phosphorylation

SIGNOR-118454

P21754

Q5JUK2

0

transcriptional regulation

up-regulates quantity by expression

0.378

Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters.

SIGNOR-266078

Q08211

P52948

2

binding

up-regulates activity

0.356

Here we report on the identification of the DExH/D-box helicase DHX9 as an intranuclear Nup98 binding partner. Various results, including in vitro assays, show that the FG/GLFG region of Nup98 binds to N- and C-terminal regions of DHX9 in an RNA facilitated manner. Importantly, binding of Nup98 stimulates the ATPase activity of DHX9, and a transcriptional reporter assay suggests Nup98 supports DHX9-stimulated transcription.

SIGNOR-260954

P31749

Q15173

0

dephosphorylation

down-regulates

0.661

Activation of pp2a is the intermediate step between the abeta-ceramide cascade and the subsequent inactivation of akt.

SIGNOR-252615

P35226

P68400

0

phosphorylation

down-regulates quantity by destabilization

0.269

Here we report that CK2α, a nuclear serine threonine kinase, phosphorylates BMI1 at Serine 110 as determined by in-vitro/ex-vivo kinase assay and mass spectrometry. e-expression of the phosphorylatable but not non-phosphorylatable BMI1 rescued clonal growth in endogenous BMI1 silenced cancer cells leading us to speculate that CK2α-mediated phosphorylation stabilizes BMI1 and promotes its oncogenic function.

SIGNOR-277345

P11912

Q9NRF2

0

dephosphorylation

down-regulates activity

0.2

SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK.

SIGNOR-268457

O15552

P30679

2

binding

up-regulates activity

0.404

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-257276

P51617

Q01638

2

binding

up-regulates activity

0.604

As shown in Figure 3D, MyD88, IRAK, IRAK4, and TRAF6 are all recruited to ST2 upon IL-33 stimulation.

SIGNOR-277706

Q9Y243

Q01860

1

phosphorylation

up-regulates quantity by stabilization

0.257

Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG.

SIGNOR-242107

Q16665

P49841

0

phosphorylation

down-regulates activity

0.332

Glycogen synthase kinase 3 \u03b2 (GSK3\u03b2) phosphorylates HIF-1\u03b1 at three serine residues (Ser-551, Ser-555, and Ser-589) located within its oxygen-dependent degradation domain (ODDD) [12] (Figure 5). Phosphorylation at these residues by GSK3\u03b2 enhances HIF-1\u03b1 degradation in a pVHL-independent manner, resulting in suppression of the HIF-1 activity [12,13].|Phosphorylation at these residues by GSK3beta enhances HIF-1alpha degradation in a pVHL independent manner, resulting in suppression of the HIF-1 activity , ].

SIGNOR-278294

P52597

Q96JP5

0

ubiquitination

down-regulates quantity

0.2

Collectively, our results indicate that ZFP91 polyubiquitinated hnRNP F at Lys 185.|We found that silencing ZFP91 increased hnRNP F protein levels, but not hnRNP F mRNA levels, while ectopically expressing ZFP91 decreased hnRNP F protein levels, but not hnRNP F mRNA levels.

SIGNOR-278802

Q13131

Q9UQL6

1

phosphorylation

down-regulates

0.341

Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs)

SIGNOR-176479

O14746

Q9UHC7

0

polyubiquitination

down-regulates quantity by destabilization

0.475

MKRN1 functions as an E3 ubiquitin-ligase for hTERT in vitro and in vivo. Furthermore, we have used the yeast two-hybrid method to identify a novel RING finger gene (MKRN1) encoding an E3 ligase that mediates ubiquitination of hTERT. Overexpression of MKRN1 in telomerase-positive cells promotes the degradation of hTERT and decreases telomerase activity and subsequently telomere length.

SIGNOR-271529

Q14004

P22674

2

binding

up-regulates activity

0.271

Cyclin O promotes lung cancer progression and cetuximab resistance via cell cycle regulation and CDK13 interaction|CCNO promoted tumor cell proliferation and survival in vivo via CDK13|

SIGNOR-275618

P49841

P46531

1

phosphorylation

up-regulates

0.463

Here, we observed that gsk3beta was able to bind and phosphorylate notch1ic in vitro, and attenuation of gsk3beta activity reduced phosphorylation of notchic in vivo.Functionally, ligand-activated signaling through the endogenous notch1 receptor was reduced in gsk3beta fibroblasts, implying a positive role for gsk3beta in mammalian notch signaling.

