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
Q16566	P09429	1	phosphorylation	up-regulates activity	0.285	Collectively, our results demonstrate that CaMKIV promotes the nucleocytoplasmic shuttling of HMGB1 and suggest that the process may be mediated through CaMKIV-dependent serine phosphorylation of HMGB1.	SIGNOR-278510
Q8N5S9	Q13131	1	phosphorylation	up-regulates	0.462	Ampka1 activators increased phosphorylation level and cytoplasmic localization (reduced nuclear/cytoplasmic ratio). Ampka1 activators reduced rna synthesis in the nucleoli.	SIGNOR-176598
O00206	P05109	2	binding	down-regulates activity	0.534	Interestingly, in the present study, we report that extracellular S100A9 induces terminal differentiation of myeloid leukemia cells in human and murine AMLs after TLR4 activation, which is highly expressed by primary myelomonocytic and monocytic leukemia cells. In contrast, anti-S100A8 induced the differentiation of AML cells, suggesting that the differentiation-promoting effect of S100A9 is inhibited by S100A8. ) S100A8 could bind to TLR4 and activate different signaling pathways, leading to the inhibition of cellular differentiation induced by S100A9.	SIGNOR-261921
Q9UBL3	P23771	2	binding	up-regulates	0.25	We identifiedgata3as the binding protein of ash2l. Ash2l was shown to potentiate the transcriptional activity ofgata3.	SIGNOR-205312
P40763	P00533	0	phosphorylation	up-regulates activity	0.879	The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation.	SIGNOR-121965
Q15596	P10275	2	binding	up-regulates activity	0.901	The NCOA2 gene encodes a transcriptional coactivator (SRC-2) that modulates gene expression by hormone receptors, including AR. NCOA2 is both amplified and rarely mutated in prostate cancers, with higher NCOA2 levels resulting in increased androgen signaling readout. Furthermore, as mentioned previously, SRC-3, a close homolog encoded by NCOA3, is a substrate of SPOP whose protein levels are increased by SPOP mutation, potentially linking these common point mutations to the androgen axis	SIGNOR-251531
Q05397	Q06124	0	dephosphorylation	down-regulates	0.731	Dca concomitantly and significantly increased association of tyrosine phosphatase shp2 with fak. Incubation of immunoprecipitated fak, in vitro, with glutathione-s-transferase-shp2 fusion protein resulted in tyrosine dephosphorylation of fak in a concentration-dependent manner.	SIGNOR-148926
O14511	P21860	2	binding	up-regulates	0.82	Direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3.The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4	SIGNOR-26881
Q8NBZ7	P29320	0	phosphorylation	up-regulates activity	0.2	However, it is possible that etk is a principal activator of Ugd.\|The phosphorylation of the Ugd protein (a UDP-glucose dehydrogenase) by Etk increases Ugd dehydrogenase activity.	SIGNOR-280006
Q96EV8	Q86Y07	0	phosphorylation	down-regulates quantity by destabilization	0.2	We show that VRK2 phosphorylates Ser 297 and Ser 299 of dysbindin using in vitro kinase assay. In addition, we found that VRK2-mediated phosphorylation of dysbindin enhanced ubiquitination of dysbindin and consequently resulted in the decrease in its protein stability through western blotting.	SIGNOR-277403
O14640	O75581	2	binding	up-regulates activity	0.707	The scaffold protein dishevelled (dvl) is required for lrp6 phosphorylation and aggregation. We propose that wnts induce coclustering of receptors and dvl in lrp6-signalosomes, which in turn triggers lrp6 phosphorylation to promote axin recruitment and beta-catenin stabilization.	SIGNOR-156072
P24941	O75469	1	phosphorylation	down-regulates quantity by destabilization	0.372	PXR Phosphorylation at S350 by CDK2 Triggers PXR Degradation via the Ubiquitin-Proteasome Pathway.	SIGNOR-279397
Q13131	P17612	0	phosphorylation	down-regulates activity	0.423	These agents also enhanced phosphorylation of alpha-Ser(485/491) by the cAMP-dependent protein kinase. AMPK alpha-Ser(485/491) phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine.	SIGNOR-256112
P46734	Q9UL54	2	binding	up-regulates activity	0.67	Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7.	SIGNOR-70947
P14784	P29350	0	dephosphorylation	down-regulates	0.532	We have found that il-2 induces association of shp-1 with the il-2 receptor complex, and that once shp-1 is recruited to the activated receptor it is able to decrease tyrosine phosphorylation of il-2rbeta and the associated tyrosine kinases jak1 and jak3.	SIGNOR-55989
P24385	O15379	2	binding	up-regulates	0.412	Collectively, these studies suggest an important role of cyclin d1 in regulation of ppargamma-mediated adipocyte differentiation through recruitment of hdacs to regulate ppar response element local chromatin structure and ppargamma function.	SIGNOR-134056
P78368	P07948	1	phosphorylation	up-regulates quantity by stabilization	0.2	Although there have been more than 40 reports of mass spectrometric studies on phosphorylation at Lyn-S13, the kinase responsible remained unclear. We succeeded in identifying casein kinase 1γ (CK1γ) as the kinase responsible for phosphorylation of Lyn-S13. In HEK293 cells co-expressing Lyn and CK1γ, the phosphorylation level of Lyn-S13 increased significantly. we concluded that S-palmitoylated CK1γ encounters N-myristoylated Lyn and specifically phosphorylates the Ser-13 residue at the Golgi during intracellular protein traffic, as shown schematically in Fig. 8. Phosphorylated dual-lipid-modified Lyn and S-palmitoylated CK1γ are then transported from the Golgi to the plasma membrane.	SIGNOR-275397
P63000	Q96Q42	2	binding	up-regulates activity	0.532	Thus, in our system, activeRac1 may recruit ALS2 only at the very early stage ofmacropinocytosis including membrane rufﬂes, suggest-ing that ALS2 is retained by some other mechanismsuntil Rab conversion.	SIGNOR-277777
Q13535	Q14191	1	phosphorylation	down-regulates quantity	0.794	Importantly, ATR-mediated phosphorylation targets Werner syndrome protein for ubiquitination and degradation.\|WRN is phosphorylated at serine 1141 by ATR in response to replication-associated DSBs A. WRN is heavily phosphorylated at S1141 in response to CPT treatment of cells.	SIGNOR-278159
P12830	P53350	0	phosphorylation	down-regulates quantity by destabilization	0.297	Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP	SIGNOR-274054
P0C5Z0	Q14493	0	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265407
