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
O43257	P15173	1	transcriptional regulation	up-regulates quantity by expression	0.259	We show that the srcap subunit named znhit1 or p18hamlet, which is a substrate of p38 mapk, is recruited to the myogenin promoter at the onset of muscle differentiation, in a p38 mapk-dependent manner. We also show that p18hamlet is required for h2a.z accumulation into this genomic region and for subsequent muscle gene transcriptional activation.	SIGNOR-165613
P19174	P17252	2	phosphorylation	up-regulates	0.556	Tnf-alfa binds to tnfr1 and activates pc-plc to induce pkcalfa and c-src activation, leading to tyrosine phosphorylation of ikkbeta at tyr188 and tyr199.	SIGNOR-99310
Q06124	P01116	1	dephosphorylation	up-regulates activity	0.66	Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling.	SIGNOR-255982
Q32MZ4	P43405	0	phosphorylation	up-regulates activity	0.2	However, this inhibitory activity TRIP can be reversed by the co-expression of Syk, which might inhibit the activity of cytoplasmic TRIP, sequester TRIP from important nucleolar targets or even counter TRIP 's inhibitory effects on TRAF and TNF signaling by regulating the activity of alternative components of the pathway.\|Syk induces phosphorylation of TRIP on tyrosine.	SIGNOR-279297
Q13535	P04637	1	phosphorylation	up-regulates quantity by stabilization	0.742	Nhibition of atr kinase activity substantially reduces hypoxia-induced phosphorylation of p53 protein on serine 15 as well as p53 protein accumulation.	SIGNOR-115134
Q8TD84	P40763	2	binding	up-regulates activity	0.2	Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels.	SIGNOR-264278
Q13315	Q9UBU7	1	phosphorylation	down-regulates	0.375	Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication.	SIGNOR-177793
Q9Y4P1	Q9P289	0	phosphorylation	up-regulates activity	0.2	ATG4B stimulates autophagy by promoting autophagosome formation through reversible modification of ATG8. We identify ATG4B as a substrate of mammalian sterile20-like kinase (STK) 26/MST4. MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux.	SIGNOR-275833
Q9C0C7	P42345	0	phosphorylation	down-regulates activity	0.471	We show that under non-autophagic conditions, mTOR inhibits AMBRA1 by phosphorylation, whereas on autophagy induction, AMBRA1 is dephosphorylated. In this condition, AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function. As ULK1 has been shown to activate AMBRA1 by phosphorylation, the proposed pathway may act as a positive regulation loop, which may be targeted in human disorders linked to impaired autophagy.\|mTOR phosphorylates AMBRA1 at Ser 52, inhibiting its role in ULK1 modification	SIGNOR-272986
Q96T51	P61106	0	relocalization	up-regulates activity	0.63	Here, we have demonstrated that Rab14 interacts with RUFY1, previously identified as a Rab4 effector, and is required for RUFY1 recruitment onto endosomes and efficient recycling of Tfn.	SIGNOR-261279
Q71DI3	Q92831	0	acetylation	down-regulates activity	0.2	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269626
P10636-2	Q05513	0	phosphorylation	down-regulates activity	0.268	We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs.	SIGNOR-275447
P31431	O14640	2	binding	up-regulates	0.356	Like other wnt co-receptors, syndecan 4 directly interacts with dvl during pcp 1.	SIGNOR-199632
Q7Z3K3	Q96GD4	2	binding	up-regulates activity	0.323	POGZ is required for the correct activation and dissociation of Aurora B kinase from chromosome arms during M phase. These results reveal POGZ as an essential protein that links HP1alpha dissociation with Aurora B kinase activation during mitosis.	SIGNOR-264497
Q96EB6	P42345	0	phosphorylation	down-regulates activity	0.551	These results demonstrate that the inhibition of SIRT1 by mTOR fosters survival of DNA damage-induced prematurely senescent squamous cell carcinoma cells via Bfl-1/A1 in the absence of functional p53.\|This process involved the mTOR-dependent phosphorylation of SIRT1 at serine 47, resulting in the inhibition of the deacetylase activity of SIRT1.	SIGNOR-280047
P08603	Q03591	2	binding	down-regulates activity	0.504	Finally, we have been able to establish that CFHR1 can sterically inhibit the interaction that CFH/CFHL-1 SCR1-4 makes with C3b.\|CFH regulates the alternative pathway of complement in both the fluid phase and on self-surfaces: It competes with complement factor B (CFB) for binding to C3b and C3(H2O) thereby blocking the formation of the pro-convertase complexes, C3bB and C3(H2O)B. It also accelerates the decay of any existing C3bBb or C3(H2O)Bb. \|these data have allowed us to consolidate one possible model of CFHR1-mediated deregulation of CFH/CFHL-1 on an activating surface in which CFHR1 directly competes with or blocks both CFH-binding sites on C3b	SIGNOR-263476
P09693	P06239	0	phosphorylation	up-regulates activity	0.56	Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex.	SIGNOR-259931
Q9Y6K1	P42229	0	transcriptional regulation	up-regulates quantity	0.326	… these data suggest that STAT5A positively regulates levels of DNMT3A, resulting in inactivation of tumor suppressor genes by epigenetic mechanisms in AML cells	SIGNOR-255631
P42574	O75475	1	cleavage	down-regulates	0.348	Ledgf/ p75 has a cooh-terminally truncated splice variant, p52 / during apoptosis, caspase-3 cleaved p52 to generate a p38 fragment that lacked the nh2-terminal pwwp domain and failed to transactivate the hsp27 promoter in reporter assays. However, p38 retained chromatin association properties and repressed the transactivation potential of ledgf/p75	SIGNOR-180144
Q14493	Q7Z2G1	1	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265387
P03372	Q9Y5X4	0	transcriptional regulation	up-regulates quantity by expression	0.251	NR2E3 directly regulates expression of ESR1 \| Furthermore, overexpression of exogenous NR2E3 further increased expression of ESR1 and its downstream targets as well as its transcriptional activity in MCF-7 cells (Fig S1 of Supporting Information), strongly demonstrating that NR2E3 regulates ESR1 expression and subsequent ESR1-mediated induction of target genes.	SIGNOR-266207
P17509	P69891	1	transcriptional regulation	down-regulates quantity by repression	0.2	HOXB6 protein represses globin transcript levels in stably transfected K562 cells in a DNA-binding dependent fashion.	SIGNOR-261638
Q96BI1	Q9H6Y7	0	polyubiquitination	down-regulates quantity by destabilization	0.525	Here, we present evidences indicating that RING105, a novel conserved RING-finger protein with a PA (protease-associated) domain and a PEST sequence, is a ubiquitin ligase for TSSC5 that can function in concert with the ubiquitin-conjugating enzyme UbcH6. The polyubiquitin target site on TSSC5 was mapped to a region in the 6th hydrophilic loop.	SIGNOR-271551
