GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels float64 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
P06493	O43521	1	phosphorylation	up-regulates activity	0.404	Furthermore, active recombinant Cdk1/cyclin B1 phosphorylates BimEL and BimL in vitro and Serine 44 on BimL has been identified as a Cdk1 phosphorylation site. Collectively, these results suggest that Cdk1/cyclin B1-dependent hyper-phosphorylation of Bim during prolonged mitotic arrest is an important cell death signal.	SIGNOR-267985
P43405	Q13422	1	phosphorylation	up-regulates	0.404	Syk phoshorylatesikarosat unique c-terminal serine phosphorylation sites s358 and s361, thereby augmenting its nuclear localization and sequence-specific dna binding activity. Mechanistically, we establish that syk-inducedikarosactivation is essential for its nuclear localization and optimal transcription factor function.	SIGNOR-199100
P67775	P13639	1	dephosphorylation	up-regulates	0.404	Protein phosphatases-2a and -2c (pp-2a and pp-2c) can each efficiently dephosphorylate phosphorylated eef-2	SIGNOR-38566
Q5VT25	P53667	1	phosphorylation	up-regulates activity	0.404	Activation of LIM kinases by myotonic dystrophy kinase-related Cdc42-binding kinase alpha. \ In vitro, MRCKalpha phosphorylated the protein kinase domain of LIM kinases, and the site in LIMK2 phosphorylated by MRCKalpha proved to be threonine 505 within the activation segment.	SIGNOR-250721
Q9Y397	P01111	1	palmitoylation	up-regulates activity	0.404	Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein.	SIGNOR-261355
P00533	P0DP23	1	phosphorylation	down-regulates	0.404	Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule.	SIGNOR-24778
Q9UK99	Q9H2X6	1	binding	down-regulates quantity by destabilization	0.404	O clarify the role of PML in transcription regulation, we purified the PML complex and identified Fbxo3 (Fbx3), Skp1, and Cullin1 as novel components of this complex. Fbx3 formed SCF(Fbx3) ubiquitin ligase and promoted the degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway.	SIGNOR-271741
Q15139	P19174	1	phosphorylation	down-regulates activity	0.404	Thus, phosphorylation of PLC-gamma 1 by PKC or PKA at serine 1248 may modulate the interaction of PLC-gamma 1 with the protein tyrosine kinase or the protein tyrosine phosphatase; this altered interaction may, at least in part, be responsible for the decreased tyrosine phosphorylation of PLC-gamma 1 seen in PMA- and forskolin-treated Jurkat cells.	SIGNOR-248846
P23760	P50222	1	binding	up-regulates activity	0.404	We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family.	SIGNOR-222238
Q8IYK4	P02461	1	glycosylation	up-regulates activity	0.404	Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues.	SIGNOR-261158
P51532	P37275	1	binding	up-regulates	0.404	Zeb1 represses e-cadherin transcription / we reported that brg1 binds to the ntr of zeb1 acting as its co-repressor in the regulation of the e-cadherin promoter.	SIGNOR-165017
Q04206	Q9Y618	1	relocalization	down-regulates activity	0.404	Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm. This indicates that shuttling of p65 was necessary for Flt3-ITD-mediated SMRT nuclear export.	SIGNOR-261539
Q9Y468	Q12888	1	binding	down-regulates activity	0.404	L3MBTL1, a tumor suppressor with high affinity for H4K20me2, can block 53BP1 binding at DSBs	SIGNOR-262059
P21918	P19086	1	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
P00519	Q9H2X6	1	phosphorylation	up-regulates activity	0.403	The Tyrosine Kinase c-Abl Promotes Homeodomain-interacting Protein Kinase 2 (HIPK2) Accumulation and Activation in Response to DNA Damage	SIGNOR-260936
P34925	Q92997	1	binding	up-regulates	0.403	Ryk also binds to dishevelled, through which it activates the canonical wnt, providing a link between wnt and dishevelled	SIGNOR-129574
Q15391	P63096	1	binding	up-regulates activity	0.403	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-256723
P05129	P04049	1	phosphorylation	up-regulates	0.403	Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation.	SIGNOR-37545
Q7Z6I6	P63000	1	gtpase-activating protein	down-regulates activity	0.403	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-260486
Q16827	P04626	1	dephosphorylation	down-regulates quantity by destabilization	0.403	In this study, our co-immunoprecipitation experiment along with the results derived from in vivo , cultured cells and clinical specimen confirm that PTPRO dephosphorylates ERBB2 at Y1248.\|PTPRO overexpression remarkably accelerated degradation of ERBB2 (XREF_FIG).	SIGNOR-276979
Q06187	Q04206	1	phosphorylation	up-regulates activity	0.403	Btk induces the phosphorylation of NF-\u03baB p65 which can be induced by the expression of inflammation cytokines [ ].\|Btk induces the phosphorylation of NF-\u03baB p65 which can be induced by the expression of inflammation cytokines [ xref ].	SIGNOR-280197
Q13315	Q9H3D4	1	phosphorylation	down-regulates	0.403	Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively	SIGNOR-180747
Q969Q1	P55036	1	polyubiquitination	down-regulates quantity by destabilization	0.403	S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10).	SIGNOR-272741
P51812	P03372	1	phosphorylation	up-regulates	0.403	S6k1 regulates estrogen receptor alpha (eralpha) by phosphorylating it on serine 167, leading to transcriptional activation of eralpha.	SIGNOR-182958
Q00535	O94811	1	phosphorylation	down-regulates activity	0.403	Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP.	SIGNOR-262931
P00519	P04040	1	phosphorylation	up-regulates activity	0.403	C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases	SIGNOR-101302
P15408	P15407	1	transcriptional regulation	up-regulates quantity by expression	0.403	Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription.	SIGNOR-261602
Q15391	P08754	1	binding	up-regulates activity	0.403	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-256866
P58340	Q9UNS2	1	binding	up-regulates	0.403	As downstream elements of mlf1 leading to cell growth arrest due to p53 accumulation, we identified two factors, csn3, the third component of the cop9 signalosome (csn), and cop1, a recently characterized e3 ubiquitin ligase for p53	SIGNOR-135937
Q96JA1	P04626	1	ubiquitination	down-regulates	0.403	We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation.	SIGNOR-139948