P28482	Q17RY0	1	phosphorylation	up-regulates activity	0.325	Our results indicate that CPEB4 activation is driven by ERK2- and Cdk1 mediated hyperphosphorylation of at least 12 residues in the intrinsically disordered NTD.\|We concluded that, in interphase, unphosphorylated CPEB4 phase separates into liquid like droplets that recruit mRNAs but are inactive for cytoplasmic polyadenylation and translation, whereas in M-phase, CPEB4 is phosphorylated by ERK2 and Cdk1 and recovers its monomeric form, which can drive the cytoplasmic polyadenylation of target mRNAs.	SIGNOR-280021
P68400	Q13530	1	phosphorylation	up-regulates activity	0.2	The two serines within the PSAC of Serinc3 are phosphorylated by casein kinase II and mediate interaction with the μ subunits in vitro.	SIGNOR-273631
O14746	Q9NY12	2	binding	up-regulates activity	0.445	A complex of four proteins (GAR1, NHP2, NOP10, and the putative pseudouridine synthase dyskerin) associates with snoRNAs to form small nucleolar ribonucleoprotein particles (snoRNPs), and the binding of this complex to the H/ACA domain of TERC may have a role in the biogenesis of the telomerase RNP	SIGNOR-263333
P46531	O60684	0	relocalization	up-regulates	0.2	Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. importins alpha3, alpha4 (and to a lesser extent, alpha7) mediate nuclear import of nicd and thus are directly involved in notch signaling.	SIGNOR-165343
P07737	Q13464	0	phosphorylation	down-regulates	0.272	We previously identified pfn1 as a huntingtin aggregation inhibitor, and others have implicated it as a tumor-suppressor. Rho-associated kinase (rock) directly phosphorylates pfn1 at ser-137 to prevent its binding to polyproline sequences. This negatively regulates its anti-aggregation activity.	SIGNOR-196820
O14874	P53396	1	phosphorylation	up-regulates activity	0.2	BCKDK can activate ACLY and promote the cleavage of citric acid into acetyl-CoA, and oxaloacetate.\|BCKDK can phosphorylate BCKDHA and ATP citrate lyase (ACLY), exerting opposing effects on both.	SIGNOR-280194
P30304	O14757	0	phosphorylation	down-regulates	0.857	The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216).	SIGNOR-163134
P04049	P67775	0	dephosphorylation	up-regulates	0.592	Both pp2a holoenzymes were found to associate with raf1 and catalyze dephosphorylation of inhibitory phospho-ser-259. Together these findings indicate that pp2a abalphac and abdeltac holoenzymes function as positive regulators of raf1-mek1/2-erk1/2 signaling by targeting raf1.	SIGNOR-141170
P36897	O43541	2	binding	down-regulates activity	0.74	The inhibitory Smads (I-Smads), i.e. Smad6 and Smad7, are negative regulators of transforming growth factor-_ (TGF-_) family signaling. I-Smads inhibit TGF-_ family signaling principally through physical interaction with type I receptors (activin receptor-like kinases), so as to compete with receptor-regulated Smads (R-Smads) for activation.	SIGNOR-167160
Q99856	P0DOX6	1	transcriptional regulation	up-regulates quantity by expression	0.2	In this work, we show that TFII-I directly interacts with human Bright through amino acids in Bright's protein interaction domain and that specific tyrosine residues of TFII-I are essential for Bright-induced activity of an immunoglobulin reporter gene. Moreover, inhibition of TFII-I function in a B-cell line resulted in decreased heavy-chain transcript levels.\| Figure 3 shows that both anti-Bright and anti-TFII-I precipitated the bf150 Bright binding site from the B-cell line but not from a T-cell line that contains but does not express the V1 gene.	SIGNOR-268532
P62714	Q05655	1	dephosphorylation	down-regulates activity	0.3	PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.\|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex	SIGNOR-248595
Q15643	P61019	2	binding	up-regulates activity	0.394	Vesicle-associated Rab2 then mediates attachment to the Rab2 binding site within the central coiled-coil region of GMAP-210, bringing the vesicle into closer proximity to the target membrane. GMAP-210 function in vivo is dependent upon its ability to tether membranes, which is mediated exclusively by the amino-terminal ALPS motif. Binding to Rab2 is also important for GMAP-210 function, although it is dispensable for tethering per se.	SIGNOR-261300
P28482	Q9BY84	1	phosphorylation	up-regulates quantity by stabilization	0.808	Phosphorylation of Ser-446 determines stability of MKP-7.\|We also determined that MKP-7 phosphorylated at Ser-446 has a longer half-life than unphosphorylated form of the wild type protein, as does a phospho-mimic mutant of MKP-7. These results indicate that activation of the ERK pathway strongly blocks JNK activation through stabilization of MKP-7 mediated by phosphorylation.	SIGNOR-249389
Q13131	P98177	1	phosphorylation	up-regulates	0.371	The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt phosphorylation sites, resulting in foxo activation	SIGNOR-157947
P25098	Q14940	1	phosphorylation	down-regulates activity	0.2	Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2.	SIGNOR-275503
Q9UQD0	Q13555	0	phosphorylation	up-regulates activity	0.271	CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability\|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel.	SIGNOR-275794
O00192	P19022	2	binding	up-regulates quantity by stabilization	0.466	To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member.	SIGNOR-252128
P21802	P21802	2	phosphorylation	up-regulates activity	0.2	Our data also show that tyrosine 769 is not involved in the regulation of the endocytic process of KGFR.Following ligand binding, KGFR is rapidly autophosphorylated on specific tyrosine residues	SIGNOR-276026
P18031	P29597	1	dephosphorylation	down-regulates activity	0.646	Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5.	SIGNOR-134564
O00213	P00519	0	phosphorylation	up-regulates	0.415	The c-abl tyrosine kinase phosphorylates the fe65 adaptor protein to stimulate fe65/amyloid precursor protein nuclear signaling. Here, we show that active c-abl stimulates app/fe65-mediated gene transcription and that this effect is mediated by phosphorylation of fe65 on tyrosine 547 within its second ptb domain.	SIGNOR-123476
O15194	P06400	1	dephosphorylation	up-regulates activity	0.298	ppRB (RB phosphorylated at Ser-807/811\|Possible Mechanisms of HYA22 Action in Tumorigenesis: Dephosphorylation of RB by Transient Expression of HYA22 Isoforms.	SIGNOR-248304
P38405	Q08828	2	binding	up-regulates activity	0.539	D1-class dopamine receptors (D1 and D5) activate the G s/olf family of G proteins to stimulate cAMP produc tion by AC and are found exclusively postsynaptically on dopamine-receptive cells, such as GABA-ergic medium spiny neurons (MSNs) in the striatum.	SIGNOR-264992
P52797	P29322	2	binding	up-regulates	0.75	Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor	SIGNOR-52387
