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
Q9P126	P63244	2	binding	down-regulates quantity by destabilization	0.2	In this study, we reported that RACK1, the receptor for activated C-kinase 1, associated with the cytoplasmic tail of CLEC-2. Moreover, overexpression of RACK1 decreased the stability of CLEC-2 through promoting its ubiquitin-proteasome degradation, without impairing surface expression and downstream signaling of CLEC-2. Taken together, these results suggest RACK1 as a novel modulator of CLEC-2 expression.Previous reports indicated that RACK1 mediated ubiquitin–proteasome degradation of HIF-1a and BimEL by recruiting Elongin-C/B ubiquitin ligase complex	SIGNOR-272781
P07900	P16591	1	phosphorylation	down-regulates activity	0.3	Hsp90 and tyrosine616 are required for Fer tyrosine kinase activity.Taken together, our findings underscore the importance of Hsp90 and the residue, tyrosine616, which resides in the Hsp90 recognition loop, in maintaining Fer tyrosine kinase activity.	SIGNOR-277818
Q13541	Q14004	0	phosphorylation	up-regulates activity	0.2	CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation.	SIGNOR-273113
P24468	P19793	2	binding	up-regulates	0.281	Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site	SIGNOR-79446
P46094	P47992	2	binding	up-regulates	0.787	Scm-1 showed a high-affinity binding to xcr1 with a kd of 10 nm and induced vigorous chemotaxis and calcium mobilization in xcr1-transfected murine l1.2 cells.	SIGNOR-71164
P45984	P63104	1	phosphorylation	down-regulates	0.2	Jnk phosphorylates 14-3-3zetaat ser-184 and 14-3-3sigmaat ser-188	SIGNOR-124031
P24941	Q07817	1	phosphorylation	up-regulates activity	0.496	Our findings show that Cdk2 phosphorylation of Bcl-xL at Ser73, but not the Bcl-xL cleavage products, is necessary and sufficient to induce cell death.	SIGNOR-278242
Q13535	P09874	1	phosphorylation	down-regulates	0.357	Specifically, ATR binds to and phosphorylates PARP1 at Ser179 after the ionophore treatments.\|These data suggest that the phosphorylation of S179 is necessary and sufficient for ATR inhibition of PARP1 PARylation activity.	SIGNOR-278506
P49639	P55347	2	binding	up-regulates activity	0.588	Our results are consistent with a primary interaction of the YPWM motif of HOXA1 with the homeodomain of PBX. HOX proteins are dependent upon cofactors of the PBX family for specificity of DNA binding.	SIGNOR-220242
P36956	O75874	1	transcriptional regulation	up-regulates quantity by expression	0.282	IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells\|evidence that IDH1 may regulate lipogenesis in hepatic cells	SIGNOR-253132
P13349	P19784	0	phosphorylation	up-regulates activity	0.307	Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity.	SIGNOR-251016
P15407	Q04759	0	phosphorylation	up-regulates activity	0.2	PKCθ-induced phosphorylations, in part at T217 and T227 residues, strongly and specifically increased Fra-1 transcriptional activity through the stimulation of Fra-1 transactivation domain, without affecting JUN factors.	SIGNOR-260879
Q9UM73	P19174	2	binding	up-regulates	0.546	Proteins that interact with alk tyrosine kinase play important roles in mediating downstream cellular signals. Previously reported proteins in the alk signal pathway were identified including pi3-k, jak2, jak3, stat3, grb2, irs, and plcgamma1.	SIGNOR-122082
O75460	Q5VWQ8	2	binding	up-regulates activity	0.382	DAB2IP binds IRE1α, and was shown to be required for activation of this signaling cascade in endothelial cells. IRE1α can trigger pro-apoptotic JNK signaling through recruitment of the TRAF2–ASK1 complex. DAB2IP facilitates IRE1α activation, and participates in a signaling complex required to induce TRAF2-dependent ASK1 activation and JNK phosphorylation.	SIGNOR-254749
P56178	Q16539	0	phosphorylation	up-regulates activity	0.291	We show that Dlx5 is a novel substrate for p38 MAPK in vitro and in vivo and that Ser-34 and Ser-217 are the sites phosphorylated by p38	SIGNOR-255792
P04637	Q68DV7	0	ubiquitination	down-regulates quantity by destabilization	0.451	Moreover, RNF43 polyubiquitinates p53 which further leads to its destabilization resulting in a decrease in induction of the p53 apoptotic pathway, a hitherto unknown process targeted by NP for p53 stabilization and accumulation.	SIGNOR-278714
O00141	P42224	1	phosphorylation	up-regulates activity	0.252	Notably, A\u03b2-activated SGK1 or JAK2 kinase phosphorylates STAT1 and induces its association with Tau(1\u2013368).	SIGNOR-279281
P19793	P27361	0	phosphorylation	down-regulates activity	0.523	In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma\|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE	SIGNOR-88662
P45983	Q9H2B2	1	phosphorylation	up-regulates activity	0.411	JNK phosphorylates Syt 4 at Ser135 in vitro and in vivo.	SIGNOR-273673
P18075	Q04771	2	binding	up-regulates	0.807	Bmp-4 and gdf-5 are known to bind to activin receptor-like kinase 3 (alk-3) and/or alk-6 (also termed bmp type ia and type ib receptors, respectively), whereas bmp-6 and bmp-7 preferentially bind to alk-2	SIGNOR-236913
O14836	O75888	2	binding	up-regulates	0.71	Tumor necrosis factor (tnf) receptor superfamily member taci is a high affinity receptor for tnf family members april and blys.	SIGNOR-81308
Q8NES3	P46531	2	binding	up-regulates	0.757	We demonstrate that egf 12, a portion of the ligand-binding site, is modified with o-fucose and that this site is evolutionarily conserved. We also show that endogenous fringe proteins in chinese hamster ovary cells (lunatic fringe and radical fringe) as well as exogenous manic fringe modify o-fucose on many but not all egf repeats of mouse notch1.	SIGNOR-96537
Q14118	Q9HDB5	2	binding	up-regulates activity	0.2	The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM.	SIGNOR-265462
P84022	P35658	2	binding	up-regulates	0.55	We demonstrate that smad3 and smad4 are capable of interaction with the nucleoporin can/nup214, and this interaction is required for nuclear import.	SIGNOR-117644
P12830	O14757	0	phosphorylation	down-regulates activity	0.301	Phosphorylation of Cdh1 by Chk1 promotes recognition of Cdh1 by SCF betaTRCP1.\|These data suggest that Chk1 negatively regulates APC/C Cdh1 activity by both promoting Cdh1 destruction and by destabilizing its association with the APC/C.	SIGNOR-278396