SIGNOR-90608

O75382

Q5VSY0

1

polyubiquitination

down-regulates quantity by destabilization

0.248

Here we identify the RING finger-containing protein TRIM3 as a specific E3 ubiquitin ligase for the PSD scaffold GKAP/SAPAP1. Present in PSD fractions from rat brain, TRIM3 stimulates ubiquitination and proteasome-dependent degradation of GKAP, and induces the loss of GKAP and associated scaffold Shank1 from postsynaptic sites.

SIGNOR-271959

P53805

Q08209

2

binding

down-regulates activity

0.633

MCIP proteins can bind to and inhibit calcineurin, a calcium/calmodulin-regulated serine/threonine protein phosphatase that is activated during cardiac hypertrophy and failure

SIGNOR-252025

P15172

P84022

2

binding

down-regulates activity

0.731

We show that the TGF-beta intracellular effector Smad3, but not Smad2, mediates the inhibition of myogenic differentiation in MyoD-expressing C3H10T1/2 cells and C2C12 myoblasts by repressing the activity of the MyoD family of transcriptional factors.

SIGNOR-252071

Q9UKT8

P35548

2

binding

down-regulates quantity by destabilization

0.2

Mechanistic studies revealed that MSX2 is a new substrate of SCFFBXW2 E3 ubiquitin ligase. Taken together, our combined results showed that MSX2 is a substrate of the SCFFBXW2 E3 ligase, which ubiquitylates it and targets it for proteasome degradation.

SIGNOR-272259

O60500

P06241

0

phosphorylation

up-regulates activity

0.738

Fyn directly bound Nephrin via its SH3 domain, and Fyn directly phosphorylated Nephrin.|Similar to Fyn deletion, simultaneous deletion of Fyn and Yes reduced Nephrin phosphorylating activity.

SIGNOR-279523

Q5S007

O00429

1

phosphorylation

up-regulates activity

0.568

LRRK2 G2019S directly bound to and phosphorylated Drp1 at Threonine595, whereas P110 treatment abolished this phosphorylation.Threonine595 phosphorylation of Drp1 by LRRK2 G2019S is required for Drp1-mediated mitochondrial fragmentation and excessive autophagy

SIGNOR-276495

P08581

P08047

0

transcriptional regulation

up-regulates quantity by expression

0.319

Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region.

SIGNOR-241490

Q8N0W4

Q9ULB1

2

binding

up-regulates activity

0.77

Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)

SIGNOR-264145

Q15139

O75628

1

phosphorylation

up-regulates activity

0.356

We found that activation of protein kinase D1, a protein kinase downstream of α(1)-adrenergic signaling, leads to direct phosphorylation of Rem1 at Ser18. This results in an increase of the channel activity and plasma membrane expression observed by using a combination of electrophysiology, live cell confocal microscopy, and immunohistochemistry in heterologous expression system and neonatal cardiomyocytes.

SIGNOR-273832

Q07820

Q7Z6Z7

0

ubiquitination

down-regulates quantity by destabilization

0.502

Mule was identified as Mcl-1 ubiquitin ligase E3 to promote Mcl-1 degradation via the proteasomal pathway [46]. We found that knockdown of Mule (Fig. 4C) but not β-TRCP or FBXW7 (data not shown) prevented Mcl-1 downregulation caused by PKCη depletion.

SIGNOR-261909

P35367

P50148

2

binding

up-regulates activity

0.428

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-257376

P49137

P09917

1

phosphorylation

up-regulates activity

0.546

Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2). when stimulated with only exogenous arachidonic acid, activity for the S271A mutant was significantly lower as compared with wild type 5-LO.

SIGNOR-250143

P22681

P06213

2

ubiquitination

down-regulates

0.528

Aps couples c-cbl to theinsulinreceptor, resulting in ubiquitination of theinsulinreceptor

SIGNOR-109688

P61254

Q00987

0

ubiquitination

down-regulates quantity by destabilization

0.498

In addition, Mdm2 ubiquitylates L26, leading to its proteasome-mediated degradation.|We now report that Mdm2 regulates p53 levels also by targeting ribosomal protein L26.