P28062	Q07820	1	null	down-regulates quantity by destabilization	0.2	Surprisingly, siRNA knockdown of PSMB8 (LMP7), an ‘immunoproteasome’ component, reversed IFNγ-induced sensitivity to Fas ligation and prevented Fas/IFNγ-induced degradation of Mcl-1, but did not protect p-Bcl-2 or p-Bcl-XL. Proteasome inhibition markedly increased Mcl-1, p-Bcl-2, and p-Bcl-XL levels after IFNγ treatment	SIGNOR-261974
P35221	Q06124	0	dephosphorylation	down-regulates	0.435	Tyr148 of beta-catenin is an shp2 target dephosphorylation site. Together, these results suggest that beta-catenin plays a suppressor role in cell transformation and that shp2, by dephosphorylating beta-catenin, promotes mitogenic, cell survival and transformation signals.	SIGNOR-147075
P61981	Q9NRM7	0	phosphorylation	up-regulates	0.331	Phosphorylation of 14-3-3_ on s59 by lats2. Ser(58) phosphorylation and lys(49) acetylation of 14-3-3_ occur in a coordinated time-dependent manner to regulate 14-3-3_ homodimerization. 14-3-3_ ser(58) phosphorylation is required for star interactions under control conditions,	SIGNOR-205247
P46060	P06493	0	phosphorylation	up-regulates	0.495	Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis . Alternatively, phosphorylated rangap1 may recruit specific sumo target proteins to ranbp2's catalytic domain.	SIGNOR-123520
Q8WYK2	P15336	2	binding	down-regulates activity	0.557	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-226395
Q99558	P40763	1	phosphorylation	up-regulates activity	0.26	Activation of Stat3 by NIK requires NIK kinase activity as showed by kinase assays.\|When we transfected NIK into LNCaP cells, NIK was able to phosphorylate Stat3 at both tyrosine 705 and serine 727 residues ( Fig. 3 A).	SIGNOR-279341
O95180	Q9UQM7	0	phosphorylation	down-regulates activity	0.272	we also discovered that a novel CaMKII-phosphorylated site, S2137, underwent dephosphorylation by calcineurin.	SIGNOR-277871
P40763	Q06187	0	phosphorylation	down-regulates activity	0.382	Phosphorylation of STAT-3 by BTK may also alter the conformation of STAT-3 in such a way as to make it inaccessible as a substrate of activating kinases such as JAK3.\|The ability of BTK to negatively regulate STAT-3 activity suggests several possible models for a mechanism of BTK action.	SIGNOR-279011
P50222	O60315	0	transcriptional regulation	down-regulates quantity by repression	0.318	ZEB2 represses GAX transcription through multiple up- stream consensus binding sites.	SIGNOR-268951
P14618	Q00534	0	phosphorylation	down-regulates activity	0.259	Here, using human cancer cells and patient-derived xenografts in mice, we show that the cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2.	SIGNOR-279158
P46531	O00629	0	relocalization	up-regulates	0.287	Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7.	SIGNOR-165314
O00308	O15350	1	polyubiquitination	down-regulates quantity by destabilization	0.283	WWP2 ubiquitinates p73 and controls its protein stability. In our study, we identified WWP2, an E3 ligase, as a novel p73-associated protein that ubiquitinates and degrades p73. In contrast, WWP2 heterodimerizes with another E3 ligase, WWP1, which specifically ubiquitinates and degrades ΔNp73.	SIGNOR-272233
Q04721	Q92585	2	binding	up-regulates	0.808	Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes1.	SIGNOR-84835
Q9NQ66	P29992	2	binding	up-regulates	0.623	Plc-_1 stimulates hydrolysis of gq/11-bound gtp and acts as a gtpase-activating protein (gap) for its physiologic regulator, gq/11	SIGNOR-17239
P31749	P46527	1	phosphorylation	down-regulates	0.85	Because Thr198-phosphorylated p27Kip1 was localized only in the cytoplasm, Akt might promote 14-3-3 binding to p27Kip1 by phosphorylation at Thr198, allowing its cytoplasmic localization and degradation.	SIGNOR-88294
P01375	O75509	2	binding	up-regulates	0.337	We report the identification and initial characterization of dr6, a new member of the tnf receptor family possessing a cytoplasmic death domain.	SIGNOR-59745
Q92905	Q9NZQ7	1	deubiquitination	up-regulates quantity by stabilization	0.2	The results suggested that TNF-α upregulates expression of CSN5, which interacts and deubiquitinates PD-L1 for protein stabilization.	SIGNOR-274977
O15297	Q9NR19	0	transcriptional regulation	up-regulates quantity by expression	0.2	As expected, we found that glucose deprivation induced the binding of TFEB (Figure S4C) and ACSS2 (Figure S4D) to the promoter regions of MAP1LC3B, ATG3, and WIPI-1 as well as mRNA (Figure 3H) and protein (Figure 3I) expression of these genes;	SIGNOR-276560
Q9HAZ2	P12755	2	binding	up-regulates	0.326	Biochemical analysis demonstrated that mel1 interacts with ski and inhibits tgf-_ signaling by stabilizing the inactive smad3-ski complex on the promoter of tgf-_ target genes.	SIGNOR-182529
P23470	P09619	1	dephosphorylation	down-regulates activity	0.338	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-254715
P46934	Q00987	1	ubiquitination	up-regulates quantity by stabilization	0.466	NEDD4 promotes MDM2 ubiquitination in a dose- and time-dependent manner, whereas depletion of NEDD4 reduced the half-life of endogenous MDM2 [ xref ].	SIGNOR-278769
P53350	O43474	1	phosphorylation	up-regulates quantity by stabilization	0.249	We further found that inhibition of polo-like kinase 1 could downregulate the expression of KLF4 and that PLK1 directly phosphorylated KLF4 at Ser234. Notably, phosphorylation of KLF4 by PLK1 caused the recruitment and binding of the E3 ligase TRAF6, which resulted in KLF4 K32 K63-linked ubiquitination and stabilization.	SIGNOR-277463
O75581	O14904	2	binding	up-regulates	0.64	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-132076
P04233	P61073	2	binding	up-regulates	0.531	Cd74 forms functional complexes with cxcr4 that mediate mif-specific signaling.	SIGNOR-187461
P17252	P05204	1	phosphorylation	down-regulates	0.29	Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools.	SIGNOR-76320
Q9HBH9	P27361	0	phosphorylation	up-regulates	0.517	Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity.	SIGNOR-48355
P49840	P10636	1	phosphorylation	down-regulates	0.429	Tau is phosphorylated by gsk-3 at several sites found in alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by a-kinase.	SIGNOR-60651
P53667	O14965	2	phosphorylation	up-regulates activity	0.262	Here, we report a novel functional cooperativity between Aur-A and LIMK1 through mutual phosphorylation. LIMK1 is recruited to the centrosomes during early prophase and then to the spindle poles, where it colocalizes with Aur-A. Aur-A physically associates with LIMK1 and activates it through phosphorylation, which is important for its centrosomal and spindle pole localization. Aur-A also acts as a substrate of LIMK1, and the function of LIMK1 is important for its specific localization and regulation of spindle morphology.	SIGNOR-276400