O75385	P46937	1	phosphorylation	up-regulates quantity by stabilization	0.2	Mechanistically, hypoxia stimulates ULK1 to translocate into nucleus, where it interacts with and phosphorylates yes-associated protein (YAP) at Ser227, resulting in YAP stabilization through blockade of ubiquitin-proteasome system (UPS), which in turn facilitates PKM2 transcription, glycolysis, cell proliferation in vitro as well as PDAC growth in mice.	SIGNOR-277570
P19086	P21918	2	binding	up-regulates activity	0.404	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257311
P53355	Q9UN36	1	phosphorylation	up-regulates activity	0.273	DAPK1 phosphorylates and activates N-myc downstream-regulated gene 2 (NDRG2), resulting in increased tau phosphorylation via a reduction in Pin1 expression ( xref ; xref ).	SIGNOR-279983
Q9H2U1	Q99836	2	binding	up-regulates activity	0.524	We further showed that both DHX9 and DHX36 are localized within the cytosol and are directly bound to the Toll-interleukin receptor domain of MyD88 via their helicase-associated domain 2 and DUF domains. This study demonstrates that DHX9/DHX36 represent the MyD88-dependent DNA sensors in the cytosol of pDCs and suggests a much broader role for DHX helicases in viral sensing.	SIGNOR-260956
Q06124	P23458	0	phosphorylation	up-regulates activity	0.768	Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2	SIGNOR-236274
P24530	P38405	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-256924
P17706	P23458	1	dephosphorylation	down-regulates activity	0.767	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-134620
Q12986	O14746	1	transcriptional regulation	up-regulates quantity by expression	0.52	NFX1-123 positively regulated hTERT expression, as its knockdown decreased hTERT mRNA levels and telomerase activity and its overexpression increased telomerase activity. NFX1-123 was found to interact with cytoplasmic poly(A) binding proteins (PABPCs), and together they synergistically augmented expression from the hTERT promoter when activated by HPV16 E6.	SIGNOR-261050
P60953	Q9UQB8	2	binding	up-regulates activity	0.863	We conclude that the interaction of Cdc42 with the partial CRIB motif of IRSp53 relieves an intramolecular, autoinhibitory interaction with the N terminus, allowing the recruitment of Mena to the IRSp53 SH3 domain. This IRSp53:Mena complex initiates actin filament assembly into filopodia.	SIGNOR-268424
Q8TCY5	Q01726	2	binding	down-regulates activity	0.349	We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members.	SIGNOR-252364
P24385	Q8IYU2	0	ubiquitination	down-regulates quantity by destabilization	0.307	Mechanistically, the tumor-suppressor function of HACE1 is dependent on its E3 ligase activity and HACE1 controls adhesion-dependent growth and cell cycle progression during cell stress through degradation of cyclin D1.	SIGNOR-271405
Q92997	Q9Y608	2	binding	up-regulates	0.387	In particular, a previously unrecognized activator, lrrfip2 (leucine-rich repeat in flightless interaction protein 2), was found that interacts with dvl to increase the cellular levels of _-catenin and activate _-catenin/lef/tcf-dependent transcriptional activity	SIGNOR-133429
P51636	P12931	0	phosphorylation	down-regulates	0.676	Here, we show that cav-2 is phosphorylated at both tyrosines 19 and 27. We reconstituted this phosphorylation event by recombinantly coexpressing c-src and cav-2.Further functional analysis revealed that tyrosine phosphorylation of cav-2 has no effect on its targeting to lipid rafts, but clearly disrupts the hetero-oligomerization of cav-2 with cav-1.	SIGNOR-129961
P50613	P04637	1	phosphorylation	up-regulates	0.458	The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro. serines 371, 376, 378, and 392 may be the potential sites for this kinase.	SIGNOR-51292
Q9UK17	P09769	0	phosphorylation	up-regulates activity	0.2	These results indicate that Y108 (for Src-family kinases) and Y136 (for EGFR kinase) are involved in the tyrosine phosphorylation of hKv4.3 channels.	SIGNOR-276394
Q14524	Q9UQM7	0	phosphorylation	up-regulates activity	0.398	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate‚Äìactivated protein kinase (AMPK)‚Äìdependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).\|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. \| Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275772
P19174	P04629	0	phosphorylation	up-regulates	0.652	The nerve growth factor (ngf) receptor/trk associated with and phosphorylated phospholipase c gamma (plc gamma)	SIGNOR-38538
P18089	Q03113	2	binding	up-regulates activity	0.373	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-257201
P20226	P36508	2	binding	down-regulates activity	0.399	We identified ZNF76 as a novel transcriptional repressor that targets TBP. ZNF76 interacts with TBP through both its N and C termini. ZNF76 targets TBP for transcriptional repression.	SIGNOR-224650
Q9HAU4	Q15796	2	ubiquitination	down-regulates activity	0.778	The ability of smurf2 to promote smad2 destruction required the hect catalytic activity of smurf2 and depended on the proteasome-dependent pathway.	SIGNOR-236133
P30550	P04054	2	binding	up-regulates	0.255	Grpr stimulation activates phospholipase a2 (pla2) and cyclooxygenase 2 (cox2), which leads to prostaglandin e2 (pge2) production and ep receptor stimulation.	SIGNOR-152756
Q15599	P10398	0	phosphorylation	up-regulates activity	0.375	We also identify A-Raf as a kinase necessary for E3KARP phosphorylation at the G2/M stage of the cell cycle. Phosphorylation of Ser-303 regulates the localization, function, and dynamics of E3KARP	SIGNOR-273503
P43629	P05129	0	phosphorylation	down-regulates	0.2	Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover.	SIGNOR-158133
Q00341	P49711	2	binding	up-regulates activity	0.481	Vigilin interacts with CCCTC-binding factor (CTCF) and is involved in CTCF-dependent regulation of the imprinted genes Igf2 and H19. vigilin is present at several known CTCF target sites, such as the promoter regions of c-myc and BRCA1, the locus control region of β-globin, and several regions within the Igf2/H19 locus. These results reveal the functional relevance of vigilin and CTCF, and show that the CTCF-vigilin complex contributes to regulation of Igf2/H19.	SIGNOR-266693
