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
P53779	Q9NR28	1	phosphorylation	down-regulates	0.341	Here we demonstrate that jnk3 can phosphorylate smac. Phosphorylation of smac by jnk3 attenuates its interaction with xiap. These results suggest that jnk3 activity can attenuate the progression of apoptosis through a novel mechanism of action, the down-regulation of interaction between smac and xiap.	SIGNOR-157280
P25101	O95837	2	binding	up-regulates activity	0.471	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-257427
P63092	Q96P68	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 ‚â• -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 ‚â• -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-256770
Q92819	P54646	0	phosphorylation	down-regulates activity	0.2	We found that AMPK phosphorylated Thr-110 of human HAS2, which inhibits its enzymatic activity.	SIGNOR-276299
Q13753	P08253	0	cleavage	up-regulates activity	0.471	Induction of Cell Migration by Matrix Metalloprotease-2 Cleavage of Laminin-5\|MMP2 cleaved the Ln-5 gamma2 subunit at residue 587, exposing a putative cryptic promigratory site on Ln-5 that triggers cell motility. This altered form of Ln-5 is found in tumors and in tissues undergoing remodeling, but not in quiescent tissues. Cleavage of Ln-5 by MMP2 and the resulting activation of the Ln-5 cryptic site may provide new targets for modulation of tumor cell invasion and tissue remodeling.	SIGNOR-253240
Q9C0D0	P62136	2	binding	up-regulates activity	0.537	Phactr-1 was previously identified as protein phosphatase 1 (PP1) α-interacting protein that possesses actin-binding domains. We showed that Phactr-1 depletion decreased PP1 activity, disrupted the fine-tuning of actin polymerization and impaired lamellipodial dynamics. Taken together our results strongly suggest that Phactr-1 is a key component in the angiogenic process.	SIGNOR-260062
Q12809	P46934	0	ubiquitination	down-regulates quantity by destabilization	0.268	We have previously shown that the E3 ubiquitin (Ub) ligase Nedd4-2 (neural precursor cell expressed developmentally down-regulated protein 4-2) targets the PY motif of hERG channels to initiate channel degradation. Although both immature and mature hERG channels contain the PY motif, Nedd4-2 selectively mediates the degradation of mature hERG channels.	SIGNOR-260998
O15123	Q02763	2	binding	up-regulates	0.924	Angiopoietin-1 and -2, bound to tek with similar affinities, and angiopoietin-1 effectively induced tek phosphorylation in hematopoietic cells. Angiopoietin-2 also induced a low level of tek phosphorylation and weakened the phosphorylation induced by angiopoietin-1	SIGNOR-59808
P05129	P25098	1	phosphorylation	up-regulates	0.2	Phosphorylation of grk2 by protein kinase c abolishes its inhibition by calmodulinin vitro, grk2 was preferentially phosphorylated by pkc isoforms alpha, gamma, and delta	SIGNOR-83231
P17612	P11137	1	phosphorylation	down-regulates activity	0.36	CAMP-dependent protein kinase activity disrupts the MAP2-microtubule interaction in living HeLa cells. S319, S350, and S382 were thus identified as preferred targets of PKA	SIGNOR-250003
P68104	P51784	0	deubiquitination	up-regulates activity	0.2	USP11 interacted with and deubiquitinated eEF1A1 on Lys439, thereby inhibiting its ubiquitin-mediated degradation. Subsequently, the elevated expression of eEF1A1 resulted in its binding to SP1, which in turn drove the binding of SP1 to its target HGF gene promoter to increase its transcription	SIGNOR-278107
Q04206	P12644	1	transcriptional regulation	down-regulates quantity by repression	0.2	Co-transfection with pCMV4-RelA alone or in combination with pCMV4p50 repressed pSLA4.1 EX-Lux activity by approximately 75 percent in both H441 and A549 cells	SIGNOR-266087
Q8NI17	O60674	2	binding	up-regulates	0.381	Il-31 can activate janus kinase (jak) 1 and jak2 signaling molecules after binding to its receptor complex.	SIGNOR-161430
Q92793	P17252	0	phosphorylation	down-regulates	0.261	The action of metformin was shown to be mediated through activation of apkc?/?, Which phosphorylates cbp at ser436, and disrupts the transcriptionally active creb-cbp-crtc2 complex,	SIGNOR-166368
Q96J02	Q8NEA6	1	ubiquitination	down-regulates quantity	0.331	Itch promotes proteolytic degradation of Glis3.\|Since Itch interacts with and ubiquitinates Glis3, it was of interest to determine which regions were necessary for Itch directed degradation of Glis3.	SIGNOR-278653
Q14457	P00533	0	phosphorylation	down-regulates activity	0.521	The mechanism by which EGFR suppresses Beclin 1 function involves EGFR interaction with two domains (BH3 and ECD) of Beclin 1; EGFR mediated multisite tyrosine phosphorylation of Beclin 1 on residues Y229, Y233 and Y352; and EGFR mediated alterations in the Beclin 1 interactome (increased binding to the negative regulators, Bcl-2 and Rubicon, and decreased binding to the VPS34 lipid kinase).\|Thus, EGFR signaling suppresses autophagy via its interaction with Beclin 1 during normal mitogenic signaling as well as during aberrant cell proliferation in cancer cells.	SIGNOR-278357
P61224	Q8WZA2	0	guanine nucleotide exchange factor	up-regulates activity	0.811	Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well.	SIGNOR-263955
Q96PU4	Q8WW12	1	polyubiquitination	down-regulates quantity by destabilization	0.451	Ubiquitination of PEST containing nuclear protein (PEST) by NIRF (Np95/ICBP90‐like RING finger protein) in the nuclear core of the cell: Ubiquitin‐like domain in the N‐terminus and a RING finger motif in the C‐terminus of NIRF confirm the ubiquitin ligase function of NIRF. PCNP acts as a substrate for NIRF mediated proteasome activity.	SIGNOR-271501
P23458	Q13651	2	phosphorylation	up-regulates activity	0.809	Binding of IL-10 to the extracellular domain of IL-10R1 activates phosphorylation of the receptor-associated Janus tyrosine kinases, JAK1 and Tyk2. These kinases then phosphorylate specific tyrosine residues (Y446 and Y496) on the intracellular domain of the IL-10R1 chain. Once phosphorylated, these tyrosine residues (and their flanking peptide sequences) serve as temporary docking sites for the latent transcription factor, STAT3 (signal transducer and activator of transcription-3).	SIGNOR-251338
P08047	O43497	1	transcriptional regulation	up-regulates quantity by expression	0.261	Consistent with this, Sp1 over-expression enhanced promoter activity while siRNA-mediated Sp1 silencing significantly decreased the level of CaV 3.1 protein and reduced the amplitude of whole-cell T-type Ca(2+) currents expressed in the N1E-115 cells. These results provide new insights into the molecular mechanisms that control CaV 3.1 channel expression.	SIGNOR-264034
Q9Y6K9	P06241	0	phosphorylation	down-regulates activity	0.357	Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.	SIGNOR-276371
Q13131	O95239	1	phosphorylation	up-regulates activity	0.2	We found that the strong direct substrate KIF4A is phosphorylated by AMPK at Ser801.Using in vitro kinase assays, we found that active AMPK and Aurora B phosphorylated KIF4A at Ser801 and Thr799 respectively in a time-dependent manner (Figure 5D). KIF4A is phosphoregulated by AMPK and Aurora B. Although AMPK phosphorylation increased the ATPase activity of KIF4A, Aurora B phosphorylation resulted in a stronger increase (Figure 5I), which might be consistent with the more powerful kinase function of Aurora B during mitosis.	SIGNOR-265991