Q9UQE7	P50539	1	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
Q9UQM7	Q4G163	1	phosphorylation	up-regulates activity	0.403	CaMKII and polo-like kinase 1 sequentially phosphorylate the cytostatic factor Emi2/XErp1 to trigger its destruction and meiotic exit. \| these results implicate the 192RSST motif of Emi2 as a critical molecular target of CaMKII during CSF release	SIGNOR-260907
Q9UHD2	O14920	1	binding	up-regulates	0.403	A physical and functional map of the human tnf-alpha/nf-kappa b signal transduction pathway.	SIGNOR-121576
Q8NFZ4	Q86UL8	1	binding	up-regulates activity	0.403	S-SCAM is a member of the membrane-associated guanylate kinase (MAGUK) family of PDZ-domain-containing proteins that include the synaptic organising molecule PSD-95. The PDZ domain of S-SCAM binds to the C-terminal tail of NL2, forming a ternary complex at the cell membrane (Figure 2b). 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-265444
Q13671	P00533	1	binding	up-regulates	0.403	The interaction between egfr and rin1 delineates a novel signal transduction pathway between egfr and its effectors, rin1, rab5a, and ras, which together coordinate and regulate both signaling and membrane trafficking.	SIGNOR-101530
Q16665	P13500	1	transcriptional regulation	up-regulates quantity by expression	0.403	These findings suggest that both MCP-1 and MCP-5 are HIF-1 target genes and that HIF-1α is involved in transcriptional induction of these two chemokines in astrocytes by hypoxia.	SIGNOR-251719
P08172	P08754	1	binding	up-regulates activity	0.403	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-256828
Q9UQM7	P16949	1	phosphorylation	down-regulates	0.403	Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. In vitro, ser16 of recombinant human stathmin was phosphorylated also by purified cam kinase ii, and in vivo, cam kinase ii activity was indeed stimulated in cd2-triggered jurkat cells. Altogether, our results favor an association of cam kinase ii activity with costimulatory signals of t lymphocyte activation and phosphorylation of stathmin on ser16.	SIGNOR-149640
P08173	P08754	1	binding	up-regulates activity	0.403	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-256829
Q8NG27	Q01082	1	ubiquitination	down-regulates	0.403	The present study indicates that praja, a ring finger e3 ubiquitin ligase, interacts with elf and ubiquitinates it.	SIGNOR-141216
Q9Y3R0	Q06413	1	binding	up-regulates	0.403	The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis.	SIGNOR-83883
O15033	Q8N2W9	1	ubiquitination	down-regulates quantity by destabilization	0.403	In this study, we discovered a new protein isoform encoded by KIAA0317, termed fibrosis-inducing E3 ligase 1 (FIEL1), which potently stimulates the TGFβ signaling pathway through the site-specific ubiquitination of PIAS4.FIEL1 targets PIAS4 using a double locking mechanism that is facilitated by the kinases PKCζ and GSK3β. Specifically, PKCζ phosphorylation of PIAS4 and GSK3β phosphorylation of FIEL1 are both essential for the degradation of PIAS4.	SIGNOR-275575
Q99500	P09471	1	binding	up-regulates activity	0.403	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-257263
P28482	P41162	1	phosphorylation	down-regulates activity	0.403	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. Among the ERK2 substrates, we identified the E-twenty six (ETS) domain-containing protein ETV3. We determined that phosphorylation of this protein by ERK2 was functionally relevant, abrogating the DNA-binding activity of ETV3 at thousands of targets across the genome, thereby providing an additional mechanism for transcriptional regulation downstream of ERK2 activation.	SIGNOR-262758
Q9UGL1	P55316	1	binding	up-regulates activity	0.403	Human PLU-1 Has transcriptional repression properties and interacts with the developmental transcription factors BF-1 and PAX9. In a reporter assay system, PLU-1 has potent transcriptional repression activity. BF-1 and PAX9 also represses transcription in the same assay, but co-expression of PLU-1 with BF-1 or PAX9 significantly enhances this repression	SIGNOR-223878
O15550	P49639	1	transcriptional regulation	up-regulates quantity by expression	0.403	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260019
O43164	Q9Y4C4	1	ubiquitination	up-regulates activity	0.403	These results suggest that the ubiquitylation of MFHAS1 by praja2 has a vital role in M1 macrophage polarization and promotes the transformation of M2 macrophages to M1 macrophages through both the JNK and p38 pathways.	SIGNOR-278559
Q13308	P35222	1	binding	down-regulates	0.403	Ptk7 has been strongly implicated in pcp and, like many pcp activators, is a negative regulator of beta-catenin-dependent wnt.	SIGNOR-199536
Q13153	Q13363	1	phosphorylation	down-regulates activity	0.403	Pak1 phosphorylates ctbp selectively on ser158 within a putative regulatory loop, triggering ctbp cellular redistribution and blocking ctbp ak1 superphosphorylates ctbp and inhibits ctbp dehydrogenase activitycorepressor functions.	SIGNOR-103943
P06213	P0DP23	1	phosphorylation	down-regulates	0.403	The in vitro phosphorylation of calmodulin by the insulin receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule.	SIGNOR-24782
P25490	O14763	1	transcriptional regulation	down-regulates quantity by repression	0.403	Depletion of FKBP51 impairs the acetylation status of YY1 and interferes with its binding on the DR5 promoter. The lack of the repressor activity of YY1 increases DR5 transcription and sensitizes melanoma cell to TRAIL-induced apoptosis.	SIGNOR-268793
Q969H0	P23771	1	ubiquitination	down-regulates quantity by destabilization	0.403	Fbw7 promotes degradation of GATA3 in a Thr-156-dependent manner.	SIGNOR-276635
Q16539	Q14934	1	phosphorylation	down-regulates activity	0.402	P38 MAP kinase phosphorylates Ser168 and Ser170 of NFATc4. Mutational replacement of Ser168,170 with Ala promotes NFATc4 nuclear localization and increases NFATc4-mediated transcription activity.	SIGNOR-250107
P28482	Q15831	1	phosphorylation	down-regulates activity	0.402	Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK.	SIGNOR-209876
Q9Y2U5	Q15208	1	phosphorylation	up-regulates quantity by stabilization	0.402	Our data suggest that Ser91 phosphorylation of STK38 by MEKK2 possibly blocks the interaction of calpain with STK38 or disrupts proper conformation for cleaving, thereby protecting STK38 from calpain-dependent degradation.	SIGNOR-279066