P20290	Q86VG3	2	binding	down-regulates activity	0.2	Furthermore, we co-immunoprecipitated HEPIS with BTF3, a component of the RNA pol II initiation complex, and observed reduced proliferation of HeLa cells transfected with the HEPIS gene.	SIGNOR-260252
P67775	Q9BUB5	1	dephosphorylation	down-regulates	0.514	Moreover, a dephosphorylation assay revealed that pp2a could directly dephosphorylate mnk1 and eif4e.	SIGNOR-168314
P07949	P28482	1	phosphorylation	up-regulates	0.423	We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1).	SIGNOR-140294
P54764	O60674	1	phosphorylation	up-regulates activity	0.281	EphA4 phosphorylates JAK2.\|These findings suggest that EphA4 activates not only growth hormone receptor, as shown above, but also JAK2 by direct phosphorylation.	SIGNOR-279040
P29350	P00519	0	phosphorylation	up-regulates activity	0.414	The results demonstrate that the SH3 domain of ABL1 interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that ABL1 phosphorylates C terminal Y536 and Y564 sites.	SIGNOR-260820
P10916	Q5VT25	0	phosphorylation	up-regulates activity	0.65	These approximately 190-kDa myotonic dystrophy kinase-related Cdc42-binding kinases (MRCKs) preferentially phosphorylate nonmuscle myosin light chain at serine 19, which is known to be crucial for activating actin-myosin contractility.	SIGNOR-250723
Q07890	P62993	2	binding	up-regulates	0.88	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85.	SIGNOR-175180
Q96KB5	Q96EP1	0	polyubiquitination	down-regulates quantity by destabilization	0.346	CHFR ubiquitinates and degrades TOPK. Our in vivo ubiquitination assays revealed that the polyubiquitination of TOPK occurs only in the presence of full length CHFR but not with the ΔRING or Δcysteine-rich domain deletion mutants (Fig. 2a).	SIGNOR-271471
Q92819	Q14541	0	transcriptional regulation	up-regulates quantity by expression	0.337	Transcription was activated by HNF4G in reporter assays using the promoter/enhancer region of the HAS2 gene. The endogenous expression of the HAS2 gene was suppressed by knockdown of HNF4G.	SIGNOR-261626
Q14457	Q8NEB9	2	binding	up-regulates activity	0.936	The beclin 1-vps34 interaction regulates autophagy.	SIGNOR-184521
O75469	Q00535	0	phosphorylation	down-regulates activity	0.345	In vitro kinase assays showed that Cdk5 directly phosphorylates PXR.\|Taken together, these data indicate that Cdk5 negatively regulates PXR activity, and that inhibition of Cdk5 is at least partially responsible for flavonoids induced activation of PXR.	SIGNOR-279402
P49137	P42574	1	phosphorylation	up-regulates activity	0.311	MK2 Phosphorylates Caspase-3, Facilitates Nuclear Translocation of Caspase 3, and Regulates Apoptosis.\|Over-expression of MK2 led to an increase in nuclear caspase-3 activity.	SIGNOR-278960
P54727	P15927	2	binding	up-regulates activity	0.523	GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process\|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).\|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo	SIGNOR-275699
P35568	P62993	2	binding	up-regulates activity	0.803	Association ofinsulinreceptor substrate 1 (irs-1) y895 with grb-2 mediates theinsulinsignaling involved in irs-1-deficient brown adipocyte mitogenesis.	SIGNOR-236614
Q05655	Q9H257	1	phosphorylation	up-regulates activity	0.432	Here we demonstrated that protein kinase C-delta (PKCdelta) was activated upon Dectin-1-Syk signaling, mediated phosphorylation of Card9 at Thr231, and was responsible for Card9 and Bcl10 complex assembly and canonical NF-kappaB control.	SIGNOR-278383
O60674	P02647	1	null	up-regulates activity	0.298	ApoA-I interactions with ABCA1 and lipid efflux to apoA-I were substantially impaired by inhibiting or abolishing JAK2, whereas ABCA1 protein levels were unaffected, and ABCA1 cholesterol translocase activity was only slightly reduced. The most likely explanation for these findings is that JAK2 promotes apolipoprotein interactions with ABCA1 or a closely proximal site, and this facilitates the removal of cellular lipids. the interaction of apolipoproteins with ABCA1-expressing cells activates JAK2, which in turn activates a process that enhances apolipoprotein interactions with ABCA1 and lipid removal from cells	SIGNOR-252107
P62805	Q86Y97	0	methylation	down-regulates activity	0.2	SUV420H1 and SUV420H2 are two highly homologous enzymes that methylate lysine 20 of histone H4 (H4K20), a mark that has been implicated in transcriptional regulation.	SIGNOR-266650
P38936	Q9P1W9	0	phosphorylation	up-regulates quantity by stabilization	0.402	Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellsere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo	SIGNOR-164646
P41279	P19838	2	binding	down-regulates	0.688	Tpl-2 is stoichiometrically complexed with the nf-kb inhibitory protein, nf-kb1 p105, and the ubiquitin-binding protein abin-2, both of which are required to maintain tpl-2 protein stability. Binding to p105 also prevents tpl-2 from phosphorylating mek	SIGNOR-196747
P60953	O00401	2	binding	up-regulates activity	0.919	In the presence of Cdc42 and PI(4,5)P2, the potency of N-WASP was increased to a level approaching that of GST-VCA, suggesting that N-WASP was fully activated by the two molecules.	SIGNOR-261868
Q9UPN9	P35222	1	ubiquitination	down-regulates quantity by destabilization	0.457	TRIM33 ubiquitylates nuclear beta-catenin.\|Tumour suppressor TRIM33 targets nuclear beta-catenin degradation.	SIGNOR-278578
P31749	P04150	1	phosphorylation	down-regulates	0.486	Akt1 impairs glucocorticoid-induced gene expression by direct phosphorylation of nr3c1 at position s134 and blocking glucocorticoid-induced nr3c1 translocation to the nucleus	SIGNOR-252543
P28482	P49407	1	phosphorylation	down-regulates	0.727	Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation	SIGNOR-67630
Q16665	P09467	2	binding	down-regulates activity	0.326	FBP1, but not FBP2, suppresses HIF-1a activity by directly binding to its inhibitory domain.	SIGNOR-267590
P08754	P29371	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-257179