P06748	Q8N726	2	binding	up-regulates activity	0.552	The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division	SIGNOR-245073
P15976	P31749	0	phosphorylation	up-regulates	0.514	We found that akt directly phosphorylates the transcription factor gata-1 at serine 310 and that this site-specific phosphorylation is required for the transcriptional activation of the timp-1 promoter.	SIGNOR-139782
Q9H0A0	Q00987	1	ubiquitination	down-regulates quantity by destabilization	0.33	NAT10 acetylates p53 at K120 and stabilizes p53 by counteracting Mdm2 action. In addition, NAT10 promotes Mdm2 degradation with its intrinsic E3 ligase activity.	SIGNOR-272405
Q8NFP9	Q92796	2	binding	up-regulates activity	0.42	Interestingly, a recent proteomic analysis (Lauks et al., 2012) revealed that Nbea binds SAP102, which interacts with glutamate receptors early in the biosynthetic route and regulates their targeting. This finding, along with the interaction of Nbea with the glycine receptor beta subunit (del Pino et al., 2011), further strengthens the notion that Nbea targets neurotransmitter receptors to synapses.	SIGNOR-266004
Q9P286	Q92934	1	phosphorylation	down-regulates activity	0.2	P21-Activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD. Pak5 phosphorylates BAD Ser-112	SIGNOR-250247
Q9BZL6	Q8WUI4	1	phosphorylation	up-regulates activity	0.437	Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67].	SIGNOR-275933
P22681	O00459	1	ubiquitination	down-regulates	0.606	Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner.	SIGNOR-110063
P46531	Q9Y219	2	binding	up-regulates	0.625	Immunohistochemistry revealed coexpression of jagged2 and notch1 within thymus and other fetal murine tissues, consistent with interaction of the two proteins in vivo. Coculture of fibroblasts expressing human jagged2 with murine c2c12 myoblasts inhibited myogenic differentiation, accompanied by increased notch1 and the appearance of a novel 115-kda notch1 fragment. Exposure of c2c12 cells to jagged2 led to increased amounts of notch mrna as well as mrnas for a second notch receptor, notch3, and a second notch ligand, jagged1. Constitutively active forms of notchl in c2c12 cells also induced increased levels of the same set of mrnas, suggesting positive feedback control of these genes initiated by binding of jagged2 to notch1.	SIGNOR-236922
Q8TF40	P08238	2	binding	down-regulates activity	0.2	FNIP1 and FNIP2 facilitate FLCN binding to Hsp90 chaperone. Our results suggest that FNIP1 is a potent inhibitor of Hsp90 ATPase activity, as 200 nM of FNIP1 inhibits Hsp90 ATPase activity by 50-fold. FNIP2 also has shown inhibitory activity towards Hsp90; however, it required 1.6 μM of FNIP2 to inhibit the ATPase activity by eightfold. Although we use the term ‘inhibition' here, FNIPs seem only to be slowing the chaperone cycle.	SIGNOR-261415
Q6PHR2	Q96CF2	1	phosphorylation	down-regulates activity	0.286	CHMP4C was phosphorylated by recombinant ULK3 in these experiments, whereas CHMP4A and CHMP4B were not (Figure 7\u2014figure supplement 1A).	SIGNOR-279771
P04637	Q9BV47	0	dephosphorylation	down-regulates activity	0.366	Dual-specificity phosphatase 26 is a novel p53 phosphatase and inhibits p53 tumor suppressor functions in human neuroblastoma\|Inhibiting DUSP26 expression in the IMR-32 neuroblastoma cell line enhanced doxorubicin-induced p53 phosphorylation at Ser20 and Ser37, p21, Puma, Bax expression as well as apoptosis	SIGNOR-248765
Q8IYW5	P16403	1	polyubiquitination	down-regulates	0.2	ITCH biochemically antagonized RNF168 and RNF8 in polyubiquitination of histone H1.2 ITCH interacts with and ubiquitinates linker histone H1.2 at K46. ITCH biochemically competes with RNF168 and RNF8 to polyubiquitinate histone H1.2. Both RNF168 and RNF8 elicited higher Ubn levels of K46R-H1.2 compared to WT-H1.2, suggesting that Ubn of H1.2 by both E3 ligases occurs at a site apart from K46.	SIGNOR-272927
Q8NES3	Q9NYJ7	2	binding	up-regulates	0.448	We find that mammalian lunatic fringe (lfng) inhibits jagged1-mediated signalling and potentiates delta1-mediated signalling through notch1.	SIGNOR-80524
P49841	Q9NR50	2	binding	down-regulates	0.261	Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b).	SIGNOR-175520
Q9HD43	P06213	1	dephosphorylation	down-regulates	0.27	These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase	SIGNOR-76072
Q05513	P55211	1	phosphorylation	down-regulates	0.348	Inhibitor sensitivity and interactions with caspase 9 indicate that the predominant kinase that targets ser144 is the atypical protein kinase c isoform zeta (pkczeta).	SIGNOR-141629
O14640	Q9Y4D1	2	binding	up-regulates activity	0.735	B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1.	SIGNOR-185271
P45984	P16949	1	phosphorylation	down-regulates	0.256	Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress.	SIGNOR-166698
Q5S007	Q9UNE7	0	ubiquitination	down-regulates quantity by destabilization	0.433	CHIP can ubiquitinate LRRK2.\|These results indicate that both the chaperone interaction and the ubiquitin ligase activity of CHIP are required for CHIP mediated degradation of LRRK2 protein.	SIGNOR-278615
Q15349	P25963	1	phosphorylation	down-regulates	0.267	Rsk2 is activated by treatment with tumor necrosis factor-alfa (tnf-alfa) and directly phosphorylates ikbalfa at ser-32, leading to ikbalfa degradation.	SIGNOR-164790
O75129	O14525	2	binding	down-regulates quantity	0.2	Biochemical and flow cytometry experiments show that ASTN2 forms a complex with ASTN1 and regulates surface expression of ASTN1. Coexpression with ASTN2 reduces the cell surface localization of ASTN1.	SIGNOR-269813
P10912	P01241	2	binding	up-regulates	0.859	The hghr only binds primate gh. Arg43 in hghr interacts with asp171 of hgh.	SIGNOR-34129
P43405	P43405	2	phosphorylation	up-regulates activity	0.2	These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520	SIGNOR-246621
P49841	Q00613	1	phosphorylation	down-regulates activity	0.557	Ser-303 is phosphorylated by glycogen synthase kinase 3 (GSK3) through a mechanism dependent on primary phosphorylation of Ser-307 by MAPK. Secondary phosphorylation of Ser-303 by GSK3 may thus repress the activity of HSF-1, and its requirement for priming by MAPK phosphorylation of Ser-307 provides a potential link between the MAPK cascade and HSF-1.	SIGNOR-251216
P19338	P68871	1	post transcriptional regulation	up-regulates quantity by expression	0.2	Nucleolin binds human β-globin mRNA. A Nucleolin-Binding 3′ Untranslated Region Element Stabilizes β-Globin mRNA In Vivo	SIGNOR-251844
Q99683	Q12933	2	binding	up-regulates activity	0.737	Traf2 is a strong activator of ask1	SIGNOR-60747
Q9ULG1	Q9UNE7	0	ubiquitination	up-regulates activity	0.2	Then, by an in vivo ubiquitination assay under denaturing conditions (hereafter, all in vivo ubiquitination assays were carried out under denaturing conditions), we determined whether CHIP ubiquitinates Ino80.\|We also show that CHIP works together with BAP1 to enhance the stabilization of Ino80, leading to its chromatin binding.	SIGNOR-278646