P22455	P40763	1	phosphorylation	up-regulates activity	0.402	Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3.	SIGNOR-251142
Q969H4	Q9NS23	1	binding	up-regulates	0.402	Cnk1 binds to rassf1a and promotes apoptosis through a pathway that requires rassf1a and mst kinases.	SIGNOR-198432
Q9UNW8	P30679	1	binding	up-regulates activity	0.402	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-257444
P41743	P08151	1	phosphorylation	up-regulates activity	0.402	Although functioning downstream of SMO, aPKC-\u03b9/\u03bb phosphorylates and activates GLI1, resulting in maximal DNA binding and transcriptional activation [ xref ].	SIGNOR-279262
P23469	P12931	1	dephosphorylation	up-regulates activity	0.402	PTPepsilonM activated c-Src kinase probably by directly dephosphorylating phospho-Tyr527, a negative regulatory site of c-Src.	SIGNOR-238074
P67775	O43524	1	dephosphorylation	up-regulates	0.402	Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a.	SIGNOR-163680
Q9H1R3	Q06413	1	phosphorylation	up-regulates activity	0.402	Here, we show that phosphorylation of MEF2C on T(80) by skeletal myosin light chain kinase (skMLCK) enhances skeletal and not cardiac myogenesis.	SIGNOR-238118
P25116	P63096	1	binding	up-regulates	0.402	Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13).	SIGNOR-196009
Q15139	Q13671	1	phosphorylation	down-regulates	0.402	Rin1 also binds to 14-3-3 proteins through a sequence including serine 351. Mutation of this residue abolished the 14-3-3 binding capacity of rin1 and led to more efficient blockade of ras-mediated transformation. The mutant protein, rin1(s351a), showed a shift in localization to the plasma membrane. Serine 351 is a substrate for protein kinase d (pkd [also known as pkcmu]) in vitro and in vivo. These data suggest that the normal localization and function of rin1, as well as its ability to compete with raf, are regulated in part by 14-3-3 binding, which in turn is controlled by pkd phosphorylation.	SIGNOR-113960
P53350	P46531	1	phosphorylation	down-regulates quantity by destabilization	0.402	As shown in Fig. S4D, the C-terminal NOTCH1 fragment was readily phosphorylated by PLK1. Additionally, when the two putative phosphorylation sites, Ser-1791 and Ser-2349, were replaced by Ala, WT NOTCH1-IC but not the mutant was efficiently phosphorylated (Fig. S4E). We found that mutation of Ser-1791/2349 promotes NOTCH1-IC stabilization (Fig. S4F).	SIGNOR-277491
Q5VT97	P63000	1	gtpase-activating protein	down-regulates activity	0.402	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-260522
P54764	P11362	1	phosphorylation	up-regulates activity	0.402	EphA4 and FGFR1 heterodimer promotes FGFR1 signaling in glioma cell line.\|Ligand stimulation of EphA4 stimulates FGFR1 phosphorylation and signaling.	SIGNOR-280007
P54257	O60282	1	binding	up-regulates activity	0.402	HAP1 and GRIP1 are kinesin-1 adaptors that have been implicated individually in the transport of vesicular cargoes in the dendrites of neurons. We find that HAP1a and GRIP1 form a protein complex in the brain, and co-operate to activate the kinesin-1 subunit KIF5C in vitro	SIGNOR-264062
Q9HBW0	Q14344	1	binding	up-regulates	0.402	Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13.	SIGNOR-135837
P14373	O00750	1	ubiquitination	down-regulates	0.402	We now show that trim27 functions as an e3 ligase and mediates lysine 48 polyubiquitination of pi3kc2_, leading to a decrease in pi3k enzyme activity.	SIGNOR-177935
Q14980	P04350	1	binding	up-regulates	0.402	Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.	SIGNOR-117025
Q13322	P27986	1	binding	up-regulates activity	0.402	Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation	SIGNOR-255945
O43791	Q9HCU9	1	ubiquitination	down-regulates quantity	0.402	Intriguingly, BRMS1 turns out to be a potent substrate that is ubiquitinated by the Cul3-SPOP complex. Knockdown of SPOP increases the level of BRMS1 protein and represses the expression of BRMS1 repressive target genes such as OPN and uPA in breast cancer cells.	SIGNOR-268857
P11229	O95837	1	binding	up-regulates activity	0.402	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-257130
Q9P1W9	P38936	1	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
P16591	P40763	1	phosphorylation	up-regulates activity	0.402	Replacing the unique 43-amino acid-long N-terminal tail of p51 (ferT) with a parallel segment from the N-terminal tail of p94 (fer) did not change the subcellular localization of p51 (ferT) but enabled it to activate Stat3.\|When combined with immunoprecipitation analysis, this assay showed that p94 (fer) can lead to the tyrosine phosphorylation and activation of Stat3 but not of Stat1 or Stat2.	SIGNOR-279713
P28482	Q13153	1	phosphorylation	down-regulates activity	0.402	We also show that ERK2 phosphorylates PAK1 on Thr(212) in vitro and that Thr(212) is phosphorylated in smooth muscle cells following PDGF-BB treatment in an adhesion- and MEK/ERK-dependent fashion. Expression of a phosphomimic variant, PAK-T212E, does not alter ERK association, but markedly attenuates downstream ERK signaling. Taken together, these data suggest that PAK1 may facilitate ERK signaling by serving as a scaffold to recruit Raf, MEK, and ERK to adhesion complexes, and that subsequent growth factor-stimulated phosphorylation of PAK-Thr(212) by ERK may serve to provide a negative feedback signal	SIGNOR-249432
O43293	P40429	1	phosphorylation	up-regulates	0.402	Zipk phosphorylates l13a in vitro / l13a is phosphorylated on ser77 in vitro	SIGNOR-182117
Q00535	P40763	1	phosphorylation	up-regulates	0.402	We report here that the cdk5/p35 complex associates with stat3 and phosphorylates stat3 on the ser-727 residue in vitro and in vivo. Ser phosphorylation of stat3 and transcription of stat3 target genes, such as c-fos and junb, in a cdk5-dependent manner.	SIGNOR-124325
Q8N103	P63000	1	gtpase-activating protein	down-regulates activity	0.402	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-260524
P30408	Q9H190	1	relocalization	up-regulates activity	0.402	TM4SF1 functions as a membrane adaptor connecting DDR1 to syntenin2.	SIGNOR-272401