Q09472	Q13131	0	phosphorylation	down-regulates	0.376	The mechanism of ampk-mediated anti- inflammation involves the induction of p300 ser89 phosphor- ylation and subsequent inactivation of p300 hat activity.	SIGNOR-176637
P43403	P15941	1	phosphorylation	up-regulates activity	0.448	Indeed, the present results demonstrate that ZAP-70 phosphorylates MUC1-CD and that the MUC1-CD Y-20 site functions, at least in part, as a ZAP-70 substrate (Fig. 4C). In this regard, the in vivo phosphorylation data indicate that ZAP-70 may also contribute to phosphorylation of MUC1-CD Y-46.The results further show that ZAP-70 phosphorylation of MUC1-CD stimulates the interaction of MUC1 andBeta-catenin.	SIGNOR-247039
P27361	O75676	1	phosphorylation	up-regulates	0.586	Rsk-b is a p38alphamapk substrate, and activated by p38alphamapk and, more weakly, by erk1	SIGNOR-60998
Q03135	P43003	2	binding	down-regulates activity	0.2	EAAT3 has previously been shown to form complexes with caveolin-1, a major component of caveolae, which participate in the regulation of transport proteins. The present study explored the impact of caveolin-1 on electrogenic transport by excitatory amino acid transporter isoforms EAAT1-4. caveolin-1 is a powerful negative regulator of the excitatory glutamate transporters EAAT1, EAAT2, EAAT3, and EAAT4. Caveolin-1 has been shown to form complexes with the excitatory amino acid transporter EAAT3 (EAAC1) (Gonzalez et al. 2007) and may thus modify the EAAT isoforms by direct interaction with the carriers.	SIGNOR-264808
Q96SN8	Q9P209	0	relocalization	up-regulates activity	0.663	By bringing CDK5RAP2 to the centrosome, the centriolar satellite proteins CEP72 and SPAG5 are required for the centrosomal localization of the other three MCPH proteins despite not interacting with them biochemically.	SIGNOR-271720
Q9NYJ7	Q86YT6	0	ubiquitination	up-regulates activity	0.35	Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity.	SIGNOR-209672
Q9P107	P60953	1	gtpase-activating protein	down-regulates activity	0.512	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-260507
P28482	Q13285	1	phosphorylation	up-regulates activity	0.463	Here we show that maximal SF-1-mediated transcription and interaction with general nuclear receptor cofactors depends on phosphorylation of a single serine residue (Ser-203) located in a major activation domain (AF-1) of the protein. Moreover, phosphorylation-dependent SF-1 activation is likely mediated by the mitogen-activated protein kinase (MAPK) signaling pathway.	SIGNOR-249431
Q4KMG0	P00519	2	binding	up-regulates activity	0.518	Abl binds a proline-rich motif in cdo via its sh3 domain, and these regions of abl and cdo are required for their promyogenic effects. Cdo is important for full abl kinase activity	SIGNOR-185762
Q8WW12	Q96PU4	0	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
Q99717	P12755	2	binding	down-regulates	0.697	Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad6	SIGNOR-95468
P28482	P78347	1	phosphorylation	up-regulates	0.364	Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation.	SIGNOR-74296
O14757	Q96E09	1	phosphorylation	down-regulates activity	0.2	Knockout of FAM122A results in activation of PP2A-B55α, a phosphatase that dephosphorylates the WEE1 protein and rescues WEE1 from ubiquitin-mediated degradation. in tumor cells with oncogene-driven replication stress, CHK1 can directly phosphorylate FAM122A, leading to activation of the PP2A-B55α phosphatase and increased WEE1 expression.	SIGNOR-266380
P48730	Q13315	0	phosphorylation	up-regulates activity	0.34	These results elucidated the specificity of this in vivo degradation assay, and further implicated that CKI\u03b4-dependent phosphorylation events is the major signaling route through which DNA damage-dependent activation of ATM might control timely turnover of Mdm2 during genotoxic stress. (A) ATM-mediated phosphorylation of CK1\u03b4 promotes CK1\u03b4 nuclear localization.\|We further demonstrated that DNA damage-induced activation of ATM directly phosphorylated CKI\u03b4 at two well-conserved S/TQ sites, which promotes CKI\u03b4 nuclear localization to increase CKI\u03b4-mediated phosphorylation of Mdm2, thereby facilitating subsequent Mdm2 ubiquitination by SCF\u03b2-TRCP.	SIGNOR-279504
P35222	Q08050	2	binding	up-regulates activity	0.519	Nuclear FoxM1 then directly interacted with nuclear β‐catenin, which released β‐catenin from ICAT and enhanced recruitment of β‐catenin to the promoter of Wnt target gene, hence increasing the expression of Wnt target gene.	SIGNOR-277211
O14827	P63000	1	guanine nucleotide exchange factor	up-regulates activity	0.498	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-260574
P28482	Q9NYA1	1	phosphorylation	up-regulates	0.561	Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation.	SIGNOR-118546
Q8NFU7	P31269	1	transcriptional regulation	up-regulates quantity by expression	0.306	Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9.	SIGNOR-259094
Q9UQE7	P50539	2	binding	down-regulates activity	0.403	We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive eects of Mad proteins on c-myc functions.	SIGNOR-241223
Q8N6T7	P48163	1	deacetylation	down-regulates activity	0.25	PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation.	SIGNOR-275572
Q04760	P07948	0	phosphorylation	up-regulates activity	0.2	We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).	SIGNOR-276186
P07948	P29350	2	phosphorylation	up-regulates activity	0.734	Lyn phosphorylates SHPTP1 at the C-terminal Tyr-564 site. Lyn-mediated phosphorylation of SHPTP1 stimulates SHPTP1 tyrosine phosphatase activity.	SIGNOR-251409
P30968	P63092	2	binding	up-regulates activity	0.444	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-256792
P16220	Q15418	0	phosphorylation	up-regulates activity	0.747	The rsks phosphorylate the trascription factor creb at serine 133 to promote cell survival.	SIGNOR-72117
P78352	Q8NFZ4	0	relocalization	up-regulates activity	0.759	Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions.	SIGNOR-264193
P63167	P61586	1	gtpase-activating protein	down-regulates activity	0.273	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-260501