O75379	P68400	0	phosphorylation	up-regulates	0.446	The r-snare vamp4, which contains a dileucine motif, binds to the ap-1 or the ggas. Serine 20 and leucines 25,26 are essential for this binding. Ap-1 association with vamp4 is enhanced when serine 30 is phosphorylated by casein kinase 2. This phosphorylation-dependent modulation of ap-1 binding is mediated by pacs-1 (phosphofurin acidic cluster sorting protein). Ablation of both the dileucine motif and serine 30 results in a dramatic mislocalization of vamp4 in the regulated secretory pathway.	SIGNOR-119090
P17252	Q13224	1	phosphorylation	up-regulates activity	0.469	These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels.	SIGNOR-249083
P29350	P06213	2	dephosphorylation	down-regulates	0.359	Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1.	SIGNOR-75938
P78563	P19525	2	binding	up-regulates activity	0.459	Both forms of ADAR1 show enhanced interactions with PKR at the peak of HIV infection, suggesting a role for this protein in the regulation of PKR activation.	SIGNOR-266359
Q00535	P16949	1	phosphorylation	down-regulates	0.376	Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. The kinases involved in phosphorylating stmn ser-16 and ser-63 include camp-dependent protein kinase (pka) and pak1, whereas stmn ser-25 and ser-38 have been shown to be targets for proline-directed serine/threonine kinases such as cyclin-dependent kinases, erk1/2, and members of the p38 mapk subfamily.	SIGNOR-166682
Q86Z02	O60829	1	phosphorylation	up-regulates activity	0.456	Here, we have identified homeodomain-interacting protein kinase 1 (HIPK1), also a component of the stress-response pathway, as a kinase that phosphorylates PAGE4 at T51 \| We show that phosphorylation of PAGE4 is critical for its transcriptional activity since mutating this T residue abolishes its ability to potentiate c-Jun transactivation.	SIGNOR-260929
Q99714	O60260	0	ubiquitination	down-regulates quantity by destabilization	0.2	This study identifies the multifunctional PD-related mitochondrial matrix enzyme 17-β hydroxysteroid dehydrogenase type 10 (HSD17B10) as a new Parkin substrate.	SIGNOR-272823
P28845	P49715	0	transcriptional regulation	up-regulates quantity by expression	0.274	Cotransfection with human CCAAT/enhancer binding protein-alpha (C/EBPalpha) and C/EBPbeta-LAP expression vectors activated the HSD11B1 promoter with the strongest effect within the same region.	SIGNOR-268971
Q86V15	Q9UHF1	1	transcriptional regulation	up-regulates quantity	0.425	We have recently demonstrated that a novel transcriptional pathway involving activation of the Epidermal Growth Factor-like Domain 7 (Egfl7) gene by the transcription factor CASTOR (CASZ1) is required for blood vessel assembly and lumen morphogenesis.	SIGNOR-266858
P35590	Q02763	0	phosphorylation	up-regulates activity	0.348	Thus, Tie2 was able to induce Tie1 phosphorylation.\|When cotransfected, Tie2 formed heteromeric complexes with Tie1, enhanced Tie1 activation, and induced phosphorylation of a kinase-inactive Tie1 in a ligand-dependent manner.	SIGNOR-279769
P05771	Q16820	1	phosphorylation	down-regulates quantity	0.2	These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate.	SIGNOR-263173
Q06124	P36888	2	binding	up-regulates activity	0.525	Y599 was additionally found to interact with the protein tyrosine phosphatase SHP2 in a phosphorylation-dependent manner. As Y599F-Flt3-32D was unable to associate with and to phosphorylate SHP2 and since silencing of SHP2 in WT-Flt3-expressing cells mimicked the Y599F-Flt3 phenotype, we hypothesize that recruitment of SHP2 to pY599 contributes to FL-mediated Erk activation and proliferation.	SIGNOR-245057
P28482	Q15256	2	phosphorylation	up-regulates activity	0.824	Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL.	SIGNOR-249438
P49841	Q9Y2T1	2	binding	up-regulates activity	0.832	It has been found that a multiprotein complex assembled by the cytoplasmic component conductin induces degradation of cytoplasmic beta-catenin. The complex includes apc, the serine/threonine kinase gsk3 beta, and beta-catenin, which bind to conductin at distinct domains.	SIGNOR-79950
P49916	P24941	0	phosphorylation	down-regulates	0.418	Dna ligase iii_ is specifically phosphorylated in replicating cells by the cell cycle kinase cdk2. However, in response to oxidative dna damage, dna ligase iii_ is dephosphorylated in a pathway that is dependent upon the dna damage-activated, phosphatidylinositol 3-phosphate (pi3)1-related kinase atm.	SIGNOR-150121
P20273	Q9NRF2	2	binding	up-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-268444
Q9NX47	Q8IWA4	1	ubiquitination	down-regulates quantity by destabilization	0.2	MARCH5, a mitochondrial E3 ubiquitin ligase, has been identified as a molecule that binds mitochondrial fission 1 protein (hFis1), dynamin-related protein 1 (Drp1) and mitofusin 2 (Mfn2), key proteins in the control of mitochondrial fission and fusion.\|Notably, a significant increase in Mfn1 level, but not Mfn2, Drp1 or hFis1 levels, was observed in MARCH5-depleted cells, indicating that Mfn1 is a major ubiquitylation substrate.	SIGNOR-274133
P35222	Q13153	0	phosphorylation	up-regulates	0.557	Pak1 directly phosphorylates _-catenin proteins at ser675 site and this leads to more stable and transcriptional active _-catenin	SIGNOR-175944
Q13761	P11309	0	phosphorylation	up-regulates quantity	0.353	Inhibition of Pim1 kinase prevents peanut allergy by enhancing Runx3 expression and suppressing T (H) 2 and T (H) 17 T-cell differentiation.\|Pim1 kinase phosphorylates and stabilizes Runx3 and alters its subcellular localization.	SIGNOR-279547
Q9UNE7	P53350	1	ubiquitination	down-regulates quantity by destabilization	0.252	As indicated in xref , all three Plk1 fragments were ubiquitinated by CHIP, suggesting that CHIP targets multiple sites of Plk1 for ubiquitination.\|Mechanistically, CHIP mediated degradation of AR and Plk1 leads to enhanced efficacy of HSP90 inhibitors.	SIGNOR-278532
Q9H4B4	P30307	1	phosphorylation	up-regulates	0.731	Cdc25c phosphorylation on serine 191 by plk3 promotes its nuclear translocation	SIGNOR-122090
P42773	Q00534	2	binding	down-regulates	0.88	The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb.	SIGNOR-44601
P60953	Q96M96	0	guanine nucleotide exchange factor	up-regulates activity	0.619	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-260554
O14920	P04637	1	phosphorylation	up-regulates activity	0.52	Here , we show that IKKbeta modulates the activity of p53 in response to glutamine depletion to promote cancer cell adaptation .\|Taken together, these results indicate that IKK\u03b2 phosphorylates p53 on Ser392 as an early response to glutamine deprivation and possibly later facilitates its phosphorylation at Ser15 and transcriptional activity.	SIGNOR-278516
P12931	P17302	1	phosphorylation	down-regulates	0.588	The oncogenic tyrosine kinase, v-src, phosphorylates connexin43 (cx43) on y247 and y265 and inhibits cx43 gap junctional communication (gjc), the process of intercellular exchange of ions and metabolites.	SIGNOR-148913