Q96BR1	Q92597	1	phosphorylation	down-regulates activity	0.402	It has been shown that SGK3 phosphorylation of NDRG1 primes for subsequent phosphorylation by GSK-3beta.\|Since NDRG1 is a direct SGK substrate, this correlation suggests that SGK3 activation and signaling may modulate NDRG1 degradation.	SIGNOR-279282
Q9ULU8	Q16623	1	binding	up-regulates activity	0.402	CAPS interacted independently with either syntaxin-1 or SNAP-25 suggesting that CAPS might promote QaQbc-SNARE heterodimer formation. CAPS binding to syntaxin-1 was mediated by the membrane-proximal C-terminal SNARE motif (H3) and membrane linker domain sequences of syntaxin-1	SIGNOR-264336
Q8NBJ5	P02462	1	glycosylation	up-regulates activity	0.402	Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues.	SIGNOR-261155
P07332	P40763	1	phosphorylation	up-regulates activity	0.402	Fes also induced Tyr 705 phosphorylation and DNA binding activity of STAT3, in agreement with the idea that Fes can regulate transcriptional activation through Fes dependent phosphorylation of transcription factors.On the basis of these findings, we propose that Fes activation of critical transcriptional regulators such as PU.1 is part of the mechanism by which this kinase induces macrophage differentiation of myeloid progenitors.\|We conclude that Fes may regulate granulocytic differentiation at least in part through activation of C/EBP-alpha and STAT3.In 32D cells, Fes activated STAT3 and C/EBP-alpha, two important regulators of granulocytic differentiation [14,15].	SIGNOR-278937
Q9NR96	Q86XR7	1	binding	up-regulates activity	0.401	To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group	SIGNOR-266750
P19338	P10242	1	binding	down-regulates activity	0.401	We identify nucleolin as one of the nuclear polypeptides that interact specifically with the A-Myb and c-Myb. We show that the interaction of nucleolin with Myb is functional because co-transfection of nucleolin down-regulates Myb transcriptional activity.	SIGNOR-221236
Q6PCD5	Q06609	1	ubiquitination	up-regulates activity	0.401	Rad51 directly interacts with the N-terminal of RFWD3 and is ubiquitinated by RFWD3.	SIGNOR-278543
P30411	P08754	1	binding	up-regulates activity	0.401	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-256838
P67775	P19429	1	dephosphorylation	down-regulates	0.401	The major phosphatase thought to dephosphorylate ctni and phospholamban is type 2a protein phosphatase (pp2a) [61]. Activation of pp2a and ensuing dephosphorylation of regulatory proteins is involved in the anti-adrenergic effects of adenosine and muscarinic receptor activation see also fig2.	SIGNOR-134601
P46934	O75843	2	monoubiquitination	up-regulates activity	0.401	Gamma2-Adaptin is a putative member of the clathrin adaptor protein family with unknown physiological function. We previously reported that gamma2-adaptin acts as a ubiquitin receptor by virtue of its ubiquitin-interacting motif. Here we demonstrate that this motif mediates a specific physical interaction with the ubiquitin ligase Nedd4 and promotes ubiquitination of gamma2-adaptin. These antibodies clearly recognized the 96 kDa form, thus demonstrating that a fraction of γ2-adaptin is modified by monoubiquitination (Fig. 1C). Thus, binding of γ2-adaptin to Nedd4 is not necessary for its membrane association.Accordingly, one possible function of γ2-adaptin may be to act as an adaptor for Nedd4, recruiting it to membrane compartments for subsequent ubiquitination.	SIGNOR-272634
O43293	P40763	1	phosphorylation	up-regulates activity	0.401	ZIPK phosphorylated STAT3 on serine 727 (Ser727) and enhanced STAT3 transcriptional activity.	SIGNOR-279702
P24941	Q8WYH8	1	phosphorylation	up-regulates quantity	0.401	We report that ING5 is phosphorylated in a cell cycle dependent manner by CDK2 at T152 (Figs 1 and 3).	SIGNOR-279447
Q05086	P33993	1	polyubiquitination	down-regulates quantity by destabilization	0.401	The characterization of this interaction in turn led to the discovery that Mcm7 is a substrate for both E6-AP-dependent and -independent ubiquitination and is specifically targeted for degradation by the 26 S proteasome.	SIGNOR-272543
P10275	P36952	1	transcriptional regulation	down-regulates quantity by repression	0.401	In addition, androgen receptor (AR) can recognize and bind to the ARE element, and then inhibit the activity of maspin promoter	SIGNOR-253685
P17252	P29353	1	phosphorylation	up-regulates activity	0.401	Among them, Ser(29) in p52(Shc) (equivalent to Ser(138) in p66(Shc)) was phosphorylated only after TPA stimulation. Phosphorylation of this site together with the intact phosphotyrosine-binding domain was essential for ShcA binding to the protein-tyrosine phosphatase PTP-PEST. TPA-induced ShcA phosphorylation at this site (and hence, its association with PTP-PEST) was inhibited by a protein kinase C-specific inhibitor and was induced by overexpression of constitutively active mutants of protein kinase Calpha, -epsilon, and -delta isoforms.	SIGNOR-249150
Q8IW41	Q15382	1	phosphorylation	down-regulates activity	0.401	Phosphorylation of Rheb at Ser 130 by PRAK impairs the nucleotide-binding ability of Rheb and inhibits Rheb-mediated mTORC1 activation.	SIGNOR-276313
Q15077	P30679	1	binding	up-regulates activity	0.401	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-257277
P35790	P00533	1	binding	up-regulates activity	0.401	We find that CHKA forms a complex with EGFR in a c-Src-dependent manner. Endogenous CHKA and EGFR co-immunoprecipitated from a variety of breast cancer cell lines and immortalized mammary epithelial cells. CHKA interacted with the EGFR kinase domain upon c-Src co-overexpression and was phosphorylated in a c-Src-dependent manner on Y197 and Y333. CHKA is required for maximum EGF-dependent cell growth in mammary epithelium-derived cell lines	SIGNOR-266352
Q8IYU2	Q96CV9	1	ubiquitination	down-regulates quantity by destabilization	0.401	Here we report that tumor suppressor HACE1, a ubiquitin ligase, ubiquitylates OPTN and promotes its interaction with p62 and SQSTM1 to form the autophagy receptor complex, thus accelerating autophagic flux.\|Ubiquitylation of Autophagy Receptor Optineurin by HACE1 Activates Selective Autophagy for Tumor Suppression.\|HACE1 mediated K48 linked poly-Ub chains targets OPTN for autophagic degradation.	SIGNOR-278748