Q9P126

P63244

2

binding

down-regulates quantity by destabilization

0.2

In this study, we reported that RACK1, the receptor for activated C-kinase 1, associated with the cytoplasmic tail of CLEC-2. Moreover, overexpression of RACK1 decreased the stability of CLEC-2 through promoting its ubiquitin-proteasome degradation, without impairing surface expression and downstream signaling of CLEC-2. Taken together, these results suggest RACK1 as a novel modulator of CLEC-2 expression.Previous reports indicated that RACK1 mediated ubiquitin–proteasome degradation of HIF-1a and BimEL by recruiting Elongin-C/B ubiquitin ligase complex

SIGNOR-272781

P07900

P16591

1

phosphorylation

down-regulates activity

0.3

Hsp90 and tyrosine616 are required for Fer tyrosine kinase activity.Taken together, our findings underscore the importance of Hsp90 and the residue, tyrosine616, which resides in the Hsp90 recognition loop, in maintaining Fer tyrosine kinase activity.

SIGNOR-277818

Q13541

Q14004

0

phosphorylation

up-regulates activity

0.2

CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation.

SIGNOR-273113

P24468

P19793

2

binding

up-regulates

0.281

Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site

SIGNOR-79446

P46094

P47992

2

binding

up-regulates

0.787

Scm-1 showed a high-affinity binding to xcr1 with a kd of 10 nm and induced vigorous chemotaxis and calcium mobilization in xcr1-transfected murine l1.2 cells.

SIGNOR-71164

P45984

P63104

1

phosphorylation

down-regulates

0.2

Jnk phosphorylates 14-3-3zetaat ser-184 and 14-3-3sigmaat ser-188

SIGNOR-124031

P24941

Q07817

1

phosphorylation

up-regulates activity

0.496

Our findings show that Cdk2 phosphorylation of Bcl-xL at Ser73, but not the Bcl-xL cleavage products, is necessary and sufficient to induce cell death.

SIGNOR-278242

Q13535

P09874

1

phosphorylation

down-regulates

0.357

Specifically, ATR binds to and phosphorylates PARP1 at Ser179 after the ionophore treatments.|These data suggest that the phosphorylation of S179 is necessary and sufficient for ATR inhibition of PARP1 PARylation activity.

SIGNOR-278506

P49639

P55347

2

binding

up-regulates activity

0.588

Our results are consistent with a primary interaction of the YPWM motif of HOXA1 with the homeodomain of PBX. HOX proteins are dependent upon cofactors of the PBX family for specificity of DNA binding.

SIGNOR-220242

P36956

O75874

1

transcriptional regulation

up-regulates quantity by expression

0.282

IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells|evidence that IDH1 may regulate lipogenesis in hepatic cells

SIGNOR-253132

P13349

P19784

0

phosphorylation

up-regulates activity

0.307

Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity.

SIGNOR-251016

P15407

Q04759

0

phosphorylation

up-regulates activity

0.2

PKCθ-induced phosphorylations, in part at T217 and T227 residues, strongly and specifically increased Fra-1 transcriptional activity through the stimulation of Fra-1 transactivation domain, without affecting JUN factors.

SIGNOR-260879

Q9UM73

P19174

2

binding

up-regulates

0.546

Proteins that interact with alk tyrosine kinase play important roles in mediating downstream cellular signals. Previously reported proteins in the alk signal pathway were identified including pi3-k, jak2, jak3, stat3, grb2, irs, and plcgamma1.

SIGNOR-122082

O75460

Q5VWQ8

2

binding

up-regulates activity

0.382

DAB2IP binds IRE1α, and was shown to be required for activation of this signaling cascade in endothelial cells. IRE1α can trigger pro-apoptotic JNK signaling through recruitment of the TRAF2–ASK1 complex. DAB2IP facilitates IRE1α activation, and participates in a signaling complex required to induce TRAF2-dependent ASK1 activation and JNK phosphorylation.

SIGNOR-254749

P56178

Q16539

0

phosphorylation

up-regulates activity

0.291

We show that Dlx5 is a novel substrate for p38 MAPK in vitro and in vivo and that Ser-34 and Ser-217 are the sites phosphorylated by p38

SIGNOR-255792

P04637

Q68DV7

0

ubiquitination

down-regulates quantity by destabilization

0.451

Moreover, RNF43 polyubiquitinates p53 which further leads to its destabilization resulting in a decrease in induction of the p53 apoptotic pathway, a hitherto unknown process targeted by NP for p53 stabilization and accumulation.

SIGNOR-278714

O00141

P42224

1

phosphorylation

up-regulates activity

0.252

Notably, A\u03b2-activated SGK1 or JAK2 kinase phosphorylates STAT1 and induces its association with Tau(1\u2013368).

SIGNOR-279281

P19793

P27361

0

phosphorylation

down-regulates activity

0.523

In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE

SIGNOR-88662

P45983

Q9H2B2

1

phosphorylation

up-regulates activity

0.411

JNK phosphorylates Syt 4 at Ser135 in vitro and in vivo.

SIGNOR-273673

P18075

Q04771

2

binding

up-regulates

0.807

Bmp-4 and gdf-5 are known to bind to activin receptor-like kinase 3 (alk-3) and/or alk-6 (also termed bmp type ia and type ib receptors, respectively), whereas bmp-6 and bmp-7 preferentially bind to alk-2

SIGNOR-236913

O14836

O75888

2

binding

up-regulates

0.71

Tumor necrosis factor (tnf) receptor superfamily member taci is a high affinity receptor for tnf family members april and blys.

SIGNOR-81308

Q8NES3

P46531

2

binding

up-regulates

0.757

We demonstrate that egf 12, a portion of the ligand-binding site, is modified with o-fucose and that this site is evolutionarily conserved. We also show that endogenous fringe proteins in chinese hamster ovary cells (lunatic fringe and radical fringe) as well as exogenous manic fringe modify o-fucose on many but not all egf repeats of mouse notch1.

SIGNOR-96537

Q14118

Q9HDB5

2

binding

up-regulates activity

0.2

The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM.

SIGNOR-265462

P84022

P35658

2

binding

up-regulates

0.55

We demonstrate that smad3 and smad4 are capable of interaction with the nucleoporin can/nup214, and this interaction is required for nuclear import.