SIGNOR-278828

O43193

P50148

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-257016

P28482

Q9BUB5

1

phosphorylation

up-regulates

0.594

We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity toward a substrate, eukaryotic initiation factor-4e (eif-4e).

SIGNOR-48298

P34972

P09471

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-256979

P00519

O60674

1

phosphorylation

up-regulates activity

0.41

Jak2 peptide substrate studies indicated that the Bcr-Abl and Abl tyrosine kinases specifically phosphorylated Y1007 of Jak2 but only poorly phosphorylated Y1008. Phosphorylation of Y1007 of Jak2 is known to be critical for its tyrosine kinase activation.

SIGNOR-245365

P40763

Q16539

0

phosphorylation

up-regulates

0.621

All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below).

SIGNOR-154783

Q86WV6

P35813

0

dephosphorylation

down-regulates activity

0.2

Collectively, our findings suggest that the overexpression of PPM1A antagonizes the STING- and TBK1-induced type I interferon signaling pathway.|First, PPM1A directly dephosphorylated STING, likely via its S358 site (Figs.|Moreover, our study demonstrates that while TBK1 enhances STING aggregation in a kinase activity-dependent manner, PPM1A suppresses STING aggregation by dephosphorylating both STING and TBK1.

SIGNOR-276958

P00533

O14965

0

phosphorylation

up-regulates activity

0.393

Because AURKA associated with EGFR, we next investigated whether AURKA phosphorylates EGFR at Thr654 and Ser1046.|Protein phosphorylation profiling using an in situ proximity ligation assay: phosphorylation of AURKA-elicited EGFR-Thr654 and EGFR-Ser1046 in lung cancer cells.

SIGNOR-279589

Q9GZU7

Q15797

1

dephosphorylation

down-regulates

0.498

In human cells, rnai-mediated depletion of scp1 and scp2 increases the extent and duration of smad1 phosphorylation in response to bmp, the transcriptional action of smad1, and the strength of endogenous bmp gene responses. The present identification of the scp family as smad c-terminal phosphatases sheds light on the events that attenuate smad signaling and reveals unexpected links to the essential phosphatases that control rna polymerase ii in eukaryotes.

SIGNOR-148396

Q86UX7

P05556

2

binding

up-regulates activity

0.386

Mechanistically, Kindlin-3 can directly bind to regions of beta-integrin tails distinct from those of Talin and trigger integrin activation. We have therefore identified Kindlin-3 as a novel and essential element for platelet integrin activation in hemostasis and thrombosis|Kindlin-3 was also able to interact with the wild-type beta1 and beta3 integrin tails (Fig. 3c), in the presence and absence of Talin1 (Supplementary Fig. 3 online), and the F3 subdomain of Kindlin-3 was sufficient for this interaction and this interaction occurred in a direct manner

SIGNOR-266065

P27986

P68400

0

phosphorylation

up-regulates activity

0.246

Protein kinase CK2 phosphorylates p85α on Ser608 when p85α is free but not when it is complexed with p110α.

SIGNOR-276005

O95837

Q15391

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-257210

P68400

P53539

1

phosphorylation

up-regulates

0.2

Our findings indicate that ck2 activation increases deltafosb's transactivation potential, while ck2 inhibition decreases it. Further, we show that preventing ser27 phosphorylation by mutating the site to ala results in a significant decrease in deltafosb transactivation

SIGNOR-152403

P00519

Q05209

0

dephosphorylation

down-regulates activity

0.439

Several experiments suggest that the pest-type ptps negatively regulate c-abl activity: c-abl was hyperphosphorylated in ptp-pest-deficient cells dephosphorylation of c-abl by pest-type ptp represents a novel mechanism by which c-abl activity is regulated.

SIGNOR-235568

Q14247

P28482

0

phosphorylation

up-regulates

0.467

Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement.