P06493

O43521

1

phosphorylation

up-regulates activity

0.404

Furthermore, active recombinant Cdk1/cyclin B1 phosphorylates BimEL and BimL in vitro and Serine 44 on BimL has been identified as a Cdk1 phosphorylation site. Collectively, these results suggest that Cdk1/cyclin B1-dependent hyper-phosphorylation of Bim during prolonged mitotic arrest is an important cell death signal.

SIGNOR-267985

P43405

Q13422

1

phosphorylation

up-regulates

0.404

Syk phoshorylatesikarosat unique c-terminal serine phosphorylation sites s358 and s361, thereby augmenting its nuclear localization and sequence-specific dna binding activity. Mechanistically, we establish that syk-inducedikarosactivation is essential for its nuclear localization and optimal transcription factor function.

SIGNOR-199100

P67775

P13639

1

dephosphorylation

up-regulates

0.404

Protein phosphatases-2a and -2c (pp-2a and pp-2c) can each efficiently dephosphorylate phosphorylated eef-2

SIGNOR-38566

Q5VT25

P53667

1

phosphorylation

up-regulates activity

0.404

Activation of LIM kinases by myotonic dystrophy kinase-related Cdc42-binding kinase alpha. \ In vitro, MRCKalpha phosphorylated the protein kinase domain of LIM kinases, and the site in LIMK2 phosphorylated by MRCKalpha proved to be threonine 505 within the activation segment.

SIGNOR-250721

Q9Y397

P01111

1

palmitoylation

up-regulates activity

0.404

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

SIGNOR-261355

P00533

P0DP23

1

phosphorylation

down-regulates

0.404

Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule.

SIGNOR-24778

Q9UK99

Q9H2X6

1

binding

down-regulates quantity by destabilization

0.404

O clarify the role of PML in transcription regulation, we purified the PML complex and identified Fbxo3 (Fbx3), Skp1, and Cullin1 as novel components of this complex. Fbx3 formed SCF(Fbx3) ubiquitin ligase and promoted the degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway.

SIGNOR-271741

Q15139

P19174

1

phosphorylation

down-regulates activity

0.404

Thus, phosphorylation of PLC-gamma 1 by PKC or PKA at serine 1248 may modulate the interaction of PLC-gamma 1 with the protein tyrosine kinase or the protein tyrosine phosphatase; this altered interaction may, at least in part, be responsible for the decreased tyrosine phosphorylation of PLC-gamma 1 seen in PMA- and forskolin-treated Jurkat cells.

SIGNOR-248846

P23760

P50222

1

binding

up-regulates activity

0.404

We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family.

SIGNOR-222238

Q8IYK4

P02461

1

glycosylation

up-regulates activity

0.404

Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues.

SIGNOR-261158

P51532

P37275

1

binding

up-regulates

0.404

Zeb1 represses e-cadherin transcription / we reported that brg1 binds to the ntr of zeb1 acting as its co-repressor in the regulation of the e-cadherin promoter.

SIGNOR-165017

Q04206

Q9Y618

1

relocalization

down-regulates activity

0.404

Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm. This indicates that shuttling of p65 was necessary for Flt3-ITD-mediated SMRT nuclear export.

SIGNOR-261539

Q9Y468

Q12888

1

binding

down-regulates activity

0.404

L3MBTL1, a tumor suppressor with high affinity for H4K20me2, can block 53BP1 binding at DSBs

SIGNOR-262059

P21918

P19086

1

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

P00519

Q9H2X6

1

phosphorylation

up-regulates activity

0.403

The Tyrosine Kinase c-Abl Promotes Homeodomain-interacting Protein Kinase 2 (HIPK2) Accumulation and Activation in Response to DNA Damage

SIGNOR-260936

P34925

Q92997

1

binding

up-regulates

0.403

Ryk also binds to dishevelled, through which it activates the canonical wnt, providing a link between wnt and dishevelled

SIGNOR-129574

Q15391

P63096

1

binding

up-regulates activity

0.403

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-256723

P05129

P04049

1

phosphorylation

up-regulates

0.403

Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation.

SIGNOR-37545

Q7Z6I6

P63000

1

gtpase-activating protein

down-regulates activity

0.403

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-260486

Q16827

P04626

1

dephosphorylation

down-regulates quantity by destabilization

0.403

In this study, our co-immunoprecipitation experiment along with the results derived from in vivo , cultured cells and clinical specimen confirm that PTPRO dephosphorylates ERBB2 at Y1248.|PTPRO overexpression remarkably accelerated degradation of ERBB2 (XREF_FIG).

SIGNOR-276979

Q06187

Q04206

1

phosphorylation

up-regulates activity

0.403

Btk induces the phosphorylation of NF-\u03baB p65 which can be induced by the expression of inflammation cytokines [ ].|Btk induces the phosphorylation of NF-\u03baB p65 which can be induced by the expression of inflammation cytokines [ xref ].

SIGNOR-280197

Q13315

Q9H3D4

1

phosphorylation

down-regulates

0.403

Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively

SIGNOR-180747

Q969Q1

P55036

1

polyubiquitination

down-regulates quantity by destabilization

0.403

S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10).

SIGNOR-272741

P51812

P03372

1

phosphorylation

up-regulates

0.403

S6k1 regulates estrogen receptor alpha (eralpha) by phosphorylating it on serine 167, leading to transcriptional activation of eralpha.

SIGNOR-182958

Q00535

O94811

1

phosphorylation

down-regulates activity

0.403

Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP.

SIGNOR-262931

P00519

P04040

1

phosphorylation

up-regulates activity

0.403

C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases

SIGNOR-101302

P15408

P15407

1

transcriptional regulation

up-regulates quantity by expression

0.403

Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription.

SIGNOR-261602

Q15391

P08754

1

binding

up-regulates activity

0.403

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-256866

P58340

Q9UNS2

1

binding

up-regulates

0.403

As downstream elements of mlf1 leading to cell growth arrest due to p53 accumulation, we identified two factors, csn3, the third component of the cop9 signalosome (csn), and cop1, a recently characterized e3 ubiquitin ligase for p53

SIGNOR-135937

Q96JA1

P04626

1

ubiquitination

down-regulates

0.403

We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation.