SIGNOR-117644

P12830

O14757

0

phosphorylation

down-regulates activity

0.301

Phosphorylation of Cdh1 by Chk1 promotes recognition of Cdh1 by SCF betaTRCP1.|These data suggest that Chk1 negatively regulates APC/C Cdh1 activity by both promoting Cdh1 destruction and by destabilizing its association with the APC/C.

SIGNOR-278396

O75385

P46937

1

phosphorylation

up-regulates quantity by stabilization

0.2

Mechanistically, hypoxia stimulates ULK1 to translocate into nucleus, where it interacts with and phosphorylates yes-associated protein (YAP) at Ser227, resulting in YAP stabilization through blockade of ubiquitin-proteasome system (UPS), which in turn facilitates PKM2 transcription, glycolysis, cell proliferation in vitro as well as PDAC growth in mice.

SIGNOR-277570

P19086

P21918

2

binding

up-regulates activity

0.404

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

SIGNOR-257311

P53355

Q9UN36

1

phosphorylation

up-regulates activity

0.273

DAPK1 phosphorylates and activates N-myc downstream-regulated gene 2 (NDRG2), resulting in increased tau phosphorylation via a reduction in Pin1 expression ( xref ; xref ).

SIGNOR-279983

Q9H2U1

Q99836

2

binding

up-regulates activity

0.524

We further showed that both DHX9 and DHX36 are localized within the cytosol and are directly bound to the Toll-interleukin receptor domain of MyD88 via their helicase-associated domain 2 and DUF domains. This study demonstrates that DHX9/DHX36 represent the MyD88-dependent DNA sensors in the cytosol of pDCs and suggests a much broader role for DHX helicases in viral sensing.

SIGNOR-260956

Q06124

P23458

0

phosphorylation

up-regulates activity

0.768

Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2

SIGNOR-236274

P24530

P38405

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-256924

P17706

P23458

1

dephosphorylation

down-regulates activity

0.767

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-134620

Q12986

O14746

1

transcriptional regulation

up-regulates quantity by expression

0.52

NFX1-123 positively regulated hTERT expression, as its knockdown decreased hTERT mRNA levels and telomerase activity and its overexpression increased telomerase activity. NFX1-123 was found to interact with cytoplasmic poly(A) binding proteins (PABPCs), and together they synergistically augmented expression from the hTERT promoter when activated by HPV16 E6.

SIGNOR-261050

P60953

Q9UQB8

2

binding

up-regulates activity

0.863

We conclude that the interaction of Cdc42 with the partial CRIB motif of IRSp53 relieves an intramolecular, autoinhibitory interaction with the N terminus, allowing the recruitment of Mena to the IRSp53 SH3 domain. This IRSp53:Mena complex initiates actin filament assembly into filopodia.

SIGNOR-268424

Q8TCY5

Q01726

2

binding

down-regulates activity

0.349

We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members.

SIGNOR-252364

P24385

Q8IYU2

0

ubiquitination

down-regulates quantity by destabilization

0.307

Mechanistically, the tumor-suppressor function of HACE1 is dependent on its E3 ligase activity and HACE1 controls adhesion-dependent growth and cell cycle progression during cell stress through degradation of cyclin D1.

SIGNOR-271405

Q92997

Q9Y608

2

binding

up-regulates

0.387

In particular, a previously unrecognized activator, lrrfip2 (leucine-rich repeat in flightless interaction protein 2), was found that interacts with dvl to increase the cellular levels of _-catenin and activate _-catenin/lef/tcf-dependent transcriptional activity

SIGNOR-133429

P51636

P12931

0

phosphorylation

down-regulates

0.676

Here, we show that cav-2 is phosphorylated at both tyrosines 19 and 27. We reconstituted this phosphorylation event by recombinantly coexpressing c-src and cav-2.Further functional analysis revealed that tyrosine phosphorylation of cav-2 has no effect on its targeting to lipid rafts, but clearly disrupts the hetero-oligomerization of cav-2 with cav-1.

SIGNOR-129961

P50613

P04637

1

phosphorylation

up-regulates

0.458

The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro. serines 371, 376, 378, and 392 may be the potential sites for this kinase.

SIGNOR-51292

Q9UK17

P09769

0

phosphorylation

up-regulates activity

0.2

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

SIGNOR-276394

Q14524

Q9UQM7

0

phosphorylation

up-regulates activity

0.398

Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate‚Äìactivated protein kinase (AMPK)‚Äìdependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5

SIGNOR-275772

P19174

P04629

0

phosphorylation

up-regulates

0.652

The nerve growth factor (ngf) receptor/trk associated with and phosphorylated phospholipase c gamma (plc gamma)

SIGNOR-38538

P18089

Q03113

2

binding

up-regulates activity

0.373

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-257201

P20226

P36508

2

binding

down-regulates activity

0.399

We identified ZNF76 as a novel transcriptional repressor that targets TBP. ZNF76 interacts with TBP through both its N and C termini. ZNF76 targets TBP for transcriptional repression.

SIGNOR-224650

Q9HAU4

Q15796

2

ubiquitination

down-regulates activity

0.778

The ability of smurf2 to promote smad2 destruction required the hect catalytic activity of smurf2 and depended on the proteasome-dependent pathway.

SIGNOR-236133

P30550

P04054

2

binding

up-regulates

0.255

Grpr stimulation activates phospholipase a2 (pla2) and cyclooxygenase 2 (cox2), which leads to prostaglandin e2 (pge2) production and ep receptor stimulation.

SIGNOR-152756

Q15599

P10398

0

phosphorylation

up-regulates activity

0.375

We also identify A-Raf as a kinase necessary for E3KARP phosphorylation at the G2/M stage of the cell cycle. Phosphorylation of Ser-303 regulates the localization, function, and dynamics of E3KARP

SIGNOR-273503

P43629

P05129

0

phosphorylation

down-regulates

0.2

Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover.

SIGNOR-158133

Q00341

P49711

2

binding

up-regulates activity

0.481

Vigilin interacts with CCCTC-binding factor (CTCF) and is involved in CTCF-dependent regulation of the imprinted genes Igf2 and H19. vigilin is present at several known CTCF target sites, such as the promoter regions of c-myc and BRCA1, the locus control region of β-globin, and several regions within the Igf2/H19 locus. These results reveal the functional relevance of vigilin and CTCF, and show that the CTCF-vigilin complex contributes to regulation of Igf2/H19.