P63096	Q9Y271	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-256740
Q8IXL6	Q9GZV9	1	phosphorylation	down-regulates activity	0.64	Here we show that Fam20C directly phosphorylates FGF23 on Ser(180) \| Our above results support, phosphorylation of FGF23 at Ser180 inhibits O-glycosylation and would therefore promote hormone proteolysis and thus inactivation.	SIGNOR-260925
P43405	P40763	1	phosphorylation	up-regulates activity	0.552	The current study indicates that the plasma cell malignancy is also associated with Syk-activated STAT3 directly downstream of reelin-induced integrin \u03b21 engagement and FAK/Src activation (Figure xref ).\|The integrin-activated spleen tyrosine kinase (Syk) was shown to promote STAT3 phosphorylation [42, 44].	SIGNOR-279298
P29317	P12931	0	phosphorylation	up-regulates activity	0.454	SRC phosphorylates EPHA2 on Tyr594\|. It is therefore likely that this phosphorylation site is included in the binding motif of an additional signalling molecule required for cell transformation.	SIGNOR-246104
Q15349	Q92934	1	phosphorylation	down-regulates	0.373	The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival.	SIGNOR-184591
P55010	P68400	0	phosphorylation	up-regulates	0.394	We find that eif5 is associated with ck2 when the kinase activity is at the highest level in vivo, and is phosphorylated at ser389 and ser390 by ck2.	SIGNOR-141159
Q9UER7	Q00987	2	binding	up-regulates	0.673	The optimal function of mdm2 requires daxx, which stabilizes mdm2 through the deubiquitinase hausp/usp7 and also directly promotes mdm2's ubiquitin ligase activity towards p53.	SIGNOR-200892
Q8NG31	O60566	2	binding	up-regulates	0.2	Association of the amino and middle domain of blinkin with the tpr domains in the amino termini of bubr1 and bub1 is essential for bubr1 and bub1 to execute their distinct mitotic functions	SIGNOR-158894
Q15628	Q93038	2	binding	up-regulates	0.739	Dr3 induces apoptosis by tradd-mediated recruitment of fadd and caspase-8	SIGNOR-100480
P45984	P52564	0	phosphorylation	up-regulates	0.473	A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase)	SIGNOR-45369
O15530	Q96PN8	1	phosphorylation	up-regulates activity	0.261	We elucidated the mechanism of regulation of TSSK3 activity showing that autophosphorylation and PDK1 phosphorylation in the ‘activation loop’ are necessary for activation.	SIGNOR-260786
P10071	Q9Y297	0	ubiquitination	down-regulates quantity by destabilization	0.671	Third, we and others have recently shown that only phosphorylated Ci/Gli3 are able to directly bind Slimb/BetaTrCP, that Gli3 is polyubiquitinated in the cell, and that mutations of 4 lysine residues, the putative ubiquitination sites in the Gli3 C-terminal region, inhibit Gli3 processing These observations further support the notion that Ci/Gli3 processing is carried out by the proteasome because the deletion of the cleavage site is expected to often disrupt the protease-mediated site-specific cleavage.	SIGNOR-145116
Q86UR1	Q9HBY0	2	binding	up-regulates activity	0.632	Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner\|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein\|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation	SIGNOR-264711
P17480	P24941	0	phosphorylation	up-regulates activity	0.372	Phosphorylation of ubf at serine 388 is required for interaction with rna polymerase i and activation of rdna transcription. After g(1) progression ubf is phosphorylated at serine 388 by cdk2/cyclin e and cdk2/cyclin a. Conversion of serine 388 to glycine abolishes ubf activity	SIGNOR-235419
Q99962	Q5S007	0	phosphorylation	down-regulates	0.472	We show that lrrk2 affects synaptic endocytosis by phosphorylating endophilin-a1 at s75.	SIGNOR-192072
P35968	P27986	2	binding	up-regulates activity	0.505	null	SIGNOR-261917
P17509	P69905	1	transcriptional regulation	down-regulates quantity by repression	0.2	HOXB6 protein represses globin transcript levels in stably transfected K562 cells in a DNA-binding dependent fashion.	SIGNOR-261637
Q02763	Q9Y264	2	binding	up-regulates	0.699	In experiments with human endothelial cell lines, ang3 was identified as an antagonist of tie2 and ang4 was identified as an agonist of tie2.	SIGNOR-127351
Q07820	P28062	0	null	down-regulates quantity by destabilization	0.2	Surprisingly, siRNA knockdown of PSMB8 (LMP7), an ‘immunoproteasome’ component, reversed IFNγ-induced sensitivity to Fas ligation and prevented Fas/IFNγ-induced degradation of Mcl-1, but did not protect p-Bcl-2 or p-Bcl-XL. Proteasome inhibition markedly increased Mcl-1, p-Bcl-2, and p-Bcl-XL levels after IFNγ treatment	SIGNOR-261974
Q14344	P32238	2	binding	up-regulates activity	0.25	Our studies indicate that CCK-A receptors inserted into NIH3T3 cells also activate RhoA through G12/13	SIGNOR-278062
P48729	O15534	1	phosphorylation	down-regulates quantity by destabilization	0.318	CKI\u03b1-Dependent Phosphorylation and Degradation of PER1.	SIGNOR-279700
Q9UBW7	Q9H9S0	2	binding	down-regulates activity	0.3	In this work, we identified ZMYM2/ZFP198, which physically associates with NANOG as a key negative regulator of NANOG-mediated reprogramming of both epiblast stem cells and somatic cells.	SIGNOR-269802
Q07812	Q15818	0	relocalization	up-regulates activity	0.2	Immunofluorescence staining and subcellular fractionation analyses revealed increased mitochondrial translocation of Bad and Bax proteins from cytoplasm following OGD (4 h) and simultaneously increased release of Cyt C from mitochondria followed by activation of caspase-3. NP1 protein was immunoprecipitated with Bad and Bax proteins; OGD caused increased interactions of NP1 with Bad and Bax, thereby, facilitating their mitochondrial translocation and dissipation of mitochondrial membrane potential	SIGNOR-261439
P11802	P07947	0	phosphorylation	down-regulates	0.254	We purified tyrosine 17 kinases from hela cells and found that the src family non-receptor tyrosine kinase c-yes contributes a large fraction of the tyrosine 17 kinase activity in hela lysatesthis site is equivalent to tyrosine 15 of cyclin dependent kinase 1, which undergoes inhibitory phosphorylation by wee1 and myt1	SIGNOR-178624
P08754	Q8TDV5	2	binding	up-regulates activity	0.25	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257153
Q96T58	Q9Y618	2	binding	up-regulates	0.467	Sharp is a potent transcriptional repressor whose repression domain (rd) interacts directly with smrt	SIGNOR-107260
P49841	O00213	1	phosphorylation	up-regulates quantity	0.293	In this regards, GSK3beta may promote amyloidogenic processing of APP by regulating the cellular level of monomeric FE65 for the formation of LRP1, FE65, and APP complex.\|In this study, we showed that FE65 is phosphorylated at T579 by GSK3beta.	SIGNOR-278359