P50148	Q9NPG1	2	binding	up-regulates	0.408	Gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families.	SIGNOR-122895
Q96P68	P38405	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-256913
Q9UQL6	Q02078	2	binding	down-regulates	0.706	The histone deacetylase hdac-5, upon dephosphorylation and translocation to the nucleus, directly inactivates mef2, preventing myogenesis.	SIGNOR-84023
Q9Y297	P10070	1	ubiquitination	down-regulates quantity by destabilization	0.651	The phosphorylated gli2 protein interacts with beta-trcp, and is ubiquitinated and degraded by the proteasome	SIGNOR-146109
P31749	Q01813	1	phosphorylation	up-regulates quantity	0.564	A reduction in AKT expression as a result of AKT1 shRNA expression or MK-2206 treatment decreased the half-life of endogenous PFKP, while the expression of active Myr-AKT1 prolonged the half-life of PFKP.\|In addition, depletion of endogenous PFKP and reconstitution of RNAi resistant WT Flag-rPFKP or Flag-rPFKP S386A expression in U251 or U87 and EGFRvIII cells revealed that the S386A mutation abolished PFKP phosphorylation induced by EGF, constitutively active Myr-AKT1, and EGFRvIII.	SIGNOR-279788
P06493	O00443	1	phosphorylation	down-regulates activity	0.281	Mitotic and stress-induced phosphorylation of HsPI3K-C2alpha targets the protein for degradation. Stress-dependent and mitotic phosphorylation of hspik3-c2alpha occurs on the same serine residue (ser259) within a recognition motif for proline-directed kinases. Mitotic phosphorylation of hspik3-c2alpha can be attributed to cdc2 activity, and stress-induced phosphorylation of hspik3-c2alpha is mediated by jnk/sapk	SIGNOR-100903
P17252	Q9UQL6	1	phosphorylation	down-regulates activity	0.2	We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. \| Finally, we assessed the ability of PKD to phosphorylate HDAC5 in cells by employing an antibody that specifically recognizes HDAC5 that has been phosphorylated at serine 259. HDAC5 was basally phosphorylated at serine 259, and phosphorylation at this site was dramatically increased by coexpression of constitutively active PKD S/E	SIGNOR-249269
Q16665	Q9UNE7	0	ubiquitination	down-regulates quantity by destabilization	0.376	the ubiquitin ligase activity of CHIP regulates HIF-1α degradation.	SIGNOR-271426
Q6DJT9	Q09472	0	acetylation	up-regulates	0.308	Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7.	SIGNOR-140915
Q13200	Q9HC98	0	phosphorylation	up-regulates activity	0.2	Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).	SIGNOR-273894
O75581	Q8NCW0	2	binding	down-regulates	0.639	Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to block wnt/beta-catenin signalling. Kremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of the wnt receptor lrp6 from the plasma membrane.	SIGNOR-88894
P61088	Q969Q1	1	ubiquitination	up-regulates activity	0.539	We used MuRF1 as the E3 as it functions with all these E2s to ubiquitinate one of its typical substrates, troponin I Although UbcH1 and UbcH13/Uev1a support ubiquitination of troponin I by MuRF1, these E2s do not support ubiquitination of S5a, unlike Class I E2s.	SIGNOR-272737
Q99623	P17252	0	phosphorylation	down-regulates activity	0.2	PKC\u03b1 phosphorylates PHB2-S39.	SIGNOR-279256
O96004	Q15797	0	transcriptional regulation	up-regulates quantity	0.2	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-268936
Q16665	Q6ZMT4	1	transcriptional regulation	up-regulates quantity by expression	0.2	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271572
O60285	Q96QC0	1	phosphorylation	up-regulates activity	0.2	Here, we show that NUAK1 is a predominantly nuclear protein that associates with a network of nuclear protein phosphatase 1 (PP1) interactors and that PNUTS, a nuclear regulatory subunit of PP1, is phosphorylated by NUAK1.\|Inhibition of NUAK1 abolishes chromatin association of PNUTS, reduces spliceosome activity, and suppresses nascent RNA synthesis.	SIGNOR-280051
P68400	P35222	1	phosphorylation	up-regulates activity	0.556	The major CK2 phosphorylation site in this domain is Thr393, a solvent-accessible residue in a key hinge region of the molecule. Mutation of this single amino acid reduces beta-catenin phosphorylation, cotranscriptional activity, and stability.	SIGNOR-250849
P37173	P37173	2	phosphorylation	down-regulates activity	0.2	Ser213, in the membrane-proximal segment outside the kinase domain, undergoes intra-molecular autophosphorylation which is essential for the activation of TbetaRII kinase activity, activation of TbetaRI and TGF-beta-induced growth inhibition. In contrast, phosphorylation of Ser409 and Ser416, located in a segment corresponding to the substrate recognition T-loop region in a three-dimensional structural model of protein kinases, is enhanced by receptor dimerization and can occur via an intermolecular mechanism. Phosphorylation of Ser409 is essential for TbetaRII kinase signaling, while phosphorylation of Ser416 inhibits receptor function.	SIGNOR-246737
P63092	Q9UNW8	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 ‚â• -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 ‚â• -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-256802
P63092	P13945	2	binding	up-regulates activity	0.621	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 ‚â• -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 ‚â• -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-256753
P48426	P68400	0	phosphorylation	up-regulates	0.421	Here, we demonstrate the partial purification of a protein kinase that phosphorylates the type iialpha pip kinase at a single site unique to that isoform - ser304. This kinase was identified as protein kinase ck2 (formerly casein kinase 2). Mutation of ser304 to aspartate to mimic its phosphorylation had no effect on pip kinase activity, but promoted both redistribution of the green fluorescent protein (gfp)-tagged enzyme in hela cells from the cytosol to the plasma membrane, and membrane ruffling.	SIGNOR-71014
Q8N474	P04628	2	binding	down-regulates	0.784	Frp inhibits wnt signaling through interactions with wnt and/or formation of nonfunctional complexes with the frizzled receptor. here we demonstrate that frza, a sfrp that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to wnt-1 protein, but not wnt-5a protein, and modulates wnt-1 signaling.	SIGNOR-71423
Q9HD90	Q12857	0	transcriptional regulation	up-regulates quantity	0.2	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268891
P16234	P19174	1	phosphorylation	up-regulates	0.65	Tyrosine phosphorylation has been shown to increase the enzymatic activity of plc-? / we show that the human pdgf ?- And ?-Receptors differ quantitatively in their abilities to associate with and phosphorylate plc-? And to stimulate inositol phosphate production.	SIGNOR-28176
P78337	P28069	2	binding	up-regulates activity	0.471	A novel OTX-related homeodomain transcription factor has been identified on the basis of its ability to interact with the transactivation domain of the pituitary-specific POU domain protein, Pit-1. P-OTX is able to independently activate and to synergize with Pit-1 on pituitary-specific target gene promoters.	SIGNOR-219740
Q03181	P19793	2	binding	up-regulates	0.582	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-105442