SIGNOR-165200

P08581

P22681

0

ubiquitination

down-regulates quantity by destabilization

0.732

Tyrosine y1001, which when phosphorylated upon met activation, is involved in cbl recruitment, allowing receptor ubiquitination and down regulation

SIGNOR-185680

P43405

P68366

1

phosphorylation

up-regulates activity

0.33

Syk, Activated by Cross-linking the B-cell Antigen Receptor, Localizes to the Cytosol Where It Interacts with and Phosphorylates alpha-Tubulin on Tyrosine

SIGNOR-246626

Q9UQE7

Q9BW11

2

binding

down-regulates activity

0.296

We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive eects of Mad proteins on c-myc functions.

SIGNOR-241281

P45985

2

phosphorylation

up-regulates activity

0.2

Ser221 and, to a lesser extent, Thr225 in MKK4 as necessary sites for basal and MEKK-induced autophosphorylation and activation of MKK4.

SIGNOR-251420

P00519

Q15139

1

phosphorylation

up-regulates

0.339

By using a phospho-specific antibody, we show that abl directly phosphorylates pkd at tyr(463) in vitro, and in cells phosphorylation of this site is sufficient to mediate full activation of pkd

SIGNOR-99255

Q9H1D0

P05771

0

phosphorylation

down-regulates activity

0.2

This regulation requires PKC(betaII) and defined phosphorylation sites within the ARD and the C-terminus. Both regulatory sites act synergistically to constitute a novel mechanism by which ATP stabilizes channel activity and acts as a metabolic switch for Ca(2+) influx. Decreases in ATP concentration or activation of PKC(betaII) disable regulation of the channels by ATP, rendering them more susceptible to inactivation and rundown and preventing Ca(2+) overload.

SIGNOR-276265

Q9UDY8

Q9BXL7

2

binding

up-regulates

0.805

The carboxy-terminal part of the bcl10 card and a short stretch of 13 amino acids following the card are required for constitutive binding to malt1.

SIGNOR-167393

P12931

Q14247

1

phosphorylation

down-regulates activity

0.801

Erk phosphorylation and a mimicking S405,418D double mutation enhanced cortactin binding and activation of N-WASP. In contrast, Src phosphorylation inhibited the ability of cortactin previously phosphorylated by Erk, and that of S405,418D double mutant cortactin, to bind and activate N-WASP. Furthermore, Y-->D mutation of three tyrosine residues targeted by Src (Y421, Y466, and Y482) inhibited the ability of S405,418D cortactin to activate N-WASP.

SIGNOR-246513

P57059

P49841

0

phosphorylation

up-regulates activity

0.2

Glycogen synthase kinase-3beta (GSK-3beta) phosphorylates Ser/Thr residues located at the fourth position ahead of the pre-phosphorylated Ser/Thr residues, and inhibitors of GSK-3beta reduce the phosphorylation at Thr182. The results of an in vitro reconstitution assay also indicate that GSK-3beta could be the SIK1 kinase. However, overexpression and knockdown of GSK-3beta in LKB1-defective HeLa cells suggests that GSK-3beta alone may not be able to phosphorylate or activate SIK1, indicating that LKB1 may play a crucial role by phosphorylating SIK1 at Thr182, possibly as an initiator of the autophosphorylation cascade, and GSK-3beta may phosphorylate SIK1 at Thr182 by recognizing the priming-autophosphorylation at Ser186 in cultured cells.

SIGNOR-279742

P05556

O75365

0

dephosphorylation

down-regulates activity

0.527

In this study, we demonstrate that PRL-3 directly binds to integrin \u03b21 and dephosphorylates integrin \u03b21-Y783, a key residue for integrin \u03b21 function [ ].|These results indicate that PRL-3 dephosphorylates integrin \u03b21 in vitro and in vivo.

SIGNOR-277050

O95997

P28482

0

phosphorylation

up-regulates

0.353

Pttg is phosphorylated in vitro on ser(162) by map kinase and this phosphorylation site plays an essential role in pttg transactivation function.

SIGNOR-79515

P63096

Q9H1C0

2

binding

up-regulates activity

0.415

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-256718

P98170

O43464

2

binding

down-regulates

0.709

Here we report that a serine protease called htra2/omi is released from mitochondria and inhibits the function of xiap by direct binding in a similar way to diablo.