Q01581	P13674	0	transcriptional regulation	up-regulates quantity by expression	0.2	In this study, we found that the prolyl 4-hydroxylase (P4H) subunit P4HA1 protects NPC cells from erastin-induced ferroptosis by activating HMGCS1, a key enzyme in the mevalonate pathway. Our results show that HMGCS1 and HMGCR are regulated by P4HA subunits at the transcriptional level (Fig. S4).	SIGNOR-279853
P58340	Q9UNS2	2	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
P01100	P05412	2	binding	up-regulates activity	0.953	The cFos proto-oncoprotein associates with cJun to form a heterodimer with increased DNA binding and transcriptional activities.	SIGNOR-252087
Q96BR1	Q66PJ3	1	phosphorylation	down-regulates activity	0.2	AIP4 is phosphorylated by CISK in vitro on WW domain residues, which may impact its ability to interact with and ubiquitinate substrate proteins.\|Expression of a constitutively active CISK inhibits CXCR4 degradation, possibly by attenuating CXCR4 binding to and ubiquitination by AIP4 and/or modulating the action of AIP4 on a protein involved in CXCR4 endosomal sorting .	SIGNOR-280124
P02461	Q9Y653	2	binding	up-regulates activity	0.2	Using the N-terminal fragment of GPR56 (GPR56(N)) as a probe, we have recently demonstrated that collagen III is the ligand of GPR56 in the developing brain. In this report, we discover a new functional domain in GPR56(N), the ligand binding domain.	SIGNOR-253979
P54253	Q86Y13	0	polyubiquitination	down-regulates quantity by destabilization	0.483	HOTAIR associates with E3 ubiquitin ligases bearing RNA-binding domains, Dzip3 and Mex3b, as well as with their respective ubiquitination substrates, Ataxin-1 and Snurportin-1. In this manner, HOTAIR facilitates the ubiquitination of Ataxin-1 by Dzip3 and Snurportin-1 by Mex3b in cells and in vitro, and accelerates their degradation.	SIGNOR-272078
P42345	O15111	0	phosphorylation	up-regulates activity	0.511	In those studies, we found that IKKalpha interacts with and phosphorylates mTOR in the mTORC1 complex to activate mTORC1, and that Akt signaling drives the IKKalpha-mTORC1 interaction.\|We then studied whether IKKalpha promotes Akt and mTOR activity in other mammalian cancer cell lines.	SIGNOR-279607
P05106	O14713	2	binding	down-regulates activity	0.308	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257656
P60709	O14994	2	binding	up-regulates activity	0.2	Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner.	SIGNOR-269183
Q86X55	Q92922	1	methylation	up-regulates activity	0.537	CARM1-mediated BAF155 methylation affects gene expression by directing methylated BAF155 to unique chromatin regions (e.g., c-Myc pathway genes). Collectively, our studies uncover a mechanism by which BAF155 acquires tumorigenic functions via arginine methylation.	SIGNOR-251708
Q02763	Q03112	0	transcriptional regulation	up-regulates quantity by expression	0.2	We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2	SIGNOR-266063
O95398	P61224	1	guanine nucleotide exchange factor	up-regulates activity	0.718	Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well.	SIGNOR-263957
O15294	P06737	1	glycosylation	up-regulates activity	0.2	O-GlcNAcylation at Ser-430 promotes PYGL activity	SIGNOR-267988
P08559	Q9P2J9	0	dephosphorylation	up-regulates activity	0.658	Pyruvate dehydrogenase phosphatase (PDP) is a mitochondrial serine phosphatase that activates phosphorylated pyruvate dehydrogenase complex by dephosphorylation	SIGNOR-251665
P19174	P07948	0	phosphorylation	up-regulates activity	0.656	The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.	SIGNOR-249381
P22681	P36888	2	binding	down-regulates activity	0.436	Functionally, CBL negatively regulated FMS-like tyrosine kinase 3 (FLT3) activity and interacted with human FLT3 via the autophosphorylation sites Y589 and Y599 and colocalized in vivo.	SIGNOR-255739
O96013	Q9BY11	1	phosphorylation	up-regulates activity	0.295	We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo.	SIGNOR-263023
P17612	Q05469	1	phosphorylation	up-regulates activity	0.602	HSL activity is known to be regulated by phosphorylation (3). PKA increases HSL activity via phosphorylation at Ser563, Ser659, and Ser660 (14,15), although phosphorylation at Ser565 by glycogen synthase kinase, AMP-dependent protein kinase, or Ca2+/calmodulin-dependent protein kinase II has been reported to prevent activation of the enzyme	SIGNOR-249202
Q2MKA7	Q9ULT6	1	relocalization	down-regulates quantity	0.803	Mechanistically, R-spondin interacts with the extracellular domain of ZNRF3 and induces the association between ZNRF3 and LGR4, which results in membrane clearance of ZNRF3. These data suggest that R-spondin enhances Wnt signalling by inhibiting ZNRF3.	SIGNOR-260113
Q969R5	O76064	0	ubiquitination	up-regulates activity	0.242	L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling.	SIGNOR-266787
O60260	O43175	1	ubiquitination	down-regulates quantity by destabilization	0.2	Parkin binds to PHGDH and degrades it through ubiquitination to inhibit serine synthesis, which contributes greatly to the tumor-suppressive function of Parkin.	SIGNOR-269075
O95947	O43541	2	binding	down-regulates quantity by destabilization	0.327	Smad6 mediates Tbx6 ubiquitination and proteasomal degradation. Tbx6 forms a ternary complex with Smad6 and Smurf1. Here, we report that Tbx6 interacts directly with Smad6, an inhibitory Smad that antagonizes the BMP signal. This interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and residues 90-180 of Tbx6. We demonstrate that Smad6 facilitates the degradation of Tbx6 protein through recruitment of Smurf1, a ubiquitin E3 ligase.	SIGNOR-272785
Q9UHP3	Q86Y07	0	phosphorylation	down-regulates activity	0.294	Here, we report that USP25 is a novel TRiC interacting protein that is also phosphorylated by VRK2. USP25 catalyzed deubiquitination of the TRiC protein and stabilized the chaperonin, thereby reducing accumulation of misfolded polyglutamine protein aggregates. Notably, USP25 deubiquitinating activity was suppressed when VRK2 phosphorylated the Thr(680), Thr(727), and Ser(745) residues.	SIGNOR-273579
Q15139	Q9UBF8	1	phosphorylation	up-regulates	0.405	Binding of 14-3-3 proteins to pi4kiiibeta involved the pkd phosphorylation site ser294, evident from reduced 14-3-3 binding to a s294a pi4kiiibeta mutant. Phospho-specific binding of 14-3-3 proteins to phosphatidylinositol 4-kinase iii beta protects from dephosphorylation and stabilizes lipid kinase activity.	SIGNOR-148876
Q13153	P41182	1	phosphorylation	down-regulates activity	0.2	The transcriptional repressor B-cell lymphoma (BCL)-6 downregulates genes involved in cell-cycle progression and becomes inactivated following phosphorylation by the Rac1 GTPase-activated protein kinase PAK1.	SIGNOR-253930