P53779

Q9NR28

1

phosphorylation

down-regulates

0.341

Here we demonstrate that jnk3 can phosphorylate smac. Phosphorylation of smac by jnk3 attenuates its interaction with xiap. These results suggest that jnk3 activity can attenuate the progression of apoptosis through a novel mechanism of action, the down-regulation of interaction between smac and xiap.

SIGNOR-157280

P25101

O95837

2

binding

up-regulates activity

0.471

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-257427

P63092

Q96P68

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 ‚â• -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 ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0.

SIGNOR-256770

Q92819

P54646

0

phosphorylation

down-regulates activity

0.2

We found that AMPK phosphorylated Thr-110 of human HAS2, which inhibits its enzymatic activity.

SIGNOR-276299

Q13753

P08253

0

cleavage

up-regulates activity

0.471

Induction of Cell Migration by Matrix Metalloprotease-2 Cleavage of Laminin-5|MMP2 cleaved the Ln-5 gamma2 subunit at residue 587, exposing a putative cryptic promigratory site on Ln-5 that triggers cell motility. This altered form of Ln-5 is found in tumors and in tissues undergoing remodeling, but not in quiescent tissues. Cleavage of Ln-5 by MMP2 and the resulting activation of the Ln-5 cryptic site may provide new targets for modulation of tumor cell invasion and tissue remodeling.

SIGNOR-253240

Q9C0D0

P62136

2

binding

up-regulates activity

0.537

Phactr-1 was previously identified as protein phosphatase 1 (PP1) α-interacting protein that possesses actin-binding domains. We showed that Phactr-1 depletion decreased PP1 activity, disrupted the fine-tuning of actin polymerization and impaired lamellipodial dynamics. Taken together our results strongly suggest that Phactr-1 is a key component in the angiogenic process.

SIGNOR-260062

Q12809

P46934

0

ubiquitination

down-regulates quantity by destabilization

0.268

We have previously shown that the E3 ubiquitin (Ub) ligase Nedd4-2 (neural precursor cell expressed developmentally down-regulated protein 4-2) targets the PY motif of hERG channels to initiate channel degradation. Although both immature and mature hERG channels contain the PY motif, Nedd4-2 selectively mediates the degradation of mature hERG channels.

SIGNOR-260998

O15123

Q02763

2

binding

up-regulates

0.924

Angiopoietin-1 and -2, bound to tek with similar affinities, and angiopoietin-1 effectively induced tek phosphorylation in hematopoietic cells. Angiopoietin-2 also induced a low level of tek phosphorylation and weakened the phosphorylation induced by angiopoietin-1

SIGNOR-59808

P05129

P25098

1

phosphorylation

up-regulates

0.2

Phosphorylation of grk2 by protein kinase c abolishes its inhibition by calmodulinin vitro, grk2 was preferentially phosphorylated by pkc isoforms alpha, gamma, and delta

SIGNOR-83231

P17612

P11137

1

phosphorylation

down-regulates activity

0.36

CAMP-dependent protein kinase activity disrupts the MAP2-microtubule interaction in living HeLa cells. S319, S350, and S382 were thus identified as preferred targets of PKA

SIGNOR-250003

P68104

P51784

0

deubiquitination

up-regulates activity

0.2

USP11 interacted with and deubiquitinated eEF1A1 on Lys439, thereby inhibiting its ubiquitin-mediated degradation. Subsequently, the elevated expression of eEF1A1 resulted in its binding to SP1, which in turn drove the binding of SP1 to its target HGF gene promoter to increase its transcription

SIGNOR-278107

Q04206

P12644

1

transcriptional regulation

down-regulates quantity by repression

0.2

Co-transfection with pCMV4-RelA alone or in combination with pCMV4p50 repressed pSLA4.1 EX-Lux activity by approximately 75 percent in both H441 and A549 cells

SIGNOR-266087

Q8NI17

O60674

2

binding

up-regulates

0.381

Il-31 can activate janus kinase (jak) 1 and jak2 signaling molecules after binding to its receptor complex.

SIGNOR-161430

Q92793

P17252

0

phosphorylation

down-regulates

0.261

The action of metformin was shown to be mediated through activation of apkc?/?, Which phosphorylates cbp at ser436, and disrupts the transcriptionally active creb-cbp-crtc2 complex,

SIGNOR-166368

Q96J02

Q8NEA6

1

ubiquitination

down-regulates quantity

0.331

Itch promotes proteolytic degradation of Glis3.|Since Itch interacts with and ubiquitinates Glis3, it was of interest to determine which regions were necessary for Itch directed degradation of Glis3.

SIGNOR-278653

Q14457

P00533

0

phosphorylation

down-regulates activity

0.521

The mechanism by which EGFR suppresses Beclin 1 function involves EGFR interaction with two domains (BH3 and ECD) of Beclin 1; EGFR mediated multisite tyrosine phosphorylation of Beclin 1 on residues Y229, Y233 and Y352; and EGFR mediated alterations in the Beclin 1 interactome (increased binding to the negative regulators, Bcl-2 and Rubicon, and decreased binding to the VPS34 lipid kinase).|Thus, EGFR signaling suppresses autophagy via its interaction with Beclin 1 during normal mitogenic signaling as well as during aberrant cell proliferation in cancer cells.

SIGNOR-278357

P61224

Q8WZA2

0

guanine nucleotide exchange factor

up-regulates activity

0.811

Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well.

SIGNOR-263955

Q96PU4

Q8WW12

1

polyubiquitination

down-regulates quantity by destabilization

0.451

Ubiquitination of PEST containing nuclear protein (PEST) by NIRF (Np95/ICBP90‐like RING finger protein) in the nuclear core of the cell: Ubiquitin‐like domain in the N‐terminus and a RING finger motif in the C‐terminus of NIRF confirm the ubiquitin ligase function of NIRF. PCNP acts as a substrate for NIRF mediated proteasome activity.

SIGNOR-271501

P23458

Q13651

2

phosphorylation

up-regulates activity

0.809

Binding of IL-10 to the extracellular domain of IL-10R1 activates phosphorylation of the receptor-associated Janus tyrosine kinases, JAK1 and Tyk2. These kinases then phosphorylate specific tyrosine residues (Y446 and Y496) on the intracellular domain of the IL-10R1 chain. Once phosphorylated, these tyrosine residues (and their flanking peptide sequences) serve as temporary docking sites for the latent transcription factor, STAT3 (signal transducer and activator of transcription-3).

SIGNOR-251338

P08047

O43497

1

transcriptional regulation

up-regulates quantity by expression

0.261

Consistent with this, Sp1 over-expression enhanced promoter activity while siRNA-mediated Sp1 silencing significantly decreased the level of CaV 3.1 protein and reduced the amplitude of whole-cell T-type Ca(2+) currents expressed in the N1E-115 cells. These results provide new insights into the molecular mechanisms that control CaV 3.1 channel expression.

SIGNOR-264034

Q9Y6K9

P06241

0

phosphorylation

down-regulates activity

0.357

Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.

SIGNOR-276371

Q13131

O95239

1

phosphorylation

up-regulates activity

0.2

We found that the strong direct substrate KIF4A is phosphorylated by AMPK at Ser801.Using in vitro kinase assays, we found that active AMPK and Aurora B phosphorylated KIF4A at Ser801 and Thr799 respectively in a time-dependent manner (Figure 5D). KIF4A is phosphoregulated by AMPK and Aurora B. Although AMPK phosphorylation increased the ATPase activity of KIF4A, Aurora B phosphorylation resulted in a stronger increase (Figure 5I), which might be consistent with the more powerful kinase function of Aurora B during mitosis.