SIGNOR-110834

P15907

P20273

1

glycosylation

down-regulates activity

0.471

CD22-ligand interaction is regulated by the activity of a b-galactoside a2,6- sialyltransferase that can inactivate CD22-mediated binding by sialylating the CD22 receptor itself. These observations suggest that N-linked glycosylation sites on the CD22 molecule may play a role in the regulation of CD22-mediated adhesion.

SIGNOR-261741

Q9Y5F6

Q9Y5I2

2

binding

up-regulates activity

0.2

The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.

SIGNOR-265705

Q9UQL6

Q15139

0

phosphorylation

down-regulates activity

0.516

Here, we demonstrate that signaling by protein kinase C (PKC) is sufficient and, in some cases, necessary to drive nuclear export of class II HDAC5 in cardiomyocytes.

SIGNOR-249270

P31751

P98177

1

phosphorylation

down-regulates activity

0.606

FOXO4 transcription factor, also referred to AFX, contains three putative phosphorylation motif sites for protein kinase B (PKB), Thr32, Ser197, and Ser262, and it is proposed that phosphorylated FOXO4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression.[...]These results indicate that phosphorylation at Thr32 and Ser197 is indispensable, whereas that at Ser262 is not critical, for regulation of the nuclear localization and transcriptional activity of FOXO4

SIGNOR-248055

Q9Y572

P09622

1

phosphorylation

up-regulates activity

0.2

Here, we show that RIP3 activates the pyruvate dehydrogenase complex (PDC, also known as PDH), the rate-limiting enzyme linking glycolysis to aerobic respiration, by directly phosphorylating the PDC E3 subunit (PDC-E3) on T135.

SIGNOR-266372

O94989

P60953

1

guanine nucleotide exchange factor

up-regulates activity

0.556

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-260541

P84022

Q6ZNA4

0

ubiquitination

down-regulates activity

0.654

Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblasts. Arkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling.

SIGNOR-235388

P30518

P01185

2

binding

up-regulates

0.738

We report here the cloning of a complementary dna encoding the hepatic v1a arginine vasopressin receptor. The liver cdna encodes a protein with seven putative transmembrane domains, which binds arginine vasopressin.

SIGNOR-20185

O95644

P05112

1

transcriptional regulation

up-regulates quantity by expression

0.549

Recombinant NFAT1 can mediate transcription of the interleukin-2, interleukin-4, tumor necrosis factor alpha, and granulocyte-macrophage colony-stimulating factor promoters in T cells, suggesting that NFAT1 contributes to the CsA-sensitive transcription of these genes during the immune response.

SIGNOR-254498

Q13315

Q8TAQ5

1

phosphorylation

down-regulates activity

0.459

These results indicate that Apak is a genuine substrate of ATM kinase. Apak phosphorylation on Ser 68 is critical for p53-mediated apoptosis. in response to DNA damage, ATM is rapidly activated by autophosphorylation and mediates p53 activation through disruption of the Apak–p53 complex by phosphorylating Apak on Ser 68.

SIGNOR-273513

P62745

O14757

0

phosphorylation

up-regulates activity

0.328

We identified that Thr173 and Thr175 of RhoB was phosphorylated by Chk1 using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) (Supplementary Fig.\u00a06f).

SIGNOR-279727

Q9NQ66

O14641

0

null

up-regulates activity

0.268

Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin

SIGNOR-258979

Q9Y5B0

P06493

1

dephosphorylation

down-regulates activity

0.333

Thus, Fcp1 coordinates Cdk1 and Gwl inactivation to derepress PP2A-B55, generating a dephosphorylation switch that drives mitosis progression.|We can not exclude that, in addition to S90 and S453, other Cdk1 phosphorylation sites in Gwl are dephosphorylated by Fcp1; nevertheless, assaying S67-Ensa kinase activity of V5-GwlS90A and V5-GwlS453A mutant proteins, isolated from transfected and prometaphase arrested HeLa cells, revealed that both mutants had significantly reduced S67-Ensa kinase activity compared to V5-GwlWT (XREF_FIG).|We show here that activation of PP2A-B55, a major mitosis exit phosphatase, required the phosphatase Fcp1 downstream Cdk1 inactivation in human cells.