Q9NP77	P24928	1	dephosphorylation	up-regulates activity	0.855	Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.\| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248815
P63027	Q86UW7	2	binding	up-regulates activity	0.255	CAPS interactions with N-terminal regions of the SNARE motif of VAMP2 were also detected, which suggests that CAPS might recruit VAMP2 into syntaxin-1/SNAP-25 heterodimers for RQaQbc-SNARE complex assembly.	SIGNOR-264341
P53567	Q15744	2	binding	up-regulates activity	0.373	C/EBP-epsilon interacts with C/EBP-gamma through the leucine-zipper containing domain. C/EBP-epsilon and C/EBP-gamma synergistically activate transcription of lactoferrin promoter	SIGNOR-224900
P11362	O60506	1	phosphorylation	down-regulates	0.2	Novel in vivo tyrosine phosphorylation sites were found in the fgfr-1, phospholipase cgamma, p90 ribosomal s6 kinase, cortactin, and ns-1-associated protein-1. Syncrip, was very recently found to be phosphorylated in response to insulin treatment of 3t3-l1 adipocytes (32). Phosphorylation of syncrip was accommodated by the insulin receptor tyrosine kinase in vitro but was inhibited upon binding of rna. Tyrosine phosphorylation at tyr-373 in the third rna recognition motif domain of nsap1/syncrip can possibly influence its rna binding properties and thus link fgfr-1 signaling to mrna metabolism.	SIGNOR-98704
Q9H257	O95999	2	binding	up-regulates quantity by stabilization	0.76	To identify upstream signaling partners of BCL10, we performed a mammalian two-hybrid analysis and identified CARD9 as a novel CARD-containing protein that interacts selectively with the CARD activation domain of BCL10. When expressed in cells, CARD9 binds to BCL10 and activates NF-kappaB.	SIGNOR-257602
P51813	P42680	0	phosphorylation	up-regulates activity	0.332	Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop.The major phosphorylation sites were identified as conserved tyrosines, for Itk Y180 and for Bmx Y215, both sites being homologous to the Y223 site in Btk	SIGNOR-246647
Q13547	P15172	2	binding	down-regulates	0.547	Interaction of myod with hdac1 in undifferentiated myoblasts mediates repression of muscle-specific gene expression.	SIGNOR-111243
O43157	Q92854	2	binding	up-regulates	0.808	Binding of sema 4d to plexin b1 stimulates the tyrosine kinase activity of met, resulting in tyrosine phosphorylation of both receptors.	SIGNOR-92201
Q68CZ2	P12931	0	phosphorylation	up-regulates	0.408	Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate	SIGNOR-187843
P35579	P68400	0	phosphorylation	up-regulates	0.34	In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943)	SIGNOR-155987
Q9Y6H5	O60260	0	ubiquitination	down-regulates quantity by destabilization	0.2	Here we show that parkin interacts with and ubiquitinates the alpha-synuclein-interacting protein, synphilin-1.	SIGNOR-278550
P31350	P06493	0	phosphorylation	down-regulates	0.504	We found that, during g2, following cdk-mediated phosphorylation of thr33, rrm2 is degraded via scf(cyclin f) to maintain balanced dntp pools and genome stability.	SIGNOR-197630
Q9NX47	P00441	1	ubiquitination	down-regulates quantity by destabilization	0.2	Mitochondrial ubiquitin ligase MITOL ubiquitinates mutant SOD1 and attenuates mutant SOD1-induced reactive oxygen species generation	SIGNOR-272982
P49450	P06748	2	binding	up-regulates activity	0.566	Here we demonstrate that prenucleosomal CENP-A is complexed with histone H4, nucleophosmin 1, and HJURPA minority of NPM1 cofractionated with prenucleosomal CENP-A, consistent with only a small proportion of total NPM1 stably associated with CENP-A. The partial overlap of NPM1 and HJURP with each other supports their formation of distinct prenucleosomal complexes with CENP-A. it is also possible that NPM1 plays a non essential role in the assembly of CENP-A nucleosomes or the nucleophosmin paralogues NPM2 and NPM3 may compensate for the absence of NPM1.	SIGNOR-263708
P45983	P31946	1	phosphorylation	down-regulates	0.2	The c-jun n-terminal kinase (jnk) protein is activated in the cellular response to dna damage and phosphorylates 14-3-3 on ser 184 these results support a role for 14-3-3 proteins in inhibiting c-abl-mediated apoptosis by sequestering c-abl into the cytoplasm. these findings support a model in which jnk phosphorylation of 14-3-3 proteins induces dissociation of the c-abl_14-3-3 complex and thereby targeting of c-abl to the nucleus.	SIGNOR-133875
P43146	Q13936	1	null	up-regulates activity	0.2	DCC activation by a netrin-1 gradient creates a high-level [Ca2+]i gradient by triggering LCC activity and by stimulating the cAMP–PKA pathway, which further activates LCC in the plasma membrane (PM) and Ca2+ channels in the ER.	SIGNOR-268291
O00206	P58753	2	binding	up-regulates activity	0.78	Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TlR-domain-containing protein in the human genome. Mal activates NF-_B, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2.	SIGNOR-252064
P18848	Q9Y6Q9	2	binding	up-regulates activity	0.2	Mechanistically, Dyrk3 directly phosphorylated NCOA3 at Ser-1330, disrupting its binding to ATF4 and thereby causing the inhibition of ATF4 transcriptional activity.	SIGNOR-275452
P41968	Q03113	2	binding	up-regulates activity	0.25	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257407
O15111	P25963	1	phosphorylation	down-regulates quantity by destabilization	0.896	We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation	SIGNOR-52875
P04264	P05164	2	binding	up-regulates quantity	0.247	CK1 and CK9 specifically bind MPO. MPO is internalized by endothelial cells through a direct interaction with the endothelial surface protein CK1	SIGNOR-251886
Q9BQ15	Q13315	0	phosphorylation	up-regulates activity	0.501	Ataxia telangiectasia mutated (ATM) kinase phosphorylates hSSB1 in response to DNA double-strand breaks (DSBs). This phosphorylation event is required for DNA damage-induced stabilization of hSSB1.	SIGNOR-262639
O14493	P29317	0	phosphorylation	down-regulates activity	0.477	EphA2 associates with claudin-4 via their extracellular domains. This association, in turn, leads to phosphorylation of the cytoplasmic carboxyl terminus of claudin-4 at Tyr-208. The tyrosine phosphorylation of claudin-4 attenuates association of claudin-4 with ZO-1, decreasing integration of claudin-4 into sites of cell-cell contact and enhancing paracellular permeability. These results indicate that EphA2 moderates the function of tight junctions via phosphorylation of claudin-4.	SIGNOR-262859
P68400	P19447	1	phosphorylation	down-regulates activity	0.2	Phosphorylation of S751 by CKII inhibits 5′ incision.	SIGNOR-276013
P09471	Q15391	2	binding	up-regulates activity	0.248	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-257002