SIGNOR-266693

P20290

Q86VG3

2

binding

down-regulates activity

0.2

Furthermore, we co-immunoprecipitated HEPIS with BTF3, a component of the RNA pol II initiation complex, and observed reduced proliferation of HeLa cells transfected with the HEPIS gene.

SIGNOR-260252

P67775

Q9BUB5

1

dephosphorylation

down-regulates

0.514

Moreover, a dephosphorylation assay revealed that pp2a could directly dephosphorylate mnk1 and eif4e.

SIGNOR-168314

P07949

P28482

1

phosphorylation

up-regulates

0.423

We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1).

SIGNOR-140294

P54764

O60674

1

phosphorylation

up-regulates activity

0.281

EphA4 phosphorylates JAK2.|These findings suggest that EphA4 activates not only growth hormone receptor, as shown above, but also JAK2 by direct phosphorylation.

SIGNOR-279040

P29350

P00519

0

phosphorylation

up-regulates activity

0.414

The results demonstrate that the SH3 domain of ABL1 interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that ABL1 phosphorylates C terminal Y536 and Y564 sites.

SIGNOR-260820

P10916

Q5VT25

0

phosphorylation

up-regulates activity

0.65

These approximately 190-kDa myotonic dystrophy kinase-related Cdc42-binding kinases (MRCKs) preferentially phosphorylate nonmuscle myosin light chain at serine 19, which is known to be crucial for activating actin-myosin contractility.

SIGNOR-250723

Q07890

P62993

2

binding

up-regulates

0.88

Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85.

SIGNOR-175180

Q96KB5

Q96EP1

0

polyubiquitination

down-regulates quantity by destabilization

0.346

CHFR ubiquitinates and degrades TOPK. Our in vivo ubiquitination assays revealed that the polyubiquitination of TOPK occurs only in the presence of full length CHFR but not with the ΔRING or Δcysteine-rich domain deletion mutants (Fig. 2a).

SIGNOR-271471

Q92819

Q14541

0

transcriptional regulation

up-regulates quantity by expression

0.337

Transcription was activated by HNF4G in reporter assays using the promoter/enhancer region of the HAS2 gene. The endogenous expression of the HAS2 gene was suppressed by knockdown of HNF4G.

SIGNOR-261626

Q14457

Q8NEB9

2

binding

up-regulates activity

0.936

The beclin 1-vps34 interaction regulates autophagy.

SIGNOR-184521

O75469

Q00535

0

phosphorylation

down-regulates activity

0.345

In vitro kinase assays showed that Cdk5 directly phosphorylates PXR.|Taken together, these data indicate that Cdk5 negatively regulates PXR activity, and that inhibition of Cdk5 is at least partially responsible for flavonoids induced activation of PXR.

SIGNOR-279402

P49137

P42574

1

phosphorylation

up-regulates activity

0.311

MK2 Phosphorylates Caspase-3, Facilitates Nuclear Translocation of Caspase 3, and Regulates Apoptosis.|Over-expression of MK2 led to an increase in nuclear caspase-3 activity.

SIGNOR-278960

P54727

P15927

2

binding

up-regulates activity

0.523

GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo

SIGNOR-275699

P35568

P62993

2

binding

up-regulates activity

0.803

Association ofinsulinreceptor substrate 1 (irs-1) y895 with grb-2 mediates theinsulinsignaling involved in irs-1-deficient brown adipocyte mitogenesis.

SIGNOR-236614

Q05655

Q9H257

1

phosphorylation

up-regulates activity

0.432

Here we demonstrated that protein kinase C-delta (PKCdelta) was activated upon Dectin-1-Syk signaling, mediated phosphorylation of Card9 at Thr231, and was responsible for Card9 and Bcl10 complex assembly and canonical NF-kappaB control.

SIGNOR-278383

O60674

P02647

1

null

up-regulates activity

0.298

ApoA-I interactions with ABCA1 and lipid efflux to apoA-I were substantially impaired by inhibiting or abolishing JAK2, whereas ABCA1 protein levels were unaffected, and ABCA1 cholesterol translocase activity was only slightly reduced. The most likely explanation for these findings is that JAK2 promotes apolipoprotein interactions with ABCA1 or a closely proximal site, and this facilitates the removal of cellular lipids. the interaction of apolipoproteins with ABCA1-expressing cells activates JAK2, which in turn activates a process that enhances apolipoprotein interactions with ABCA1 and lipid removal from cells

SIGNOR-252107

P62805

Q86Y97

0

methylation

down-regulates activity

0.2

SUV420H1 and SUV420H2 are two highly homologous enzymes that methylate lysine 20 of histone H4 (H4K20), a mark that has been implicated in transcriptional regulation.

SIGNOR-266650

P38936

Q9P1W9

0

phosphorylation

up-regulates quantity by stabilization

0.402

Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellsere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo

SIGNOR-164646

P41279

P19838

2

binding

down-regulates

0.688

Tpl-2 is stoichiometrically complexed with the nf-kb inhibitory protein, nf-kb1 p105, and the ubiquitin-binding protein abin-2, both of which are required to maintain tpl-2 protein stability. Binding to p105 also prevents tpl-2 from phosphorylating mek

SIGNOR-196747

P60953

O00401

2

binding

up-regulates activity

0.919

In the presence of Cdc42 and PI(4,5)P2, the potency of N-WASP was increased to a level approaching that of GST-VCA, suggesting that N-WASP was fully activated by the two molecules.

SIGNOR-261868

Q9UPN9

P35222

1

ubiquitination

down-regulates quantity by destabilization

0.457

TRIM33 ubiquitylates nuclear beta-catenin.|Tumour suppressor TRIM33 targets nuclear beta-catenin degradation.

SIGNOR-278578

P31749

P04150

1

phosphorylation

down-regulates

0.486

Akt1 impairs glucocorticoid-induced gene expression by direct phosphorylation of nr3c1 at position s134 and blocking glucocorticoid-induced nr3c1 translocation to the nucleus

SIGNOR-252543

P28482

P49407

1

phosphorylation

down-regulates

0.727

Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation

SIGNOR-67630

Q16665

P09467

2

binding

down-regulates activity

0.326

FBP1, but not FBP2, suppresses HIF-1a activity by directly binding to its inhibitory domain.