SIGNOR-265991

P06748

Q8N726

2

binding

up-regulates activity

0.552

The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division

SIGNOR-245073

P15976

P31749

0

phosphorylation

up-regulates

0.514

We found that akt directly phosphorylates the transcription factor gata-1 at serine 310 and that this site-specific phosphorylation is required for the transcriptional activation of the timp-1 promoter.

SIGNOR-139782

Q9H0A0

Q00987

1

ubiquitination

down-regulates quantity by destabilization

0.33

NAT10 acetylates p53 at K120 and stabilizes p53 by counteracting Mdm2 action. In addition, NAT10 promotes Mdm2 degradation with its intrinsic E3 ligase activity.

SIGNOR-272405

Q8NFP9

Q92796

2

binding

up-regulates activity

0.42

Interestingly, a recent proteomic analysis (Lauks et al., 2012) revealed that Nbea binds SAP102, which interacts with glutamate receptors early in the biosynthetic route and regulates their targeting. This finding, along with the interaction of Nbea with the glycine receptor beta subunit (del Pino et al., 2011), further strengthens the notion that Nbea targets neurotransmitter receptors to synapses.

SIGNOR-266004

Q9P286

Q92934

1

phosphorylation

down-regulates activity

0.2

P21-Activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD. Pak5 phosphorylates BAD Ser-112

SIGNOR-250247

Q9BZL6

Q8WUI4

1

phosphorylation

up-regulates activity

0.437

Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67].

SIGNOR-275933

P22681

O00459

1

ubiquitination

down-regulates

0.606

Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner.

SIGNOR-110063

P46531

Q9Y219

2

binding

up-regulates

0.625

Immunohistochemistry revealed coexpression of jagged2 and notch1 within thymus and other fetal murine tissues, consistent with interaction of the two proteins in vivo. Coculture of fibroblasts expressing human jagged2 with murine c2c12 myoblasts inhibited myogenic differentiation, accompanied by increased notch1 and the appearance of a novel 115-kda notch1 fragment. Exposure of c2c12 cells to jagged2 led to increased amounts of notch mrna as well as mrnas for a second notch receptor, notch3, and a second notch ligand, jagged1. Constitutively active forms of notchl in c2c12 cells also induced increased levels of the same set of mrnas, suggesting positive feedback control of these genes initiated by binding of jagged2 to notch1.

SIGNOR-236922

Q8TF40

P08238

2

binding

down-regulates activity

0.2

FNIP1 and FNIP2 facilitate FLCN binding to Hsp90 chaperone. Our results suggest that FNIP1 is a potent inhibitor of Hsp90 ATPase activity, as 200 nM of FNIP1 inhibits Hsp90 ATPase activity by 50-fold. FNIP2 also has shown inhibitory activity towards Hsp90; however, it required 1.6 μM of FNIP2 to inhibit the ATPase activity by eightfold. Although we use the term ‘inhibition' here, FNIPs seem only to be slowing the chaperone cycle.

SIGNOR-261415

Q6PHR2

Q96CF2

1

phosphorylation

down-regulates activity

0.286

CHMP4C was phosphorylated by recombinant ULK3 in these experiments, whereas CHMP4A and CHMP4B were not (Figure 7\u2014figure supplement 1A).

SIGNOR-279771

P04637

Q9BV47

0

dephosphorylation

down-regulates activity

0.366

Dual-specificity phosphatase 26 is a novel p53 phosphatase and inhibits p53 tumor suppressor functions in human neuroblastoma|Inhibiting DUSP26 expression in the IMR-32 neuroblastoma cell line enhanced doxorubicin-induced p53 phosphorylation at Ser20 and Ser37, p21, Puma, Bax expression as well as apoptosis

SIGNOR-248765

Q8IYW5

P16403

1

polyubiquitination

down-regulates

0.2

ITCH biochemically antagonized RNF168 and RNF8 in polyubiquitination of histone H1.2 ITCH interacts with and ubiquitinates linker histone H1.2 at K46. ITCH biochemically competes with RNF168 and RNF8 to polyubiquitinate histone H1.2. Both RNF168 and RNF8 elicited higher Ubn levels of K46R-H1.2 compared to WT-H1.2, suggesting that Ubn of H1.2 by both E3 ligases occurs at a site apart from K46.

SIGNOR-272927

Q8NES3

Q9NYJ7

2

binding

up-regulates

0.448

We find that mammalian lunatic fringe (lfng) inhibits jagged1-mediated signalling and potentiates delta1-mediated signalling through notch1.

SIGNOR-80524

P49841

Q9NR50

2

binding

down-regulates

0.261

Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b).

SIGNOR-175520

Q9HD43

P06213

1

dephosphorylation

down-regulates

0.27

These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase

SIGNOR-76072

Q05513

P55211

1

phosphorylation

down-regulates

0.348

Inhibitor sensitivity and interactions with caspase 9 indicate that the predominant kinase that targets ser144 is the atypical protein kinase c isoform zeta (pkczeta).

SIGNOR-141629

O14640

Q9Y4D1

2

binding

up-regulates activity

0.735

B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1.

SIGNOR-185271

P45984

P16949

1

phosphorylation

down-regulates

0.256

Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress.

SIGNOR-166698

Q5S007

Q9UNE7

0

ubiquitination

down-regulates quantity by destabilization

0.433

CHIP can ubiquitinate LRRK2.|These results indicate that both the chaperone interaction and the ubiquitin ligase activity of CHIP are required for CHIP mediated degradation of LRRK2 protein.

SIGNOR-278615

Q15349

P25963

1

phosphorylation

down-regulates

0.267

Rsk2 is activated by treatment with tumor necrosis factor-alfa (tnf-alfa) and directly phosphorylates ikbalfa at ser-32, leading to ikbalfa degradation.

SIGNOR-164790

O75129

O14525

2

binding

down-regulates quantity

0.2

Biochemical and flow cytometry experiments show that ASTN2 forms a complex with ASTN1 and regulates surface expression of ASTN1. Coexpression with ASTN2 reduces the cell surface localization of ASTN1.

SIGNOR-269813

P10912

P01241

2

binding

up-regulates

0.859

The hghr only binds primate gh. Arg43 in hghr interacts with asp171 of hgh.

SIGNOR-34129

P43405

2

phosphorylation

up-regulates activity

0.2

These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520

SIGNOR-246621

P49841

Q00613

1

phosphorylation

down-regulates activity

0.557

Ser-303 is phosphorylated by glycogen synthase kinase 3 (GSK3) through a mechanism dependent on primary phosphorylation of Ser-307 by MAPK. Secondary phosphorylation of Ser-303 by GSK3 may thus repress the activity of HSF-1, and its requirement for priming by MAPK phosphorylation of Ser-307 provides a potential link between the MAPK cascade and HSF-1.

SIGNOR-251216

P19338

P68871

1

post transcriptional regulation

up-regulates quantity by expression

0.2

Nucleolin binds human β-globin mRNA. A Nucleolin-Binding 3′ Untranslated Region Element Stabilizes β-Globin mRNA In Vivo

SIGNOR-251844

Q99683

Q12933

2

binding

up-regulates activity

0.737

Traf2 is a strong activator of ask1

SIGNOR-60747

Q9ULG1

Q9UNE7

0

ubiquitination

up-regulates activity

0.2

Then, by an in vivo ubiquitination assay under denaturing conditions (hereafter, all in vivo ubiquitination assays were carried out under denaturing conditions), we determined whether CHIP ubiquitinates Ino80.|We also show that CHIP works together with BAP1 to enhance the stabilization of Ino80, leading to its chromatin binding.