O43257

P15173

1

transcriptional regulation

up-regulates quantity by expression

0.259

We show that the srcap subunit named znhit1 or p18hamlet, which is a substrate of p38 mapk, is recruited to the myogenin promoter at the onset of muscle differentiation, in a p38 mapk-dependent manner. We also show that p18hamlet is required for h2a.z accumulation into this genomic region and for subsequent muscle gene transcriptional activation.

SIGNOR-165613

P19174

P17252

2

phosphorylation

up-regulates

0.556

Tnf-alfa binds to tnfr1 and activates pc-plc to induce pkcalfa and c-src activation, leading to tyrosine phosphorylation of ikkbeta at tyr188 and tyr199.

SIGNOR-99310

Q06124

P01116

1

dephosphorylation

up-regulates activity

0.66

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

SIGNOR-255982

Q32MZ4

P43405

0

phosphorylation

up-regulates activity

0.2

However, this inhibitory activity TRIP can be reversed by the co-expression of Syk, which might inhibit the activity of cytoplasmic TRIP, sequester TRIP from important nucleolar targets or even counter TRIP 's inhibitory effects on TRAF and TNF signaling by regulating the activity of alternative components of the pathway.|Syk induces phosphorylation of TRIP on tyrosine.

SIGNOR-279297

Q13535

P04637

1

phosphorylation

up-regulates quantity by stabilization

0.742

Nhibition of atr kinase activity substantially reduces hypoxia-induced phosphorylation of p53 protein on serine 15 as well as p53 protein accumulation.

SIGNOR-115134

Q8TD84

P40763

2

binding

up-regulates activity

0.2

Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels.

SIGNOR-264278

Q13315

Q9UBU7

1

phosphorylation

down-regulates

0.375

Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication.

SIGNOR-177793

Q9Y4P1

Q9P289

0

phosphorylation

up-regulates activity

0.2

ATG4B stimulates autophagy by promoting autophagosome formation through reversible modification of ATG8. We identify ATG4B as a substrate of mammalian sterile20-like kinase (STK) 26/MST4. MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux.

SIGNOR-275833

Q9C0C7

P42345

0

phosphorylation

down-regulates activity

0.471

We show that under non-autophagic conditions, mTOR inhibits AMBRA1 by phosphorylation, whereas on autophagy induction, AMBRA1 is dephosphorylated. In this condition, AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function. As ULK1 has been shown to activate AMBRA1 by phosphorylation, the proposed pathway may act as a positive regulation loop, which may be targeted in human disorders linked to impaired autophagy.|mTOR phosphorylates AMBRA1 at Ser 52, inhibiting its role in ULK1 modification

SIGNOR-272986

Q96T51

P61106

0

relocalization

up-regulates activity

0.63

Here, we have demonstrated that Rab14 interacts with RUFY1, previously identified as a Rab4 effector, and is required for RUFY1 recruitment onto endosomes and efficient recycling of Tfn.

SIGNOR-261279

Q71DI3

Q92831

0

acetylation

down-regulates activity

0.2

The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.

SIGNOR-269626

P10636-2

Q05513

0

phosphorylation

down-regulates activity

0.268

We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs.

SIGNOR-275447

P31431

O14640

2

binding

up-regulates

0.356

Like other wnt co-receptors, syndecan 4 directly interacts with dvl during pcp 1.

SIGNOR-199632

Q7Z3K3

Q96GD4

2

binding

up-regulates activity

0.323

POGZ is required for the correct activation and dissociation of Aurora B kinase from chromosome arms during M phase. These results reveal POGZ as an essential protein that links HP1alpha dissociation with Aurora B kinase activation during mitosis.

SIGNOR-264497

Q96EB6

P42345

0

phosphorylation

down-regulates activity

0.551

These results demonstrate that the inhibition of SIRT1 by mTOR fosters survival of DNA damage-induced prematurely senescent squamous cell carcinoma cells via Bfl-1/A1 in the absence of functional p53.|This process involved the mTOR-dependent phosphorylation of SIRT1 at serine 47, resulting in the inhibition of the deacetylase activity of SIRT1.

SIGNOR-280047

P08603

Q03591

2

binding

down-regulates activity

0.504

Finally, we have been able to establish that CFHR1 can sterically inhibit the interaction that CFH/CFHL-1 SCR1-4 makes with C3b.|CFH regulates the alternative pathway of complement in both the fluid phase and on self-surfaces: It competes with complement factor B (CFB) for binding to C3b and C3(H2O) thereby blocking the formation of the pro-convertase complexes, C3bB and C3(H2O)B. It also accelerates the decay of any existing C3bBb or C3(H2O)Bb. |these data have allowed us to consolidate one possible model of CFHR1-mediated deregulation of CFH/CFHL-1 on an activating surface in which CFHR1 directly competes with or blocks both CFH-binding sites on C3b

SIGNOR-263476

P09693

P06239

0

phosphorylation

up-regulates activity

0.56

Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex.

SIGNOR-259931

Q9Y6K1

P42229

0

transcriptional regulation

up-regulates quantity

0.326

… these data suggest that STAT5A positively regulates levels of DNMT3A, resulting in inactivation of tumor suppressor genes by epigenetic mechanisms in AML cells

SIGNOR-255631

P42574

O75475

1

cleavage

down-regulates

0.348

Ledgf/ p75 has a cooh-terminally truncated splice variant, p52 / during apoptosis, caspase-3 cleaved p52 to generate a p38 fragment that lacked the nh2-terminal pwwp domain and failed to transactivate the hsp27 promoter in reporter assays. However, p38 retained chromatin association properties and repressed the transactivation potential of ledgf/p75

SIGNOR-180144

Q14493

Q7Z2G1

1

translation regulation

up-regulates quantity by expression

0.2

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

SIGNOR-265387

P03372

Q9Y5X4

0

transcriptional regulation

up-regulates quantity by expression

0.251

NR2E3 directly regulates expression of ESR1 | Furthermore, overexpression of exogenous NR2E3 further increased expression of ESR1 and its downstream targets as well as its transcriptional activity in MCF-7 cells (Fig S1 of Supporting Information), strongly demonstrating that NR2E3 regulates ESR1 expression and subsequent ESR1-mediated induction of target genes.

SIGNOR-266207

P17509

P69891

1

transcriptional regulation

down-regulates quantity by repression

0.2

HOXB6 protein represses globin transcript levels in stably transfected K562 cells in a DNA-binding dependent fashion.

SIGNOR-261638

Q96BI1

Q9H6Y7

0

polyubiquitination

down-regulates quantity by destabilization

0.525

Here, we present evidences indicating that RING105, a novel conserved RING-finger protein with a PA (protease-associated) domain and a PEST sequence, is a ubiquitin ligase for TSSC5 that can function in concert with the ubiquitin-conjugating enzyme UbcH6. The polyubiquitin target site on TSSC5 was mapped to a region in the 6th hydrophilic loop.