P06241	Q14524	1	phosphorylation	down-regulates	0.293	This study addresses the effects of the src family tyrosine kinase fyn on na(v)1.5 cardiac sodium channels. Sodium currents were acquired by whole cell recording on hek-293 cells transiently expressing na(v)1.5. Acute treatment of cells with insulin caused a depolarizing shift in steady-state inactivation, an effect eliminated by the src-specific tyrosine kinase inhibitor pp2 we provide evidence that this linker is a substrate for fyn in vitro, and that y1495 is a preferred phosphorylation site.	SIGNOR-135600
A7MCY6	Q9BWT7	1	relocalization	up-regulates activity	0.2	TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation	SIGNOR-272470
Q15722	P09471	2	binding	up-regulates activity	0.265	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-256970
P00533	P22681	2	relocalization	up-regulates	0.886	Likewise, cbl is recruited to erbb1 either directly (tyr1045), or indirectly, trough grb2	SIGNOR-147826
Q06124	P01111	1	dephosphorylation	up-regulates activity	0.673	Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling.	SIGNOR-255754
P78527	Q13535	0	phosphorylation	up-regulates	0.31	Finally, in vitro atr-mediated phosphorylation at the t2609 cluster was further confirmed by western blot analysis using phosphospecific antibodies against t2647 (fig. ?(Fig.7e),7e), suggesting that dna-pkcs could be the direct target of atr kinase.	SIGNOR-148722
Q13233	O14920	1	phosphorylation	up-regulates activity	0.595	These results suggested that IKK\u03b2 was a likely substrate for MEKK1 and that MEKK1 phosphorylation of IKK\u03b2 increased its kinase activity.	SIGNOR-279339
P09429	P31277	2	binding	up-regulates activity	0.292	We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein.	SIGNOR-240559
P35226	Q14157	2	binding	up-regulates activity	0.514	We identified UBAP2L as a novel BMI1-interacting protein. UBAP2L, BMI1, RNF2, and PHC1 define a novel Polycomb subcomplex	SIGNOR-261315
Q9BRS8	P42345	0	phosphorylation	up-regulates activity	0.2	Binding of La ribonucleoprotein domain family, member 6 (LARP6) to collagen mRNAs regulates their translation and is necessary for high type I collagen expression. Here we show that mTORC1 phosphorylates LARP6 on S348 and S409. The S348A/S409A mutant of LARP6 acts as a dominant negative protein in collagen biosynthesis, which retards secretion of type I collagen and causes excessive posttranslational modifications.	SIGNOR-273679
P35241	Q9H270	2	binding	up-regulates activity	0.347	Vps11 was found to interact with radixin. ERM proteins and the HOPS complex are required for the transition from early to late endosomes. We report that an interaction between subunits of the HOPS complex and the ERM (ezrin, radixin, moesin) proteins is required for the delivery of EGF receptor (EGFR) to lysosomes. Inhibiting either ERM proteins or the HOPS complex leads to the accumulation of the EGFR into early endosomes, delaying its degradation.	SIGNOR-261312
Q9BW92	Q2TAL8	0	transcriptional regulation	up-regulates quantity by expression	0.2	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269407
P61586	Q9NZN5	0	guanine nucleotide exchange factor	up-regulates activity	0.905	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-260539
O15264	O00418	1	phosphorylation	down-regulates activity	0.578	eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta. eEF2K[S359A] was phosphorylated (presumably at Ser396) by the high concentrations of SAPK4/p38 used in this experiment. However, the inhibition of eEF2K under these conditions was reduced from 82% in the wild-type enzyme to 19% in eEF2K[S359A]	SIGNOR-250089
Q9Y5H7	P05556	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.	SIGNOR-265669
P13591	P39905	2	binding	up-regulates activity	0.7	Recently, NCAM was identified as an alternative receptor for GDNF. These new results may explain the findings that, in several regions, the GDNF receptor (GFRa1) is highly expressed, while RET is undetectable.	SIGNOR-252189
A6NFN3	O00712	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-268912
P49768	P55212	0	cleavage	up-regulates activity	0.372	Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis.	SIGNOR-261753
P48454	Q6VAB6	1	dephosphorylation	up-regulates activity	0.259	These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.\|the negative regulators 14-3-3	SIGNOR-248527
P32239	P08754	2	binding	up-regulates activity	0.267	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-257150
P39905	P13591	2	binding	up-regulates activity	0.7	Recently, NCAM was identified as an alternative receptor for GDNF. These new results may explain the findings that, in several regions, the GDNF receptor (GFRa1) is highly expressed, while RET is undetectable.	SIGNOR-252189
P24941	Q03112	1	phosphorylation	up-regulates activity	0.296	The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A.	SIGNOR-273426
Q05655	Q9BZK7	1	phosphorylation	up-regulates activity	0.2	In addition, we describe that the functions and the specificity of these two highly- related exchange factors is tightly regulated by signal-induced phosphorylation events at the level of target gene promoters, as exemplified by the role of TBLR1 phosphorylation at Ser 123 by PKCδ upon retinoic acid or estrogen stimulation.	SIGNOR-260903
Q92985	P51617	0	phosphorylation	up-regulates activity	0.792	These data indicate that IRAK-1, but not IRAK-4, phosphorylates IRF7 in vitro.	SIGNOR-278235
Q9Y478	P29474	1	phosphorylation	up-regulates	0.2	Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no.	SIGNOR-112367
P14210	O15393	0	transcriptional regulation	up-regulates quantity by expression	0.2	we identified pro-hepatocyte growth factor (HGF) as a TMPRSS2 substrate and confirmed that HGF and it’s cognate receptor c-Met are activated in prostate cancers expressing TMPRSS2, a finding that also associated with the acquisition of a pro-invasive mesenchymal gene expression program.	SIGNOR-263657
Q03113	P30872	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-256958
P04637	Q9NQ88	1	transcriptional regulation	up-regulates quantity by expression	0.2	TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. TIGAR is the only known phosphatase glycolytic modulator regulated by TP53. The current study delineates the role of TIGAR in OXPHOS and glycolytic metabolic reprogramming in breast cancer.	SIGNOR-267365