SIGNOR-277141

Q05655

P49715

1

phosphorylation

down-regulates quantity by destabilization

0.2

We next demonstrated by immunoprecipitation that IL-32\u03b2 interacted with PKC\u03b4 and C/EBP\u03b1, thereby mediating C/EBP\u03b1 Ser-21 phosphorylation by PKC\u03b4.

SIGNOR-279427

Q96RI0

P19086

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-257312

P02730

P43405

0

phosphorylation

up-regulates

0.451

Our findings suggest that, upon phosphorylation by p72syk, y8 and y21 act as docking sites for the sh2 domain of lyn, which subsequently phosphorylates band 3 at additional secondary sites.

SIGNOR-80792

Q96J02

O43353

2

binding

up-regulates activity

0.528

ITCH preferentially binds to RIPK2, promoting its K63-linked ubiquitination while simultaneously protecting YAP protein levels and maintaining its nuclear localization in CRC cells.

SIGNOR-280458

Q8N6P7

P29597

2

binding

up-regulates

0.542

Il-22 activates jak1 and tyk2

SIGNOR-90165

P38405

P35348

2

binding

up-regulates activity

0.278

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-256955

Q9Y4P8

Q8TEV9

0

transcriptional regulation

up-regulates quantity

0.271

Global mRNA expression analysis revealed that SMCR8 regulates transcription of several other autophagy genes including WIPI2

SIGNOR-252028

P06241

Q9NPH5

1

phosphorylation

down-regulates activity

0.271

We found that direct phosphorylation of tyrosine 566 on NOX4 was critical for this FYN-mediated negative regulation.

SIGNOR-277273

P09238

O00755

0

transcriptional regulation

up-regulates quantity by expression

0.2

We first proved that Wnt7a activated the canonical Wnt pathway through direct regulation of the MMP10 gene.

SIGNOR-278867

P19429

P67775

0

dephosphorylation

down-regulates

0.401

The major phosphatase thought to dephosphorylate ctni and phospholamban is type 2a protein phosphatase (pp2a) [61]. Activation of pp2a and ensuing dephosphorylation of regulatory proteins is involved in the anti-adrenergic effects of adenosine and muscarinic receptor activation see also fig2.

SIGNOR-134601

P52630

P23470

0

dephosphorylation

up-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-254728

Q02410

Q9ULB1

2

binding

up-regulates activity

0.667

Mint1 and Mint2 Interact with the Cytoplasmic Domain of Neurexin I. The interaction of Mint1 with neurexins is mediated by its PDZ domains and allows the formation of mixed CASK-Mint complexes. Both CASK and Mint1 can bind directly to neurexins and to each other. Therefore, the assembly of various multimeric complexes could proceed as CASK could be indirectly recruited to neurexin-bound Mint1 and vice versa.

SIGNOR-264038

P09622

Q9Y572

0

phosphorylation

up-regulates activity

0.2

Here, we show that RIP3 activates the pyruvate dehydrogenase complex (PDC, also known as PDH), the rate-limiting enzyme linking glycolysis to aerobic respiration, by directly phosphorylating the PDC E3 subunit (PDC-E3) on T135.

SIGNOR-266372

Q9C026

P50552

1

ubiquitination

down-regulates quantity

0.345

TRIM9 ubiquitinates VASP but not Mena or EVL.|Thus TRIM9 negatively regulates VASP localization to filopodia tips, whereas netrin promotes VASP tip localization.

SIGNOR-278580

P08047

P23511

2

binding

up-regulates activity

0.617

Our results further confirm the important transactivating role for NF-Y for the CBS-1b promoter, via its synergism with Sp1. While differential phosphorylation of Sp1 likely contributes to binding to multiple GC-/GT-boxes in the CBS-1b and promoter activation [16], NF-Y is clearly necessary for a maximal activation response.

SIGNOR-254816

P98170

P31751

0

phosphorylation

up-regulates

0.42

Here, we demonstrate that akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin. Moreover, autoubiquitination of xiap is also inhibited by akt.

SIGNOR-119492

P47901

P50148

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-257264

P03372

P51948

0

phosphorylation

up-regulates activity

0.397

Human Estrogen Receptor α Is Phosphorylated at Serine 118 In Vivo by Cdk7

SIGNOR-260837

P63096

P34972

2

binding

up-regulates activity

0.468

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-256700