SIGNOR-271551

P63096

Q9Y271

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-256740

Q8IXL6

Q9GZV9

1

phosphorylation

down-regulates activity

0.64

Here we show that Fam20C directly phosphorylates FGF23 on Ser(180) | Our above results support, phosphorylation of FGF23 at Ser180 inhibits O-glycosylation and would therefore promote hormone proteolysis and thus inactivation.

SIGNOR-260925

P43405

P40763

1

phosphorylation

up-regulates activity

0.552

The current study indicates that the plasma cell malignancy is also associated with Syk-activated STAT3 directly downstream of reelin-induced integrin \u03b21 engagement and FAK/Src activation (Figure xref ).|The integrin-activated spleen tyrosine kinase (Syk) was shown to promote STAT3 phosphorylation [42, 44].

SIGNOR-279298

P29317

P12931

0

phosphorylation

up-regulates activity

0.454

SRC phosphorylates EPHA2 on Tyr594|. It is therefore likely that this phosphorylation site is included in the binding motif of an additional signalling molecule required for cell transformation.

SIGNOR-246104

Q15349

Q92934

1

phosphorylation

down-regulates

0.373

The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival.

SIGNOR-184591

P55010

P68400

0

phosphorylation

up-regulates

0.394

We find that eif5 is associated with ck2 when the kinase activity is at the highest level in vivo, and is phosphorylated at ser389 and ser390 by ck2.

SIGNOR-141159

Q9UER7

Q00987

2

binding

up-regulates

0.673

The optimal function of mdm2 requires daxx, which stabilizes mdm2 through the deubiquitinase hausp/usp7 and also directly promotes mdm2's ubiquitin ligase activity towards p53.

SIGNOR-200892

Q8NG31

O60566

2

binding

up-regulates

0.2

Association of the amino and middle domain of blinkin with the tpr domains in the amino termini of bubr1 and bub1 is essential for bubr1 and bub1 to execute their distinct mitotic functions

SIGNOR-158894

Q15628

Q93038

2

binding

up-regulates

0.739

Dr3 induces apoptosis by tradd-mediated recruitment of fadd and caspase-8

SIGNOR-100480

P45984

P52564

0

phosphorylation

up-regulates

0.473

A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase)

SIGNOR-45369

O15530

Q96PN8

1

phosphorylation

up-regulates activity

0.261

We elucidated the mechanism of regulation of TSSK3 activity showing that autophosphorylation and PDK1 phosphorylation in the ‘activation loop’ are necessary for activation.

SIGNOR-260786

P10071

Q9Y297

0

ubiquitination

down-regulates quantity by destabilization

0.671

Third, we and others have recently shown that only phosphorylated Ci/Gli3 are able to directly bind Slimb/BetaTrCP, that Gli3 is polyubiquitinated in the cell, and that mutations of 4 lysine residues, the putative ubiquitination sites in the Gli3 C-terminal region, inhibit Gli3 processing These observations further support the notion that Ci/Gli3 processing is carried out by the proteasome because the deletion of the cleavage site is expected to often disrupt the protease-mediated site-specific cleavage.

SIGNOR-145116

Q86UR1

Q9HBY0

2

binding

up-regulates activity

0.632

Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation

SIGNOR-264711

P17480

P24941

0

phosphorylation

up-regulates activity

0.372

Phosphorylation of ubf at serine 388 is required for interaction with rna polymerase i and activation of rdna transcription. After g(1) progression ubf is phosphorylated at serine 388 by cdk2/cyclin e and cdk2/cyclin a. Conversion of serine 388 to glycine abolishes ubf activity

SIGNOR-235419

Q99962

Q5S007

0

phosphorylation

down-regulates

0.472

We show that lrrk2 affects synaptic endocytosis by phosphorylating endophilin-a1 at s75.

SIGNOR-192072

P35968

P27986

2

binding

up-regulates activity

0.505

null

SIGNOR-261917

P17509

P69905

1

transcriptional regulation

down-regulates quantity by repression

0.2

HOXB6 protein represses globin transcript levels in stably transfected K562 cells in a DNA-binding dependent fashion.

SIGNOR-261637

Q02763

Q9Y264

2

binding

up-regulates

0.699

In experiments with human endothelial cell lines, ang3 was identified as an antagonist of tie2 and ang4 was identified as an agonist of tie2.

SIGNOR-127351

Q07820

P28062

0

null

down-regulates quantity by destabilization

0.2

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

SIGNOR-261974

Q14344

P32238

2

binding

up-regulates activity

0.25

Our studies indicate that CCK-A receptors inserted into NIH3T3 cells also activate RhoA through G12/13

SIGNOR-278062

P48729

O15534

1

phosphorylation

down-regulates quantity by destabilization

0.318

CKI\u03b1-Dependent Phosphorylation and Degradation of PER1.

SIGNOR-279700

Q9UBW7

Q9H9S0

2

binding

down-regulates activity

0.3

In this work, we identified ZMYM2/ZFP198, which physically associates with NANOG as a key negative regulator of NANOG-mediated reprogramming of both epiblast stem cells and somatic cells.

SIGNOR-269802

Q07812

Q15818

0

relocalization

up-regulates activity

0.2

Immunofluorescence staining and subcellular fractionation analyses revealed increased mitochondrial translocation of Bad and Bax proteins from cytoplasm following OGD (4 h) and simultaneously increased release of Cyt C from mitochondria followed by activation of caspase-3. NP1 protein was immunoprecipitated with Bad and Bax proteins; OGD caused increased interactions of NP1 with Bad and Bax, thereby, facilitating their mitochondrial translocation and dissipation of mitochondrial membrane potential

SIGNOR-261439

P11802

P07947

0

phosphorylation

down-regulates

0.254

We purified tyrosine 17 kinases from hela cells and found that the src family non-receptor tyrosine kinase c-yes contributes a large fraction of the tyrosine 17 kinase activity in hela lysatesthis site is equivalent to tyrosine 15 of cyclin dependent kinase 1, which undergoes inhibitory phosphorylation by wee1 and myt1

SIGNOR-178624

P08754

Q8TDV5

2

binding

up-regulates activity

0.25

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

SIGNOR-257153

Q96T58

Q9Y618

2

binding

up-regulates

0.467

Sharp is a potent transcriptional repressor whose repression domain (rd) interacts directly with smrt

SIGNOR-107260

P49841

O00213

1

phosphorylation

up-regulates quantity

0.293

In this regards, GSK3beta may promote amyloidogenic processing of APP by regulating the cellular level of monomeric FE65 for the formation of LRP1, FE65, and APP complex.|In this study, we showed that FE65 is phosphorylated at T579 by GSK3beta.