SIGNOR-278646

O75379

P68400

0

phosphorylation

up-regulates

0.446

The r-snare vamp4, which contains a dileucine motif, binds to the ap-1 or the ggas. Serine 20 and leucines 25,26 are essential for this binding. Ap-1 association with vamp4 is enhanced when serine 30 is phosphorylated by casein kinase 2. This phosphorylation-dependent modulation of ap-1 binding is mediated by pacs-1 (phosphofurin acidic cluster sorting protein). Ablation of both the dileucine motif and serine 30 results in a dramatic mislocalization of vamp4 in the regulated secretory pathway.

SIGNOR-119090

P17252

Q13224

1

phosphorylation

up-regulates activity

0.469

These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels.

SIGNOR-249083

P29350

P06213

2

dephosphorylation

down-regulates

0.359

Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1.

SIGNOR-75938

P78563

P19525

2

binding

up-regulates activity

0.459

Both forms of ADAR1 show enhanced interactions with PKR at the peak of HIV infection, suggesting a role for this protein in the regulation of PKR activation.

SIGNOR-266359

Q00535

P16949

1

phosphorylation

down-regulates

0.376

Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. The kinases involved in phosphorylating stmn ser-16 and ser-63 include camp-dependent protein kinase (pka) and pak1, whereas stmn ser-25 and ser-38 have been shown to be targets for proline-directed serine/threonine kinases such as cyclin-dependent kinases, erk1/2, and members of the p38 mapk subfamily.

SIGNOR-166682

Q86Z02

O60829

1

phosphorylation

up-regulates activity

0.456

Here, we have identified homeodomain-interacting protein kinase 1 (HIPK1), also a component of the stress-response pathway, as a kinase that phosphorylates PAGE4 at T51 | We show that phosphorylation of PAGE4 is critical for its transcriptional activity since mutating this T residue abolishes its ability to potentiate c-Jun transactivation.

SIGNOR-260929

Q99714

O60260

0

ubiquitination

down-regulates quantity by destabilization

0.2

This study identifies the multifunctional PD-related mitochondrial matrix enzyme 17-β hydroxysteroid dehydrogenase type 10 (HSD17B10) as a new Parkin substrate.

SIGNOR-272823

P28845

P49715

0

transcriptional regulation

up-regulates quantity by expression

0.274

Cotransfection with human CCAAT/enhancer binding protein-alpha (C/EBPalpha) and C/EBPbeta-LAP expression vectors activated the HSD11B1 promoter with the strongest effect within the same region.

SIGNOR-268971

Q86V15

Q9UHF1

1

transcriptional regulation

up-regulates quantity

0.425

We have recently demonstrated that a novel transcriptional pathway involving activation of the Epidermal Growth Factor-like Domain 7 (Egfl7) gene by the transcription factor CASTOR (CASZ1) is required for blood vessel assembly and lumen morphogenesis.

SIGNOR-266858

P35590

Q02763

0

phosphorylation

up-regulates activity

0.348

Thus, Tie2 was able to induce Tie1 phosphorylation.|When cotransfected, Tie2 formed heteromeric complexes with Tie1, enhanced Tie1 activation, and induced phosphorylation of a kinase-inactive Tie1 in a ligand-dependent manner.

SIGNOR-279769

P05771

Q16820

1

phosphorylation

down-regulates quantity

0.2

These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate.

SIGNOR-263173

Q06124

P36888

2

binding

up-regulates activity

0.525

Y599 was additionally found to interact with the protein tyrosine phosphatase SHP2 in a phosphorylation-dependent manner. As Y599F-Flt3-32D was unable to associate with and to phosphorylate SHP2 and since silencing of SHP2 in WT-Flt3-expressing cells mimicked the Y599F-Flt3 phenotype, we hypothesize that recruitment of SHP2 to pY599 contributes to FL-mediated Erk activation and proliferation.

SIGNOR-245057

P28482

Q15256

2

phosphorylation

up-regulates activity

0.824

Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL.

SIGNOR-249438

P49841

Q9Y2T1

2

binding

up-regulates activity

0.832

It has been found that a multiprotein complex assembled by the cytoplasmic component conductin induces degradation of cytoplasmic beta-catenin. The complex includes apc, the serine/threonine kinase gsk3 beta, and beta-catenin, which bind to conductin at distinct domains.

SIGNOR-79950

P49916

P24941

0

phosphorylation

down-regulates

0.418

Dna ligase iii_ is specifically phosphorylated in replicating cells by the cell cycle kinase cdk2. However, in response to oxidative dna damage, dna ligase iii_ is dephosphorylated in a pathway that is dependent upon the dna damage-activated, phosphatidylinositol 3-phosphate (pi3)1-related kinase atm.

SIGNOR-150121

P20273

Q9NRF2

2

binding

up-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-268444

Q9NX47

Q8IWA4

1

ubiquitination

down-regulates quantity by destabilization

0.2

MARCH5, a mitochondrial E3 ubiquitin ligase, has been identified as a molecule that binds mitochondrial fission 1 protein (hFis1), dynamin-related protein 1 (Drp1) and mitofusin 2 (Mfn2), key proteins in the control of mitochondrial fission and fusion.|Notably, a significant increase in Mfn1 level, but not Mfn2, Drp1 or hFis1 levels, was observed in MARCH5-depleted cells, indicating that Mfn1 is a major ubiquitylation substrate.

SIGNOR-274133

P35222

Q13153

0

phosphorylation

up-regulates

0.557

Pak1 directly phosphorylates _-catenin proteins at ser675 site and this leads to more stable and transcriptional active _-catenin

SIGNOR-175944

Q13761

P11309

0

phosphorylation

up-regulates quantity

0.353

Inhibition of Pim1 kinase prevents peanut allergy by enhancing Runx3 expression and suppressing T (H) 2 and T (H) 17 T-cell differentiation.|Pim1 kinase phosphorylates and stabilizes Runx3 and alters its subcellular localization.

SIGNOR-279547

Q9UNE7

P53350

1

ubiquitination

down-regulates quantity by destabilization

0.252

As indicated in xref , all three Plk1 fragments were ubiquitinated by CHIP, suggesting that CHIP targets multiple sites of Plk1 for ubiquitination.|Mechanistically, CHIP mediated degradation of AR and Plk1 leads to enhanced efficacy of HSP90 inhibitors.

SIGNOR-278532

Q9H4B4

P30307

1

phosphorylation

up-regulates

0.731

Cdc25c phosphorylation on serine 191 by plk3 promotes its nuclear translocation

SIGNOR-122090

P42773

Q00534

2

binding

down-regulates

0.88

The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb.

SIGNOR-44601

P60953

Q96M96

0

guanine nucleotide exchange factor

up-regulates activity

0.619

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-260554

O14920

P04637

1

phosphorylation

up-regulates activity

0.52

Here , we show that IKKbeta modulates the activity of p53 in response to glutamine depletion to promote cancer cell adaptation .|Taken together, these results indicate that IKK\u03b2 phosphorylates p53 on Ser392 as an early response to glutamine deprivation and possibly later facilitates its phosphorylation at Ser15 and transcriptional activity.