SIGNOR-139948

Q9UQE7

P50539

1

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

Q9UQM7

Q4G163

1

phosphorylation

up-regulates activity

0.403

CaMKII and polo-like kinase 1 sequentially phosphorylate the cytostatic factor Emi2/XErp1 to trigger its destruction and meiotic exit. | these results implicate the 192RSST motif of Emi2 as a critical molecular target of CaMKII during CSF release

SIGNOR-260907

Q9UHD2

O14920

1

binding

up-regulates

0.403

A physical and functional map of the human tnf-alpha/nf-kappa b signal transduction pathway.

SIGNOR-121576

Q8NFZ4

Q86UL8

1

binding

up-regulates activity

0.403

S-SCAM is a member of the membrane-associated guanylate kinase (MAGUK) family of PDZ-domain-containing proteins that include the synaptic organising molecule PSD-95. The PDZ domain of S-SCAM binds to the C-terminal tail of NL2, forming a ternary complex at the cell membrane (Figure 2b). 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-265444

Q13671

P00533

1

binding

up-regulates

0.403

The interaction between egfr and rin1 delineates a novel signal transduction pathway between egfr and its effectors, rin1, rab5a, and ras, which together coordinate and regulate both signaling and membrane trafficking.

SIGNOR-101530

Q16665

P13500

1

transcriptional regulation

up-regulates quantity by expression

0.403

These findings suggest that both MCP-1 and MCP-5 are HIF-1 target genes and that HIF-1α is involved in transcriptional induction of these two chemokines in astrocytes by hypoxia.

SIGNOR-251719

P08172

P08754

1

binding

up-regulates activity

0.403

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-256828

Q9UQM7

P16949

1

phosphorylation

down-regulates

0.403

Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. In vitro, ser16 of recombinant human stathmin was phosphorylated also by purified cam kinase ii, and in vivo, cam kinase ii activity was indeed stimulated in cd2-triggered jurkat cells. Altogether, our results favor an association of cam kinase ii activity with costimulatory signals of t lymphocyte activation and phosphorylation of stathmin on ser16.

SIGNOR-149640

P08173

P08754

1

binding

up-regulates activity

0.403

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-256829

Q8NG27

Q01082

1

ubiquitination

down-regulates

0.403

The present study indicates that praja, a ring finger e3 ubiquitin ligase, interacts with elf and ubiquitinates it.

SIGNOR-141216

Q9Y3R0

Q06413

1

binding

up-regulates

0.403

The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis.

SIGNOR-83883

O15033

Q8N2W9

1

ubiquitination

down-regulates quantity by destabilization

0.403

In this study, we discovered a new protein isoform encoded by KIAA0317, termed fibrosis-inducing E3 ligase 1 (FIEL1), which potently stimulates the TGFβ signaling pathway through the site-specific ubiquitination of PIAS4.FIEL1 targets PIAS4 using a double locking mechanism that is facilitated by the kinases PKCζ and GSK3β. Specifically, PKCζ phosphorylation of PIAS4 and GSK3β phosphorylation of FIEL1 are both essential for the degradation of PIAS4.

SIGNOR-275575

Q99500

P09471

1

binding

up-regulates activity

0.403

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-257263

P28482

P41162

1

phosphorylation

down-regulates activity

0.403

We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. Among the ERK2 substrates, we identified the E-twenty six (ETS) domain-containing protein ETV3. We determined that phosphorylation of this protein by ERK2 was functionally relevant, abrogating the DNA-binding activity of ETV3 at thousands of targets across the genome, thereby providing an additional mechanism for transcriptional regulation downstream of ERK2 activation.

SIGNOR-262758

Q9UGL1

P55316

1

binding

up-regulates activity

0.403

Human PLU-1 Has transcriptional repression properties and interacts with the developmental transcription factors BF-1 and PAX9. In a reporter assay system, PLU-1 has potent transcriptional repression activity. BF-1 and PAX9 also represses transcription in the same assay, but co-expression of PLU-1 with BF-1 or PAX9 significantly enhances this repression

SIGNOR-223878

O15550

P49639

1

transcriptional regulation

up-regulates quantity by expression

0.403

Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.

SIGNOR-260019

O43164

Q9Y4C4

1

ubiquitination

up-regulates activity

0.403

These results suggest that the ubiquitylation of MFHAS1 by praja2 has a vital role in M1 macrophage polarization and promotes the transformation of M2 macrophages to M1 macrophages through both the JNK and p38 pathways.

SIGNOR-278559

Q13308

P35222

1

binding

down-regulates

0.403

Ptk7 has been strongly implicated in pcp and, like many pcp activators, is a negative regulator of beta-catenin-dependent wnt.

SIGNOR-199536

Q13153

Q13363

1

phosphorylation

down-regulates activity

0.403

Pak1 phosphorylates ctbp selectively on ser158 within a putative regulatory loop, triggering ctbp cellular redistribution and blocking ctbp ak1 superphosphorylates ctbp and inhibits ctbp dehydrogenase activitycorepressor functions.

SIGNOR-103943

P06213

P0DP23

1

phosphorylation

down-regulates

0.403

The in vitro phosphorylation of calmodulin by the insulin receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule.

SIGNOR-24782

P25490

O14763

1

transcriptional regulation

down-regulates quantity by repression

0.403

Depletion of FKBP51 impairs the acetylation status of YY1 and interferes with its binding on the DR5 promoter. The lack of the repressor activity of YY1 increases DR5 transcription and sensitizes melanoma cell to TRAIL-induced apoptosis.

SIGNOR-268793

Q969H0

P23771

1

ubiquitination

down-regulates quantity by destabilization

0.403

Fbw7 promotes degradation of GATA3 in a Thr-156-dependent manner.

SIGNOR-276635

Q16539

Q14934

1

phosphorylation

down-regulates activity

0.402

P38 MAP kinase phosphorylates Ser168 and Ser170 of NFATc4. Mutational replacement of Ser168,170 with Ala promotes NFATc4 nuclear localization and increases NFATc4-mediated transcription activity.

SIGNOR-250107

P28482

Q15831

1

phosphorylation

down-regulates activity

0.402

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

SIGNOR-209876

Q9Y2U5

Q15208

1

phosphorylation

up-regulates quantity by stabilization

0.402

Our data suggest that Ser91 phosphorylation of STK38 by MEKK2 possibly blocks the interaction of calpain with STK38 or disrupts proper conformation for cleaving, thereby protecting STK38 from calpain-dependent degradation.