SIGNOR-267590

P08754

P29371

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-257179

Q09472

Q13131

0

phosphorylation

down-regulates

0.376

The mechanism of ampk-mediated anti- inflammation involves the induction of p300 ser89 phosphor- ylation and subsequent inactivation of p300 hat activity.

SIGNOR-176637

P43403

P15941

1

phosphorylation

up-regulates activity

0.448

Indeed, the present results demonstrate that ZAP-70 phosphorylates MUC1-CD and that the MUC1-CD Y-20 site functions, at least in part, as a ZAP-70 substrate (Fig. 4C). In this regard, the in vivo phosphorylation data indicate that ZAP-70 may also contribute to phosphorylation of MUC1-CD Y-46.The results further show that ZAP-70 phosphorylation of MUC1-CD stimulates the interaction of MUC1 andBeta-catenin.

SIGNOR-247039

P27361

O75676

1

phosphorylation

up-regulates

0.586

Rsk-b is a p38alphamapk substrate, and activated by p38alphamapk and, more weakly, by erk1

SIGNOR-60998

Q03135

P43003

2

binding

down-regulates activity

0.2

EAAT3 has previously been shown to form complexes with caveolin-1, a major component of caveolae, which participate in the regulation of transport proteins. The present study explored the impact of caveolin-1 on electrogenic transport by excitatory amino acid transporter isoforms EAAT1-4. caveolin-1 is a powerful negative regulator of the excitatory glutamate transporters EAAT1, EAAT2, EAAT3, and EAAT4. Caveolin-1 has been shown to form complexes with the excitatory amino acid transporter EAAT3 (EAAC1) (Gonzalez et al. 2007) and may thus modify the EAAT isoforms by direct interaction with the carriers.

SIGNOR-264808

Q96SN8

Q9P209

0

relocalization

up-regulates activity

0.663

By bringing CDK5RAP2 to the centrosome, the centriolar satellite proteins CEP72 and SPAG5 are required for the centrosomal localization of the other three MCPH proteins despite not interacting with them biochemically.

SIGNOR-271720

Q9NYJ7

Q86YT6

0

ubiquitination

up-regulates activity

0.35

Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity.

SIGNOR-209672

Q9P107

P60953

1

gtpase-activating protein

down-regulates activity

0.512

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-260507

P28482

Q13285

1

phosphorylation

up-regulates activity

0.463

Here we show that maximal SF-1-mediated transcription and interaction with general nuclear receptor cofactors depends on phosphorylation of a single serine residue (Ser-203) located in a major activation domain (AF-1) of the protein. Moreover, phosphorylation-dependent SF-1 activation is likely mediated by the mitogen-activated protein kinase (MAPK) signaling pathway.

SIGNOR-249431

Q4KMG0

P00519

2

binding

up-regulates activity

0.518

Abl binds a proline-rich motif in cdo via its sh3 domain, and these regions of abl and cdo are required for their promyogenic effects. Cdo is important for full abl kinase activity

SIGNOR-185762

Q8WW12

Q96PU4

0

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

Q99717

P12755

2

binding

down-regulates

0.697

Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad6

SIGNOR-95468

P28482

P78347

1

phosphorylation

up-regulates

0.364

Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation.

SIGNOR-74296

O14757

Q96E09

1

phosphorylation

down-regulates activity

0.2

Knockout of FAM122A results in activation of PP2A-B55α, a phosphatase that dephosphorylates the WEE1 protein and rescues WEE1 from ubiquitin-mediated degradation. in tumor cells with oncogene-driven replication stress, CHK1 can directly phosphorylate FAM122A, leading to activation of the PP2A-B55α phosphatase and increased WEE1 expression.

SIGNOR-266380

P48730

Q13315

0

phosphorylation

up-regulates activity

0.34

These results elucidated the specificity of this in vivo degradation assay, and further implicated that CKI\u03b4-dependent phosphorylation events is the major signaling route through which DNA damage-dependent activation of ATM might control timely turnover of Mdm2 during genotoxic stress. (A) ATM-mediated phosphorylation of CK1\u03b4 promotes CK1\u03b4 nuclear localization.|We further demonstrated that DNA damage-induced activation of ATM directly phosphorylated CKI\u03b4 at two well-conserved S/TQ sites, which promotes CKI\u03b4 nuclear localization to increase CKI\u03b4-mediated phosphorylation of Mdm2, thereby facilitating subsequent Mdm2 ubiquitination by SCF\u03b2-TRCP.

SIGNOR-279504

P35222

Q08050

2

binding

up-regulates activity

0.519

Nuclear FoxM1 then directly interacted with nuclear β‐catenin, which released β‐catenin from ICAT and enhanced recruitment of β‐catenin to the promoter of Wnt target gene, hence increasing the expression of Wnt target gene.

SIGNOR-277211

O14827

P63000

1

guanine nucleotide exchange factor

up-regulates activity

0.498

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-260574

P28482

Q9NYA1

1

phosphorylation

up-regulates

0.561

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

SIGNOR-118546

Q8NFU7

P31269

1

transcriptional regulation

up-regulates quantity by expression

0.306

Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9.

SIGNOR-259094

Q9UQE7

P50539

2

binding

down-regulates activity

0.403

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

SIGNOR-241223

Q8N6T7

P48163

1

deacetylation

down-regulates activity

0.25

PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation.

SIGNOR-275572

Q04760

P07948

0

phosphorylation

up-regulates activity

0.2

We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).

SIGNOR-276186

P07948

P29350

2

phosphorylation

up-regulates activity

0.734

Lyn phosphorylates SHPTP1 at the C-terminal Tyr-564 site. Lyn-mediated phosphorylation of SHPTP1 stimulates SHPTP1 tyrosine phosphatase activity.

SIGNOR-251409

P30968

P63092

2

binding

up-regulates activity

0.444

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-256792

P16220

Q15418

0

phosphorylation

up-regulates activity

0.747

The rsks phosphorylate the trascription factor creb at serine 133 to promote cell survival.

SIGNOR-72117

P78352

Q8NFZ4

0

relocalization

up-regulates activity

0.759

Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions.

SIGNOR-264193

P63167

P61586

1

gtpase-activating protein

down-regulates activity

0.273

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-260501