Q16566

P09429

1

phosphorylation

up-regulates activity

0.285

Collectively, our results demonstrate that CaMKIV promotes the nucleocytoplasmic shuttling of HMGB1 and suggest that the process may be mediated through CaMKIV-dependent serine phosphorylation of HMGB1.

SIGNOR-278510

Q8N5S9

Q13131

1

phosphorylation

up-regulates

0.462

Ampka1 activators increased phosphorylation level and cytoplasmic localization (reduced nuclear/cytoplasmic ratio). Ampka1 activators reduced rna synthesis in the nucleoli.

SIGNOR-176598

O00206

P05109

2

binding

down-regulates activity

0.534

Interestingly, in the present study, we report that extracellular S100A9 induces terminal differentiation of myeloid leukemia cells in human and murine AMLs after TLR4 activation, which is highly expressed by primary myelomonocytic and monocytic leukemia cells. In contrast, anti-S100A8 induced the differentiation of AML cells, suggesting that the differentiation-promoting effect of S100A9 is inhibited by S100A8. ) S100A8 could bind to TLR4 and activate different signaling pathways, leading to the inhibition of cellular differentiation induced by S100A9.

SIGNOR-261921

Q9UBL3

P23771

2

binding

up-regulates

0.25

We identifiedgata3as the binding protein of ash2l. Ash2l was shown to potentiate the transcriptional activity ofgata3.

SIGNOR-205312

P40763

P00533

0

phosphorylation

up-regulates activity

0.879

The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation.

SIGNOR-121965

Q15596

P10275

2

binding

up-regulates activity

0.901

The NCOA2 gene encodes a transcriptional coactivator (SRC-2) that modulates gene expression by hormone receptors, including AR. NCOA2 is both amplified and rarely mutated in prostate cancers, with higher NCOA2 levels resulting in increased androgen signaling readout. Furthermore, as mentioned previously, SRC-3, a close homolog encoded by NCOA3, is a substrate of SPOP whose protein levels are increased by SPOP mutation, potentially linking these common point mutations to the androgen axis

SIGNOR-251531

Q05397

Q06124

0

dephosphorylation

down-regulates

0.731

Dca concomitantly and significantly increased association of tyrosine phosphatase shp2 with fak. Incubation of immunoprecipitated fak, in vitro, with glutathione-s-transferase-shp2 fusion protein resulted in tyrosine dephosphorylation of fak in a concentration-dependent manner.

SIGNOR-148926

O14511

P21860

2

binding

up-regulates

0.82

Direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3.The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4

SIGNOR-26881

Q8NBZ7

P29320

0

phosphorylation

up-regulates activity

0.2

However, it is possible that etk is a principal activator of Ugd.|The phosphorylation of the Ugd protein (a UDP-glucose dehydrogenase) by Etk increases Ugd dehydrogenase activity.

SIGNOR-280006

Q96EV8

Q86Y07

0

phosphorylation

down-regulates quantity by destabilization

0.2

We show that VRK2 phosphorylates Ser 297 and Ser 299 of dysbindin using in vitro kinase assay. In addition, we found that VRK2-mediated phosphorylation of dysbindin enhanced ubiquitination of dysbindin and consequently resulted in the decrease in its protein stability through western blotting.

SIGNOR-277403

O14640

O75581

2

binding

up-regulates activity

0.707

The scaffold protein dishevelled (dvl) is required for lrp6 phosphorylation and aggregation. We propose that wnts induce coclustering of receptors and dvl in lrp6-signalosomes, which in turn triggers lrp6 phosphorylation to promote axin recruitment and beta-catenin stabilization.

SIGNOR-156072

P24941

O75469

1

phosphorylation

down-regulates quantity by destabilization

0.372

PXR Phosphorylation at S350 by CDK2 Triggers PXR Degradation via the Ubiquitin-Proteasome Pathway.

SIGNOR-279397

Q13131

P17612

0

phosphorylation

down-regulates activity

0.423

These agents also enhanced phosphorylation of alpha-Ser(485/491) by the cAMP-dependent protein kinase. AMPK alpha-Ser(485/491) phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine.

SIGNOR-256112

P46734

Q9UL54

2

binding

up-regulates activity

0.67

Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7.

SIGNOR-70947

P14784

P29350

0

dephosphorylation

down-regulates

0.532

We have found that il-2 induces association of shp-1 with the il-2 receptor complex, and that once shp-1 is recruited to the activated receptor it is able to decrease tyrosine phosphorylation of il-2rbeta and the associated tyrosine kinases jak1 and jak3.

SIGNOR-55989

P24385

O15379

2

binding

up-regulates

0.412

Collectively, these studies suggest an important role of cyclin d1 in regulation of ppargamma-mediated adipocyte differentiation through recruitment of hdacs to regulate ppar response element local chromatin structure and ppargamma function.

SIGNOR-134056

P78368

P07948

1

phosphorylation

up-regulates quantity by stabilization

0.2

Although there have been more than 40 reports of mass spectrometric studies on phosphorylation at Lyn-S13, the kinase responsible remained unclear. We succeeded in identifying casein kinase 1γ (CK1γ) as the kinase responsible for phosphorylation of Lyn-S13. In HEK293 cells co-expressing Lyn and CK1γ, the phosphorylation level of Lyn-S13 increased significantly. we concluded that S-palmitoylated CK1γ encounters N-myristoylated Lyn and specifically phosphorylates the Ser-13 residue at the Golgi during intracellular protein traffic, as shown schematically in Fig. 8. Phosphorylated dual-lipid-modified Lyn and S-palmitoylated CK1γ are then transported from the Golgi to the plasma membrane.

SIGNOR-275397

P63000

Q96Q42

2

binding

up-regulates activity

0.532

Thus, in our system, activeRac1 may recruit ALS2 only at the very early stage ofmacropinocytosis including membrane rufﬂes, suggest-ing that ALS2 is retained by some other mechanismsuntil Rab conversion.

SIGNOR-277777

Q13535

Q14191

1

phosphorylation

down-regulates quantity

0.794

Importantly, ATR-mediated phosphorylation targets Werner syndrome protein for ubiquitination and degradation.|WRN is phosphorylated at serine 1141 by ATR in response to replication-associated DSBs A. WRN is heavily phosphorylated at S1141 in response to CPT treatment of cells.

SIGNOR-278159

P12830

P53350

0

phosphorylation

down-regulates quantity by destabilization

0.297

Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP

SIGNOR-274054

P0C5Z0

Q14493

0

translation regulation

up-regulates quantity by expression

0.2

Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.