SIGNOR-279066

P22455

P40763

1

phosphorylation

up-regulates activity

0.402

Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3.

SIGNOR-251142

Q969H4

Q9NS23

1

binding

up-regulates

0.402

Cnk1 binds to rassf1a and promotes apoptosis through a pathway that requires rassf1a and mst kinases.

SIGNOR-198432

Q9UNW8

P30679

1

binding

up-regulates activity

0.402

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-257444

P41743

P08151

1

phosphorylation

up-regulates activity

0.402

Although functioning downstream of SMO, aPKC-\u03b9/\u03bb phosphorylates and activates GLI1, resulting in maximal DNA binding and transcriptional activation [ xref ].

SIGNOR-279262

P23469

P12931

1

dephosphorylation

up-regulates activity

0.402

PTPepsilonM activated c-Src kinase probably by directly dephosphorylating phospho-Tyr527, a negative regulatory site of c-Src.

SIGNOR-238074

P67775

O43524

1

dephosphorylation

up-regulates

0.402

Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a.

SIGNOR-163680

Q9H1R3

Q06413

1

phosphorylation

up-regulates activity

0.402

Here, we show that phosphorylation of MEF2C on T(80) by skeletal myosin light chain kinase (skMLCK) enhances skeletal and not cardiac myogenesis.

SIGNOR-238118

P25116

P63096

1

binding

up-regulates

0.402

Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13).

SIGNOR-196009

Q15139

Q13671

1

phosphorylation

down-regulates

0.402

Rin1 also binds to 14-3-3 proteins through a sequence including serine 351. Mutation of this residue abolished the 14-3-3 binding capacity of rin1 and led to more efficient blockade of ras-mediated transformation. The mutant protein, rin1(s351a), showed a shift in localization to the plasma membrane. Serine 351 is a substrate for protein kinase d (pkd [also known as pkcmu]) in vitro and in vivo. These data suggest that the normal localization and function of rin1, as well as its ability to compete with raf, are regulated in part by 14-3-3 binding, which in turn is controlled by pkd phosphorylation.

SIGNOR-113960

P53350

P46531

1

phosphorylation

down-regulates quantity by destabilization

0.402

As shown in Fig. S4D, the C-terminal NOTCH1 fragment was readily phosphorylated by PLK1. Additionally, when the two putative phosphorylation sites, Ser-1791 and Ser-2349, were replaced by Ala, WT NOTCH1-IC but not the mutant was efficiently phosphorylated (Fig. S4E). We found that mutation of Ser-1791/2349 promotes NOTCH1-IC stabilization (Fig. S4F).

SIGNOR-277491

Q5VT97

P63000

1

gtpase-activating protein

down-regulates activity

0.402

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-260522

P54764

P11362

1

phosphorylation

up-regulates activity

0.402

EphA4 and FGFR1 heterodimer promotes FGFR1 signaling in glioma cell line.|Ligand stimulation of EphA4 stimulates FGFR1 phosphorylation and signaling.

SIGNOR-280007

P54257

O60282

1

binding

up-regulates activity

0.402

HAP1 and GRIP1 are kinesin-1 adaptors that have been implicated individually in the transport of vesicular cargoes in the dendrites of neurons. We find that HAP1a and GRIP1 form a protein complex in the brain, and co-operate to activate the kinesin-1 subunit KIF5C in vitro

SIGNOR-264062

Q9HBW0

Q14344

1

binding

up-regulates

0.402

Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13.

SIGNOR-135837

P14373

O00750

1

ubiquitination

down-regulates

0.402

We now show that trim27 functions as an e3 ligase and mediates lysine 48 polyubiquitination of pi3kc2_, leading to a decrease in pi3k enzyme activity.

SIGNOR-177935

Q14980

P04350

1

binding

up-regulates

0.402

Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.

SIGNOR-117025

Q13322

P27986

1

binding

up-regulates activity

0.402

Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation

SIGNOR-255945

O43791

Q9HCU9

1

ubiquitination

down-regulates quantity

0.402

Intriguingly, BRMS1 turns out to be a potent substrate that is ubiquitinated by the Cul3-SPOP complex. Knockdown of SPOP increases the level of BRMS1 protein and represses the expression of BRMS1 repressive target genes such as OPN and uPA in breast cancer cells.

SIGNOR-268857

P11229

O95837

1

binding

up-regulates activity

0.402

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-257130

Q9P1W9

P38936

1

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

P16591

P40763

1

phosphorylation

up-regulates activity

0.402

Replacing the unique 43-amino acid-long N-terminal tail of p51 (ferT) with a parallel segment from the N-terminal tail of p94 (fer) did not change the subcellular localization of p51 (ferT) but enabled it to activate Stat3.|When combined with immunoprecipitation analysis, this assay showed that p94 (fer) can lead to the tyrosine phosphorylation and activation of Stat3 but not of Stat1 or Stat2.

SIGNOR-279713

P28482

Q13153

1

phosphorylation

down-regulates activity

0.402

We also show that ERK2 phosphorylates PAK1 on Thr(212) in vitro and that Thr(212) is phosphorylated in smooth muscle cells following PDGF-BB treatment in an adhesion- and MEK/ERK-dependent fashion. Expression of a phosphomimic variant, PAK-T212E, does not alter ERK association, but markedly attenuates downstream ERK signaling. Taken together, these data suggest that PAK1 may facilitate ERK signaling by serving as a scaffold to recruit Raf, MEK, and ERK to adhesion complexes, and that subsequent growth factor-stimulated phosphorylation of PAK-Thr(212) by ERK may serve to provide a negative feedback signal

SIGNOR-249432

O43293

P40429

1

phosphorylation

up-regulates

0.402

Zipk phosphorylates l13a in vitro / l13a is phosphorylated on ser77 in vitro

SIGNOR-182117

Q00535

P40763

1

phosphorylation

up-regulates

0.402

We report here that the cdk5/p35 complex associates with stat3 and phosphorylates stat3 on the ser-727 residue in vitro and in vivo. Ser phosphorylation of stat3 and transcription of stat3 target genes, such as c-fos and junb, in a cdk5-dependent manner.

SIGNOR-124325

Q8N103

P63000

1

gtpase-activating protein

down-regulates activity

0.402

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-260524

P30408

Q9H190

1

relocalization

up-regulates activity

0.402

TM4SF1 functions as a membrane adaptor connecting DDR1 to syntenin2.