SIGNOR-278516

P12931

P17302

1

phosphorylation

down-regulates

0.588

The oncogenic tyrosine kinase, v-src, phosphorylates connexin43 (cx43) on y247 and y265 and inhibits cx43 gap junctional communication (gjc), the process of intercellular exchange of ions and metabolites.

SIGNOR-148913

P50148

Q9NPG1

2

binding

up-regulates

0.408

Gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families.

SIGNOR-122895

Q96P68

P38405

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-256913

Q9UQL6

Q02078

2

binding

down-regulates

0.706

The histone deacetylase hdac-5, upon dephosphorylation and translocation to the nucleus, directly inactivates mef2, preventing myogenesis.

SIGNOR-84023

Q9Y297

P10070

1

ubiquitination

down-regulates quantity by destabilization

0.651

The phosphorylated gli2 protein interacts with beta-trcp, and is ubiquitinated and degraded by the proteasome

SIGNOR-146109

P31749

Q01813

1

phosphorylation

up-regulates quantity

0.564

A reduction in AKT expression as a result of AKT1 shRNA expression or MK-2206 treatment decreased the half-life of endogenous PFKP, while the expression of active Myr-AKT1 prolonged the half-life of PFKP.|In addition, depletion of endogenous PFKP and reconstitution of RNAi resistant WT Flag-rPFKP or Flag-rPFKP S386A expression in U251 or U87 and EGFRvIII cells revealed that the S386A mutation abolished PFKP phosphorylation induced by EGF, constitutively active Myr-AKT1, and EGFRvIII.

SIGNOR-279788

P06493

O00443

1

phosphorylation

down-regulates activity

0.281

Mitotic and stress-induced phosphorylation of HsPI3K-C2alpha targets the protein for degradation. Stress-dependent and mitotic phosphorylation of hspik3-c2alpha occurs on the same serine residue (ser259) within a recognition motif for proline-directed kinases. Mitotic phosphorylation of hspik3-c2alpha can be attributed to cdc2 activity, and stress-induced phosphorylation of hspik3-c2alpha is mediated by jnk/sapk

SIGNOR-100903

P17252

Q9UQL6

1

phosphorylation

down-regulates activity

0.2

We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. | Finally, we assessed the ability of PKD to phosphorylate HDAC5 in cells by employing an antibody that specifically recognizes HDAC5 that has been phosphorylated at serine 259. HDAC5 was basally phosphorylated at serine 259, and phosphorylation at this site was dramatically increased by coexpression of constitutively active PKD S/E

SIGNOR-249269

Q16665

Q9UNE7

0

ubiquitination

down-regulates quantity by destabilization

0.376

the ubiquitin ligase activity of CHIP regulates HIF-1α degradation.

SIGNOR-271426

Q6DJT9

Q09472

0

acetylation

up-regulates

0.308

Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7.

SIGNOR-140915

Q13200

Q9HC98

0

phosphorylation

up-regulates activity

0.2

Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).

SIGNOR-273894

O75581

Q8NCW0

2

binding

down-regulates

0.639

Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to block wnt/beta-catenin signalling. Kremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of the wnt receptor lrp6 from the plasma membrane.

SIGNOR-88894

P61088

Q969Q1

1

ubiquitination

up-regulates activity

0.539

We used MuRF1 as the E3 as it functions with all these E2s to ubiquitinate one of its typical substrates, troponin I Although UbcH1 and UbcH13/Uev1a support ubiquitination of troponin I by MuRF1, these E2s do not support ubiquitination of S5a, unlike Class I E2s.

SIGNOR-272737

Q99623

P17252

0

phosphorylation

down-regulates activity

0.2

PKC\u03b1 phosphorylates PHB2-S39.

SIGNOR-279256

O96004

Q15797

0

transcriptional regulation

up-regulates quantity

0.2

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-268936

Q16665

Q6ZMT4

1

transcriptional regulation

up-regulates quantity by expression

0.2

To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.

SIGNOR-271572

O60285

Q96QC0

1

phosphorylation

up-regulates activity

0.2

Here, we show that NUAK1 is a predominantly nuclear protein that associates with a network of nuclear protein phosphatase 1 (PP1) interactors and that PNUTS, a nuclear regulatory subunit of PP1, is phosphorylated by NUAK1.|Inhibition of NUAK1 abolishes chromatin association of PNUTS, reduces spliceosome activity, and suppresses nascent RNA synthesis.

SIGNOR-280051

P68400

P35222

1

phosphorylation

up-regulates activity

0.556

The major CK2 phosphorylation site in this domain is Thr393, a solvent-accessible residue in a key hinge region of the molecule. Mutation of this single amino acid reduces beta-catenin phosphorylation, cotranscriptional activity, and stability.

SIGNOR-250849

P37173

2

phosphorylation

down-regulates activity

0.2

Ser213, in the membrane-proximal segment outside the kinase domain, undergoes intra-molecular autophosphorylation which is essential for the activation of TbetaRII kinase activity, activation of TbetaRI and TGF-beta-induced growth inhibition. In contrast, phosphorylation of Ser409 and Ser416, located in a segment corresponding to the substrate recognition T-loop region in a three-dimensional structural model of protein kinases, is enhanced by receptor dimerization and can occur via an intermolecular mechanism. Phosphorylation of Ser409 is essential for TbetaRII kinase signaling, while phosphorylation of Ser416 inhibits receptor function.

SIGNOR-246737

P63092

Q9UNW8

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 ‚â• -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 ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0.

SIGNOR-256802

P63092

P13945

2

binding

up-regulates activity

0.621

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 ‚â• -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 ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0.

SIGNOR-256753

P48426

P68400

0

phosphorylation

up-regulates

0.421

Here, we demonstrate the partial purification of a protein kinase that phosphorylates the type iialpha pip kinase at a single site unique to that isoform - ser304. This kinase was identified as protein kinase ck2 (formerly casein kinase 2). Mutation of ser304 to aspartate to mimic its phosphorylation had no effect on pip kinase activity, but promoted both redistribution of the green fluorescent protein (gfp)-tagged enzyme in hela cells from the cytosol to the plasma membrane, and membrane ruffling.

SIGNOR-71014

Q8N474

P04628

2

binding

down-regulates

0.784

Frp inhibits wnt signaling through interactions with wnt and/or formation of nonfunctional complexes with the frizzled receptor. here we demonstrate that frza, a sfrp that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to wnt-1 protein, but not wnt-5a protein, and modulates wnt-1 signaling.

SIGNOR-71423

Q9HD90

Q12857

0

transcriptional regulation

up-regulates quantity

0.2

For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)

SIGNOR-268891

P16234

P19174

1

phosphorylation

up-regulates

0.65

Tyrosine phosphorylation has been shown to increase the enzymatic activity of plc-? / we show that the human pdgf ?- And ?-Receptors differ quantitatively in their abilities to associate with and phosphorylate plc-? And to stimulate inositol phosphate production.

SIGNOR-28176

P78337

P28069

2

binding

up-regulates activity

0.471

A novel OTX-related homeodomain transcription factor has been identified on the basis of its ability to interact with the transactivation domain of the pituitary-specific POU domain protein, Pit-1. P-OTX is able to independently activate and to synergize with Pit-1 on pituitary-specific target gene promoters.

SIGNOR-219740

Q03181

P19793

2

binding

up-regulates

0.582

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-105442