SIGNOR-265407

P28482

Q17RY0

1

phosphorylation

up-regulates activity

0.325

Our results indicate that CPEB4 activation is driven by ERK2- and Cdk1 mediated hyperphosphorylation of at least 12 residues in the intrinsically disordered NTD.|We concluded that, in interphase, unphosphorylated CPEB4 phase separates into liquid like droplets that recruit mRNAs but are inactive for cytoplasmic polyadenylation and translation, whereas in M-phase, CPEB4 is phosphorylated by ERK2 and Cdk1 and recovers its monomeric form, which can drive the cytoplasmic polyadenylation of target mRNAs.

SIGNOR-280021

P68400

Q13530

1

phosphorylation

up-regulates activity

0.2

The two serines within the PSAC of Serinc3 are phosphorylated by casein kinase II and mediate interaction with the μ subunits in vitro.

SIGNOR-273631

O14746

Q9NY12

2

binding

up-regulates activity

0.445

A complex of four proteins (GAR1, NHP2, NOP10, and the putative pseudouridine synthase dyskerin) associates with snoRNAs to form small nucleolar ribonucleoprotein particles (snoRNPs), and the binding of this complex to the H/ACA domain of TERC may have a role in the biogenesis of the telomerase RNP

SIGNOR-263333

P46531

O60684

0

relocalization

up-regulates

0.2

Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. importins alpha3, alpha4 (and to a lesser extent, alpha7) mediate nuclear import of nicd and thus are directly involved in notch signaling.

SIGNOR-165343

P07737

Q13464

0

phosphorylation

down-regulates

0.272

We previously identified pfn1 as a huntingtin aggregation inhibitor, and others have implicated it as a tumor-suppressor. Rho-associated kinase (rock) directly phosphorylates pfn1 at ser-137 to prevent its binding to polyproline sequences. This negatively regulates its anti-aggregation activity.

SIGNOR-196820

O14874

P53396

1

phosphorylation

up-regulates activity

0.2

BCKDK can activate ACLY and promote the cleavage of citric acid into acetyl-CoA, and oxaloacetate.|BCKDK can phosphorylate BCKDHA and ATP citrate lyase (ACLY), exerting opposing effects on both.

SIGNOR-280194

P30304

O14757

0

phosphorylation

down-regulates

0.857

The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216).

SIGNOR-163134

P04049

P67775

0

dephosphorylation

up-regulates

0.592

Both pp2a holoenzymes were found to associate with raf1 and catalyze dephosphorylation of inhibitory phospho-ser-259. Together these findings indicate that pp2a abalphac and abdeltac holoenzymes function as positive regulators of raf1-mek1/2-erk1/2 signaling by targeting raf1.

SIGNOR-141170

P36897

O43541

2

binding

down-regulates activity

0.74

The inhibitory Smads (I-Smads), i.e. Smad6 and Smad7, are negative regulators of transforming growth factor-_ (TGF-_) family signaling. I-Smads inhibit TGF-_ family signaling principally through physical interaction with type I receptors (activin receptor-like kinases), so as to compete with receptor-regulated Smads (R-Smads) for activation.

SIGNOR-167160

Q99856

P0DOX6

1

transcriptional regulation

up-regulates quantity by expression

0.2

In this work, we show that TFII-I directly interacts with human Bright through amino acids in Bright's protein interaction domain and that specific tyrosine residues of TFII-I are essential for Bright-induced activity of an immunoglobulin reporter gene. Moreover, inhibition of TFII-I function in a B-cell line resulted in decreased heavy-chain transcript levels.| Figure 3 shows that both anti-Bright and anti-TFII-I precipitated the bf150 Bright binding site from the B-cell line but not from a T-cell line that contains but does not express the V1 gene.

SIGNOR-268532

P62714

Q05655

1

dephosphorylation

down-regulates activity

0.3

PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex

SIGNOR-248595

Q15643

P61019

2

binding

up-regulates activity

0.394

Vesicle-associated Rab2 then mediates attachment to the Rab2 binding site within the central coiled-coil region of GMAP-210, bringing the vesicle into closer proximity to the target membrane. GMAP-210 function in vivo is dependent upon its ability to tether membranes, which is mediated exclusively by the amino-terminal ALPS motif. Binding to Rab2 is also important for GMAP-210 function, although it is dispensable for tethering per se.

SIGNOR-261300

P28482

Q9BY84

1

phosphorylation

up-regulates quantity by stabilization

0.808

Phosphorylation of Ser-446 determines stability of MKP-7.|We also determined that MKP-7 phosphorylated at Ser-446 has a longer half-life than unphosphorylated form of the wild type protein, as does a phospho-mimic mutant of MKP-7. These results indicate that activation of the ERK pathway strongly blocks JNK activation through stabilization of MKP-7 mediated by phosphorylation.

SIGNOR-249389

Q13131

P98177

1

phosphorylation

up-regulates

0.371

The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt phosphorylation sites, resulting in foxo activation

SIGNOR-157947

P25098

Q14940

1

phosphorylation

down-regulates activity

0.2

Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2.

SIGNOR-275503

Q9UQD0

Q13555

0

phosphorylation

up-regulates activity

0.271

CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel.

SIGNOR-275794

O00192

P19022

2

binding

up-regulates quantity by stabilization

0.466

To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member.

SIGNOR-252128

P21802

2

phosphorylation

up-regulates activity

0.2

Our data also show that tyrosine 769 is not involved in the regulation of the endocytic process of KGFR.Following ligand binding, KGFR is rapidly autophosphorylated on specific tyrosine residues

SIGNOR-276026

P18031

P29597

1

dephosphorylation

down-regulates activity

0.646

Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5.

SIGNOR-134564

O00213

P00519

0

phosphorylation

up-regulates

0.415

The c-abl tyrosine kinase phosphorylates the fe65 adaptor protein to stimulate fe65/amyloid precursor protein nuclear signaling. Here, we show that active c-abl stimulates app/fe65-mediated gene transcription and that this effect is mediated by phosphorylation of fe65 on tyrosine 547 within its second ptb domain.

SIGNOR-123476

O15194

P06400

1

dephosphorylation

up-regulates activity

0.298

ppRB (RB phosphorylated at Ser-807/811|Possible Mechanisms of HYA22 Action in Tumorigenesis: Dephosphorylation of RB by Transient Expression of HYA22 Isoforms.

SIGNOR-248304

P38405

Q08828

2

binding

up-regulates activity

0.539

D1-class dopamine receptors (D1 and D5) activate the G s/olf family of G proteins to stimulate cAMP produc tion by AC and are found exclusively postsynaptically on dopamine-receptive cells, such as GABA-ergic medium spiny neurons (MSNs) in the striatum.