SIGNOR-272401

Q96BR1

Q92597

1

phosphorylation

down-regulates activity

0.402

It has been shown that SGK3 phosphorylation of NDRG1 primes for subsequent phosphorylation by GSK-3beta.|Since NDRG1 is a direct SGK substrate, this correlation suggests that SGK3 activation and signaling may modulate NDRG1 degradation.

SIGNOR-279282

Q9ULU8

Q16623

1

binding

up-regulates activity

0.402

CAPS interacted independently with either syntaxin-1 or SNAP-25 suggesting that CAPS might promote QaQbc-SNARE heterodimer formation. CAPS binding to syntaxin-1 was mediated by the membrane-proximal C-terminal SNARE motif (H3) and membrane linker domain sequences of syntaxin-1

SIGNOR-264336

Q8NBJ5

P02462

1

glycosylation

up-regulates activity

0.402

Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues.

SIGNOR-261155

P07332

P40763

1

phosphorylation

up-regulates activity

0.402

Fes also induced Tyr 705 phosphorylation and DNA binding activity of STAT3, in agreement with the idea that Fes can regulate transcriptional activation through Fes dependent phosphorylation of transcription factors.On the basis of these findings, we propose that Fes activation of critical transcriptional regulators such as PU.1 is part of the mechanism by which this kinase induces macrophage differentiation of myeloid progenitors.|We conclude that Fes may regulate granulocytic differentiation at least in part through activation of C/EBP-alpha and STAT3.In 32D cells, Fes activated STAT3 and C/EBP-alpha, two important regulators of granulocytic differentiation [14,15].

SIGNOR-278937

Q9NR96

Q86XR7

1

binding

up-regulates activity

0.401

To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group

SIGNOR-266750

P19338

P10242

1

binding

down-regulates activity

0.401

We identify nucleolin as one of the nuclear polypeptides that interact specifically with the A-Myb and c-Myb. We show that the interaction of nucleolin with Myb is functional because co-transfection of nucleolin down-regulates Myb transcriptional activity.

SIGNOR-221236

Q6PCD5

Q06609

1

ubiquitination

up-regulates activity

0.401

Rad51 directly interacts with the N-terminal of RFWD3 and is ubiquitinated by RFWD3.

SIGNOR-278543

P30411

P08754

1

binding

up-regulates activity

0.401

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-256838

P67775

P19429

1

dephosphorylation

down-regulates

0.401

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

SIGNOR-134601

P46934

O75843

2

monoubiquitination

up-regulates activity

0.401

Gamma2-Adaptin is a putative member of the clathrin adaptor protein family with unknown physiological function. We previously reported that gamma2-adaptin acts as a ubiquitin receptor by virtue of its ubiquitin-interacting motif. Here we demonstrate that this motif mediates a specific physical interaction with the ubiquitin ligase Nedd4 and promotes ubiquitination of gamma2-adaptin. These antibodies clearly recognized the 96 kDa form, thus demonstrating that a fraction of γ2-adaptin is modified by monoubiquitination (Fig. 1C). Thus, binding of γ2-adaptin to Nedd4 is not necessary for its membrane association.Accordingly, one possible function of γ2-adaptin may be to act as an adaptor for Nedd4, recruiting it to membrane compartments for subsequent ubiquitination.

SIGNOR-272634

O43293

P40763

1

phosphorylation

up-regulates activity

0.401

ZIPK phosphorylated STAT3 on serine 727 (Ser727) and enhanced STAT3 transcriptional activity.

SIGNOR-279702

P24941

Q8WYH8

1

phosphorylation

up-regulates quantity

0.401

We report that ING5 is phosphorylated in a cell cycle dependent manner by CDK2 at T152 (Figs 1 and 3).

SIGNOR-279447

Q05086

P33993

1

polyubiquitination

down-regulates quantity by destabilization

0.401

The characterization of this interaction in turn led to the discovery that Mcm7 is a substrate for both E6-AP-dependent and -independent ubiquitination and is specifically targeted for degradation by the 26 S proteasome.

SIGNOR-272543

P10275

P36952

1

transcriptional regulation

down-regulates quantity by repression

0.401

In addition, androgen receptor (AR) can recognize and bind to the ARE element, and then inhibit the activity of maspin promoter

SIGNOR-253685

P17252

P29353

1

phosphorylation

up-regulates activity

0.401

Among them, Ser(29) in p52(Shc) (equivalent to Ser(138) in p66(Shc)) was phosphorylated only after TPA stimulation. Phosphorylation of this site together with the intact phosphotyrosine-binding domain was essential for ShcA binding to the protein-tyrosine phosphatase PTP-PEST. TPA-induced ShcA phosphorylation at this site (and hence, its association with PTP-PEST) was inhibited by a protein kinase C-specific inhibitor and was induced by overexpression of constitutively active mutants of protein kinase Calpha, -epsilon, and -delta isoforms.

SIGNOR-249150

Q8IW41

Q15382

1

phosphorylation

down-regulates activity

0.401

Phosphorylation of Rheb at Ser 130 by PRAK impairs the nucleotide-binding ability of Rheb and inhibits Rheb-mediated mTORC1 activation.

SIGNOR-276313

Q15077

P30679

1

binding

up-regulates activity

0.401

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-257277

P35790

P00533

1

binding

up-regulates activity

0.401

We find that CHKA forms a complex with EGFR in a c-Src-dependent manner. Endogenous CHKA and EGFR co-immunoprecipitated from a variety of breast cancer cell lines and immortalized mammary epithelial cells. CHKA interacted with the EGFR kinase domain upon c-Src co-overexpression and was phosphorylated in a c-Src-dependent manner on Y197 and Y333. CHKA is required for maximum EGF-dependent cell growth in mammary epithelium-derived cell lines

SIGNOR-266352

Q8IYU2

Q96CV9

1

ubiquitination

down-regulates quantity by destabilization

0.401

Here we report that tumor suppressor HACE1, a ubiquitin ligase, ubiquitylates OPTN and promotes its interaction with p62 and SQSTM1 to form the autophagy receptor complex, thus accelerating autophagic flux.|Ubiquitylation of Autophagy Receptor Optineurin by HACE1 Activates Selective Autophagy for Tumor Suppression.|HACE1 mediated K48 linked poly-Ub chains targets OPTN for autophagic degradation.

SIGNOR-278748