SIGNOR-278359

Q01581

P13674

0

transcriptional regulation

up-regulates quantity by expression

0.2

In this study, we found that the prolyl 4-hydroxylase (P4H) subunit P4HA1 protects NPC cells from erastin-induced ferroptosis by activating HMGCS1, a key enzyme in the mevalonate pathway. Our results show that HMGCS1 and HMGCR are regulated by P4HA subunits at the transcriptional level (Fig. S4).

SIGNOR-279853

P58340

Q9UNS2

2

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

P01100

P05412

2

binding

up-regulates activity

0.953

The cFos proto-oncoprotein associates with cJun to form a heterodimer with increased DNA binding and transcriptional activities.

SIGNOR-252087

Q96BR1

Q66PJ3

1

phosphorylation

down-regulates activity

0.2

AIP4 is phosphorylated by CISK in vitro on WW domain residues, which may impact its ability to interact with and ubiquitinate substrate proteins.|Expression of a constitutively active CISK inhibits CXCR4 degradation, possibly by attenuating CXCR4 binding to and ubiquitination by AIP4 and/or modulating the action of AIP4 on a protein involved in CXCR4 endosomal sorting .

SIGNOR-280124

P02461

Q9Y653

2

binding

up-regulates activity

0.2

Using the N-terminal fragment of GPR56 (GPR56(N)) as a probe, we have recently demonstrated that collagen III is the ligand of GPR56 in the developing brain. In this report, we discover a new functional domain in GPR56(N), the ligand binding domain.

SIGNOR-253979

P54253

Q86Y13

0

polyubiquitination

down-regulates quantity by destabilization

0.483

HOTAIR associates with E3 ubiquitin ligases bearing RNA-binding domains, Dzip3 and Mex3b, as well as with their respective ubiquitination substrates, Ataxin-1 and Snurportin-1. In this manner, HOTAIR facilitates the ubiquitination of Ataxin-1 by Dzip3 and Snurportin-1 by Mex3b in cells and in vitro, and accelerates their degradation.

SIGNOR-272078

P42345

O15111

0

phosphorylation

up-regulates activity

0.511

In those studies, we found that IKKalpha interacts with and phosphorylates mTOR in the mTORC1 complex to activate mTORC1, and that Akt signaling drives the IKKalpha-mTORC1 interaction.|We then studied whether IKKalpha promotes Akt and mTOR activity in other mammalian cancer cell lines.

SIGNOR-279607

P05106

O14713

2

binding

down-regulates activity

0.308

Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation

SIGNOR-257656

P60709

O14994

2

binding

up-regulates activity

0.2

Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner.

SIGNOR-269183

Q86X55

Q92922

1

methylation

up-regulates activity

0.537

CARM1-mediated BAF155 methylation affects gene expression by directing methylated BAF155 to unique chromatin regions (e.g., c-Myc pathway genes). Collectively, our studies uncover a mechanism by which BAF155 acquires tumorigenic functions via arginine methylation.

SIGNOR-251708

Q02763

Q03112

0

transcriptional regulation

up-regulates quantity by expression

0.2

We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2

SIGNOR-266063

O95398

P61224

1

guanine nucleotide exchange factor

up-regulates activity

0.718

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

SIGNOR-263957

O15294

P06737

1

glycosylation

up-regulates activity

0.2

O-GlcNAcylation at Ser-430 promotes PYGL activity

SIGNOR-267988

P08559

Q9P2J9

0

dephosphorylation

up-regulates activity

0.658

Pyruvate dehydrogenase phosphatase (PDP) is a mitochondrial serine phosphatase that activates phosphorylated pyruvate dehydrogenase complex by dephosphorylation

SIGNOR-251665

P19174

P07948

0

phosphorylation

up-regulates activity

0.656

The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.

SIGNOR-249381

P22681

P36888

2

binding

down-regulates activity

0.436

Functionally, CBL negatively regulated FMS-like tyrosine kinase 3 (FLT3) activity and interacted with human FLT3 via the autophosphorylation sites Y589 and Y599 and colocalized in vivo.

SIGNOR-255739

O96013

Q9BY11

1

phosphorylation

up-regulates activity

0.295

We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo.

SIGNOR-263023

P17612

Q05469

1

phosphorylation

up-regulates activity

0.602

HSL activity is known to be regulated by phosphorylation (3). PKA increases HSL activity via phosphorylation at Ser563, Ser659, and Ser660 (14,15), although phosphorylation at Ser565 by glycogen synthase kinase, AMP-dependent protein kinase, or Ca2+/calmodulin-dependent protein kinase II has been reported to prevent activation of the enzyme

SIGNOR-249202

Q2MKA7

Q9ULT6

1

relocalization

down-regulates quantity

0.803

Mechanistically, R-spondin interacts with the extracellular domain of ZNRF3 and induces the association between ZNRF3 and LGR4, which results in membrane clearance of ZNRF3. These data suggest that R-spondin enhances Wnt signalling by inhibiting ZNRF3.

SIGNOR-260113

Q969R5

O76064

0

ubiquitination

up-regulates activity

0.242

L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling.

SIGNOR-266787

O60260

O43175

1

ubiquitination

down-regulates quantity by destabilization

0.2

Parkin binds to PHGDH and degrades it through ubiquitination to inhibit serine synthesis, which contributes greatly to the tumor-suppressive function of Parkin.

SIGNOR-269075

O95947

O43541

2

binding

down-regulates quantity by destabilization

0.327

Smad6 mediates Tbx6 ubiquitination and proteasomal degradation. Tbx6 forms a ternary complex with Smad6 and Smurf1. Here, we report that Tbx6 interacts directly with Smad6, an inhibitory Smad that antagonizes the BMP signal. This interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and residues 90-180 of Tbx6. We demonstrate that Smad6 facilitates the degradation of Tbx6 protein through recruitment of Smurf1, a ubiquitin E3 ligase.

SIGNOR-272785

Q9UHP3

Q86Y07

0

phosphorylation

down-regulates activity

0.294

Here, we report that USP25 is a novel TRiC interacting protein that is also phosphorylated by VRK2. USP25 catalyzed deubiquitination of the TRiC protein and stabilized the chaperonin, thereby reducing accumulation of misfolded polyglutamine protein aggregates. Notably, USP25 deubiquitinating activity was suppressed when VRK2 phosphorylated the Thr(680), Thr(727), and Ser(745) residues.

SIGNOR-273579

Q15139

Q9UBF8

1

phosphorylation

up-regulates

0.405

Binding of 14-3-3 proteins to pi4kiiibeta involved the pkd phosphorylation site ser294, evident from reduced 14-3-3 binding to a s294a pi4kiiibeta mutant. Phospho-specific binding of 14-3-3 proteins to phosphatidylinositol 4-kinase iii beta protects from dephosphorylation and stabilizes lipid kinase activity.

SIGNOR-148876

Q13153

P41182

1

phosphorylation

down-regulates activity

0.2

The transcriptional repressor B-cell lymphoma (BCL)-6 downregulates genes involved in cell-cycle progression and becomes inactivated following phosphorylation by the Rac1 GTPase-activated protein kinase PAK1.