SIGNOR-264992

P52797

P29322

2

binding

up-regulates

0.75

Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor

SIGNOR-52387

P28062

Q07820

1

null

down-regulates quantity by destabilization

0.2

Surprisingly, siRNA knockdown of PSMB8 (LMP7), an ‘immunoproteasome’ component, reversed IFNγ-induced sensitivity to Fas ligation and prevented Fas/IFNγ-induced degradation of Mcl-1, but did not protect p-Bcl-2 or p-Bcl-XL. Proteasome inhibition markedly increased Mcl-1, p-Bcl-2, and p-Bcl-XL levels after IFNγ treatment

SIGNOR-261974

P35221

Q06124

0

dephosphorylation

down-regulates

0.435

Tyr148 of beta-catenin is an shp2 target dephosphorylation site. Together, these results suggest that beta-catenin plays a suppressor role in cell transformation and that shp2, by dephosphorylating beta-catenin, promotes mitogenic, cell survival and transformation signals.

SIGNOR-147075

P61981

Q9NRM7

0

phosphorylation

up-regulates

0.331

Phosphorylation of 14-3-3_ on s59 by lats2. Ser(58) phosphorylation and lys(49) acetylation of 14-3-3_ occur in a coordinated time-dependent manner to regulate 14-3-3_ homodimerization. 14-3-3_ ser(58) phosphorylation is required for star interactions under control conditions,

SIGNOR-205247

P46060

P06493

0

phosphorylation

up-regulates

0.495

Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis . Alternatively, phosphorylated rangap1 may recruit specific sumo target proteins to ranbp2's catalytic domain.

SIGNOR-123520

Q8WYK2

P15336

2

binding

down-regulates activity

0.557

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-226395

Q99558

P40763

1

phosphorylation

up-regulates activity

0.26

Activation of Stat3 by NIK requires NIK kinase activity as showed by kinase assays.|When we transfected NIK into LNCaP cells, NIK was able to phosphorylate Stat3 at both tyrosine 705 and serine 727 residues ( Fig. 3 A).

SIGNOR-279341

O95180

Q9UQM7

0

phosphorylation

down-regulates activity

0.272

we also discovered that a novel CaMKII-phosphorylated site, S2137, underwent dephosphorylation by calcineurin.

SIGNOR-277871

P40763

Q06187

0

phosphorylation

down-regulates activity

0.382

Phosphorylation of STAT-3 by BTK may also alter the conformation of STAT-3 in such a way as to make it inaccessible as a substrate of activating kinases such as JAK3.|The ability of BTK to negatively regulate STAT-3 activity suggests several possible models for a mechanism of BTK action.

SIGNOR-279011

P50222

O60315

0

transcriptional regulation

down-regulates quantity by repression

0.318

ZEB2 represses GAX transcription through multiple up- stream consensus binding sites.

SIGNOR-268951

P14618

Q00534

0

phosphorylation

down-regulates activity

0.259

Here, using human cancer cells and patient-derived xenografts in mice, we show that the cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2.

SIGNOR-279158

P46531

O00629

0

relocalization

up-regulates

0.287

Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7.

SIGNOR-165314

O00308

O15350

1

polyubiquitination

down-regulates quantity by destabilization

0.283

WWP2 ubiquitinates p73 and controls its protein stability. In our study, we identified WWP2, an E3 ligase, as a novel p73-associated protein that ubiquitinates and degrades p73. In contrast, WWP2 heterodimerizes with another E3 ligase, WWP1, which specifically ubiquitinates and degrades ΔNp73.

SIGNOR-272233

Q04721

Q92585

2

binding

up-regulates

0.808

Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes1.

SIGNOR-84835

Q9NQ66

P29992

2

binding

up-regulates

0.623

Plc-_1 stimulates hydrolysis of gq/11-bound gtp and acts as a gtpase-activating protein (gap) for its physiologic regulator, gq/11

SIGNOR-17239

P31749

P46527

1

phosphorylation

down-regulates

0.85

Because Thr198-phosphorylated p27Kip1 was localized only in the cytoplasm, Akt might promote 14-3-3 binding to p27Kip1 by phosphorylation at Thr198, allowing its cytoplasmic localization and degradation.

SIGNOR-88294

P01375

O75509

2

binding

up-regulates

0.337

We report the identification and initial characterization of dr6, a new member of the tnf receptor family possessing a cytoplasmic death domain.

SIGNOR-59745

Q92905

Q9NZQ7

1

deubiquitination

up-regulates quantity by stabilization

0.2

The results suggested that TNF-α upregulates expression of CSN5, which interacts and deubiquitinates PD-L1 for protein stabilization.

SIGNOR-274977

O15297

Q9NR19

0

transcriptional regulation

up-regulates quantity by expression

0.2

As expected, we found that glucose deprivation induced the binding of TFEB (Figure S4C) and ACSS2 (Figure S4D) to the promoter regions of MAP1LC3B, ATG3, and WIPI-1 as well as mRNA (Figure 3H) and protein (Figure 3I) expression of these genes;

SIGNOR-276560

Q9HAZ2

P12755

2

binding

up-regulates

0.326

Biochemical analysis demonstrated that mel1 interacts with ski and inhibits tgf-_ signaling by stabilizing the inactive smad3-ski complex on the promoter of tgf-_ target genes.

SIGNOR-182529

P23470

P09619

1

dephosphorylation

down-regulates activity

0.338

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-254715

P46934

Q00987

1

ubiquitination

up-regulates quantity by stabilization

0.466

NEDD4 promotes MDM2 ubiquitination in a dose- and time-dependent manner, whereas depletion of NEDD4 reduced the half-life of endogenous MDM2 [ xref ].

SIGNOR-278769

P53350

O43474

1

phosphorylation

up-regulates quantity by stabilization

0.249

We further found that inhibition of polo-like kinase 1 could downregulate the expression of KLF4 and that PLK1 directly phosphorylated KLF4 at Ser234. Notably, phosphorylation of KLF4 by PLK1 caused the recruitment and binding of the E3 ligase TRAF6, which resulted in KLF4 K32 K63-linked ubiquitination and stabilization.

SIGNOR-277463

O75581

O14904

2

binding

up-regulates

0.64

Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.

SIGNOR-132076

P04233

P61073

2

binding

up-regulates

0.531

Cd74 forms functional complexes with cxcr4 that mediate mif-specific signaling.

SIGNOR-187461

P17252

P05204

1

phosphorylation

down-regulates

0.29

Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools.

SIGNOR-76320

Q9HBH9

P27361

0

phosphorylation

up-regulates

0.517

Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity.

SIGNOR-48355

P49840

P10636

1

phosphorylation

down-regulates

0.429

Tau is phosphorylated by gsk-3 at several sites found in alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by a-kinase.

SIGNOR-60651

P53667

O14965

2

phosphorylation

up-regulates activity

0.262

Here, we report a novel functional cooperativity between Aur-A and LIMK1 through mutual phosphorylation. LIMK1 is recruited to the centrosomes during early prophase and then to the spindle poles, where it colocalizes with Aur-A. Aur-A physically associates with LIMK1 and activates it through phosphorylation, which is important for its centrosomal and spindle pole localization. Aur-A also acts as a substrate of LIMK1, and the function of LIMK1 is important for its specific localization and regulation of spindle morphology.

SIGNOR-276400

P06241

Q14524

1

phosphorylation

down-regulates

0.293

This study addresses the effects of the src family tyrosine kinase fyn on na(v)1.5 cardiac sodium channels. Sodium currents were acquired by whole cell recording on hek-293 cells transiently expressing na(v)1.5. Acute treatment of cells with insulin caused a depolarizing shift in steady-state inactivation, an effect eliminated by the src-specific tyrosine kinase inhibitor pp2 we provide evidence that this linker is a substrate for fyn in vitro, and that y1495 is a preferred phosphorylation site.

SIGNOR-135600

A7MCY6

Q9BWT7

1

relocalization

up-regulates activity

0.2

TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation

SIGNOR-272470

Q15722

P09471

2

binding

up-regulates activity

0.265

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-256970

P00533

P22681

2

relocalization

up-regulates

0.886

Likewise, cbl is recruited to erbb1 either directly (tyr1045), or indirectly, trough grb2

SIGNOR-147826

Q06124

P01111

1

dephosphorylation

up-regulates activity

0.673

Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling.

SIGNOR-255754

P78527

Q13535

0

phosphorylation

up-regulates

0.31

Finally, in vitro atr-mediated phosphorylation at the t2609 cluster was further confirmed by western blot analysis using phosphospecific antibodies against t2647 (fig. ?(Fig.7e),7e), suggesting that dna-pkcs could be the direct target of atr kinase.

SIGNOR-148722

Q13233

O14920

1

phosphorylation

up-regulates activity

0.595

These results suggested that IKK\u03b2 was a likely substrate for MEKK1 and that MEKK1 phosphorylation of IKK\u03b2 increased its kinase activity.

SIGNOR-279339

P09429

P31277

2

binding

up-regulates activity

0.292

We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein.

SIGNOR-240559

P35226

Q14157

2

binding

up-regulates activity

0.514

We identified UBAP2L as a novel BMI1-interacting protein. UBAP2L, BMI1, RNF2, and PHC1 define a novel Polycomb subcomplex

SIGNOR-261315

Q9BRS8

P42345

0

phosphorylation

up-regulates activity

0.2

Binding of La ribonucleoprotein domain family, member 6 (LARP6) to collagen mRNAs regulates their translation and is necessary for high type I collagen expression. Here we show that mTORC1 phosphorylates LARP6 on S348 and S409. The S348A/S409A mutant of LARP6 acts as a dominant negative protein in collagen biosynthesis, which retards secretion of type I collagen and causes excessive posttranslational modifications.

SIGNOR-273679

P35241

Q9H270

2

binding

up-regulates activity

0.347

Vps11 was found to interact with radixin. ERM proteins and the HOPS complex are required for the transition from early to late endosomes. We report that an interaction between subunits of the HOPS complex and the ERM (ezrin, radixin, moesin) proteins is required for the delivery of EGF receptor (EGFR) to lysosomes. Inhibiting either ERM proteins or the HOPS complex leads to the accumulation of the EGFR into early endosomes, delaying its degradation.

SIGNOR-261312

Q9BW92

Q2TAL8

0

transcriptional regulation

up-regulates quantity by expression

0.2

QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.

SIGNOR-269407

P61586

Q9NZN5

0

guanine nucleotide exchange factor

up-regulates activity

0.905

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-260539

O15264

O00418

1

phosphorylation

down-regulates activity

0.578

eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta. eEF2K[S359A] was phosphorylated (presumably at Ser396) by the high concentrations of SAPK4/p38 used in this experiment. However, the inhibition of eEF2K under these conditions was reduced from 82% in the wild-type enzyme to 19% in eEF2K[S359A]

SIGNOR-250089

Q9Y5H7

P05556

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.

SIGNOR-265669

P13591

P39905

2

binding

up-regulates activity

0.7

Recently, NCAM was identified as an alternative receptor for GDNF. These new results may explain the findings that, in several regions, the GDNF receptor (GFRa1) is highly expressed, while RET is undetectable.

SIGNOR-252189

A6NFN3

O00712

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-268912

P49768

P55212

0

cleavage

up-regulates activity

0.372

Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis.

SIGNOR-261753

P48454

Q6VAB6

1

dephosphorylation

up-regulates activity

0.259

These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3

SIGNOR-248527

P32239

P08754

2

binding

up-regulates activity

0.267

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-257150

P39905

P13591

2

binding

up-regulates activity

0.7

Recently, NCAM was identified as an alternative receptor for GDNF. These new results may explain the findings that, in several regions, the GDNF receptor (GFRa1) is highly expressed, while RET is undetectable.

SIGNOR-252189

P24941

Q03112

1

phosphorylation

up-regulates activity

0.296

The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A.

SIGNOR-273426

Q05655

Q9BZK7

1

phosphorylation

up-regulates activity

0.2

In addition, we describe that the functions and the specificity of these two highly- related exchange factors is tightly regulated by signal-induced phosphorylation events at the level of target gene promoters, as exemplified by the role of TBLR1 phosphorylation at Ser 123 by PKCδ upon retinoic acid or estrogen stimulation.

SIGNOR-260903

Q92985

P51617

0

phosphorylation

up-regulates activity

0.792

These data indicate that IRAK-1, but not IRAK-4, phosphorylates IRF7 in vitro.

SIGNOR-278235

Q9Y478

P29474

1

phosphorylation

up-regulates

0.2

Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no.

SIGNOR-112367

P14210

O15393

0

transcriptional regulation

up-regulates quantity by expression

0.2

we identified pro-hepatocyte growth factor (HGF) as a TMPRSS2 substrate and confirmed that HGF and it’s cognate receptor c-Met are activated in prostate cancers expressing TMPRSS2, a finding that also associated with the acquisition of a pro-invasive mesenchymal gene expression program.

SIGNOR-263657

Q03113

P30872

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-256958

P04637

Q9NQ88

1

transcriptional regulation

up-regulates quantity by expression

0.2

TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. TIGAR is the only known phosphatase glycolytic modulator regulated by TP53. The current study delineates the role of TIGAR in OXPHOS and glycolytic metabolic reprogramming in breast cancer.

SIGNOR-267365