SIGNOR-253930

Q9NP77

P24928

1

dephosphorylation

up-regulates activity

0.855

Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro

SIGNOR-248815

P63027

Q86UW7

2

binding

up-regulates activity

0.255

CAPS interactions with N-terminal regions of the SNARE motif of VAMP2 were also detected, which suggests that CAPS might recruit VAMP2 into syntaxin-1/SNAP-25 heterodimers for RQaQbc-SNARE complex assembly.

SIGNOR-264341

P53567

Q15744

2

binding

up-regulates activity

0.373

C/EBP-epsilon interacts with C/EBP-gamma through the leucine-zipper containing domain. C/EBP-epsilon and C/EBP-gamma synergistically activate transcription of lactoferrin promoter

SIGNOR-224900

P11362

O60506

1

phosphorylation

down-regulates

0.2

Novel in vivo tyrosine phosphorylation sites were found in the fgfr-1, phospholipase cgamma, p90 ribosomal s6 kinase, cortactin, and ns-1-associated protein-1. Syncrip, was very recently found to be phosphorylated in response to insulin treatment of 3t3-l1 adipocytes (32). Phosphorylation of syncrip was accommodated by the insulin receptor tyrosine kinase in vitro but was inhibited upon binding of rna. Tyrosine phosphorylation at tyr-373 in the third rna recognition motif domain of nsap1/syncrip can possibly influence its rna binding properties and thus link fgfr-1 signaling to mrna metabolism.

SIGNOR-98704

Q9H257

O95999

2

binding

up-regulates quantity by stabilization

0.76

To identify upstream signaling partners of BCL10, we performed a mammalian two-hybrid analysis and identified CARD9 as a novel CARD-containing protein that interacts selectively with the CARD activation domain of BCL10. When expressed in cells, CARD9 binds to BCL10 and activates NF-kappaB.

SIGNOR-257602

P51813

P42680

0

phosphorylation

up-regulates activity

0.332

Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop.The major phosphorylation sites were identified as conserved tyrosines, for Itk Y180 and for Bmx Y215, both sites being homologous to the Y223 site in Btk

SIGNOR-246647

Q13547

P15172

2

binding

down-regulates

0.547

Interaction of myod with hdac1 in undifferentiated myoblasts mediates repression of muscle-specific gene expression.

SIGNOR-111243

O43157

Q92854

2

binding

up-regulates

0.808

Binding of sema 4d to plexin b1 stimulates the tyrosine kinase activity of met, resulting in tyrosine phosphorylation of both receptors.

SIGNOR-92201

Q68CZ2

P12931

0

phosphorylation

up-regulates

0.408

Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate

SIGNOR-187843

P35579

P68400

0

phosphorylation

up-regulates

0.34

In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943)

SIGNOR-155987

Q9Y6H5

O60260

0

ubiquitination

down-regulates quantity by destabilization

0.2

Here we show that parkin interacts with and ubiquitinates the alpha-synuclein-interacting protein, synphilin-1.

SIGNOR-278550

P31350

P06493

0

phosphorylation

down-regulates

0.504

We found that, during g2, following cdk-mediated phosphorylation of thr33, rrm2 is degraded via scf(cyclin f) to maintain balanced dntp pools and genome stability.

SIGNOR-197630

Q9NX47

P00441

1

ubiquitination

down-regulates quantity by destabilization

0.2

Mitochondrial ubiquitin ligase MITOL ubiquitinates mutant SOD1 and attenuates mutant SOD1-induced reactive oxygen species generation

SIGNOR-272982

P49450

P06748

2

binding

up-regulates activity

0.566

Here we demonstrate that prenucleosomal CENP-A is complexed with histone H4, nucleophosmin 1, and HJURPA minority of NPM1 cofractionated with prenucleosomal CENP-A, consistent with only a small proportion of total NPM1 stably associated with CENP-A. The partial overlap of NPM1 and HJURP with each other supports their formation of distinct prenucleosomal complexes with CENP-A. it is also possible that NPM1 plays a non essential role in the assembly of CENP-A nucleosomes or the nucleophosmin paralogues NPM2 and NPM3 may compensate for the absence of NPM1.

SIGNOR-263708

P45983

P31946

1

phosphorylation

down-regulates

0.2

The c-jun n-terminal kinase (jnk) protein is activated in the cellular response to dna damage and phosphorylates 14-3-3 on ser 184 these results support a role for 14-3-3 proteins in inhibiting c-abl-mediated apoptosis by sequestering c-abl into the cytoplasm. these findings support a model in which jnk phosphorylation of 14-3-3 proteins induces dissociation of the c-abl_14-3-3 complex and thereby targeting of c-abl to the nucleus.

SIGNOR-133875

P43146

Q13936

1

null

up-regulates activity

0.2

DCC activation by a netrin-1 gradient creates a high-level [Ca2+]i gradient by triggering LCC activity and by stimulating the cAMP–PKA pathway, which further activates LCC in the plasma membrane (PM) and Ca2+ channels in the ER.

SIGNOR-268291

O00206

P58753

2

binding

up-regulates activity

0.78

Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TlR-domain-containing protein in the human genome. Mal activates NF-_B, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2.

SIGNOR-252064

P18848

Q9Y6Q9

2

binding

up-regulates activity

0.2

Mechanistically, Dyrk3 directly phosphorylated NCOA3 at Ser-1330, disrupting its binding to ATF4 and thereby causing the inhibition of ATF4 transcriptional activity.

SIGNOR-275452

P41968

Q03113

2

binding

up-regulates activity

0.25

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

SIGNOR-257407

O15111

P25963

1

phosphorylation

down-regulates quantity by destabilization

0.896

We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation

SIGNOR-52875

P04264

P05164

2

binding

up-regulates quantity

0.247

CK1 and CK9 specifically bind MPO. MPO is internalized by endothelial cells through a direct interaction with the endothelial surface protein CK1

SIGNOR-251886

Q9BQ15

Q13315

0

phosphorylation

up-regulates activity

0.501

Ataxia telangiectasia mutated (ATM) kinase phosphorylates hSSB1 in response to DNA double-strand breaks (DSBs). This phosphorylation event is required for DNA damage-induced stabilization of hSSB1.

SIGNOR-262639

O14493

P29317

0

phosphorylation

down-regulates activity

0.477

EphA2 associates with claudin-4 via their extracellular domains. This association, in turn, leads to phosphorylation of the cytoplasmic carboxyl terminus of claudin-4 at Tyr-208. The tyrosine phosphorylation of claudin-4 attenuates association of claudin-4 with ZO-1, decreasing integration of claudin-4 into sites of cell-cell contact and enhancing paracellular permeability. These results indicate that EphA2 moderates the function of tight junctions via phosphorylation of claudin-4.

SIGNOR-262859

P68400

P19447

1

phosphorylation

down-regulates activity

0.2

Phosphorylation of S751 by CKII inhibits 5′ incision.

SIGNOR-276013

P09471

Q15391

2

binding

up-regulates activity

0.248

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-257002