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
Q12933	Q13077	2	binding	up-regulates	0.636	Our analysis indicates that traf1 and traf2 are associated with the cytoplasmic domain of tnf-r2 in a heterodimeric complex in which traf2 contacts the receptor directly. Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2.	SIGNOR-35881
P49841	P31751	0	phosphorylation	down-regulates activity	0.623	Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1	SIGNOR-245420
P00519	Q04912	0	phosphorylation	up-regulates activity	0.272	This suggests that by interacting with Sdc4, either directly or indirectly, RON is activated via transphosphorylation when clustered, engages the ABL1 SH2 domain, and activates ABL1 by phosphorylation.	SIGNOR-272999
Q15796	P10398	0	phosphorylation	down-regulates quantity by destabilization	0.37	Araf promotes Smad2 linker phosphorylation through S253.\|In this study, we demonstrate that Araf can directly bind to and phosphorylate the linker of Smad2, leading to degradation of activated Smad2.	SIGNOR-279391
P28482	Q9GZM8	1	phosphorylation	up-regulates activity	0.287	In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites	SIGNOR-274076
Q13882	P49023	1	phosphorylation	up-regulates activity	0.63	It was also observed that the attenuation of BRK phosphorylation in turn inhibits BRK mediated activation of its direct targets, STAT3, SAM68, and Paxillin.\|The EGF pathway also stimulates BRK 's phosphorylation of paxillin to promote migratory and invasive characteristics in breast cancer cells.	SIGNOR-280102
P09471	P49683	2	binding	up-regulates activity	0.306	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-256973
P84022	P55317	2	binding	down-regulates activity	0.331	TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. Repression is mediated by SMAD3 through interactions with NKX2.1 and FOXA1, two key transcription factors that are positive regulators of SpB transcription. In this study, we found that SMAD3 interacts through its MAD domains, MH1 and MH2 with NKX2.1 and FOXA1 proteins. The sites of interaction on NKX2.1 are located within the NH2 and COOH domains, known to be involved in transactivation function.	SIGNOR-254168
Q5NUL3	P63096	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-257045
Q14766	P01137	2	binding	up-regulates activity	0.638	Together these data form strong support for the hypothesis that the LTBP plays an essential role in the activation of latent TGF-b in heterotypic cultures.	SIGNOR-235754
P54821	P78347	2	binding	up-regulates	0.345	Spin binds specifically to multiple sequences in the c-fos promoter and interacts cooperatively withphox1to promote serum-inducible transcription of a reporter gene driven by the c-fos serum response element (sre).	SIGNOR-52654
P10451	Q8IXL6	0	phosphorylation	down-regulates quantity	0.683	OPN phosphorylation by Fam20C decreased OPN secretion, and OPN neutralization reduced Fam20C-deficiency-induced osteoclast differentiation and bone metastasis.	SIGNOR-278936
P35580	P14859	0	transcriptional regulation	up-regulates quantity by expression	0.2	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238772
P62993	P36888	2	binding	up-regulates activity	0.604	FL stimulation induces association of Grb2 with Flt3, SHP-2,and Shc	SIGNOR-245060
P07947	O15524	1	phosphorylation	up-regulates quantity by stabilization	0.2	Samples from human lymphomas that often overexpress SOCS1 also displayed SRC family kinase activation, constitutive phosphorylation of SOCS1 on Y80, and SOCS1 cytoplasmic localization.	SIGNOR-277453
P05412	Q00534	0	phosphorylation	up-regulates quantity	0.423	CDK6 additionally induced c-Jun phosphorylation, but did not activate JNK, as determined by examining JNK phosphorylation at various time-points.\|CDK6 upregulates c-Jun expression.	SIGNOR-280222
P0DP25	O00418	2	binding	up-regulates	0.461	The calmodulin-binding region is located between amino acids 51 and 96	SIGNOR-266337
Q14012	P49757	1	phosphorylation	down-regulates	0.334	Based on experiments using numb mutants, both the initial phosphorylation of ser(264) and the subsequent phosphorylation of ser(283) are sufficient to abolish the binding of numb to ap-2.	SIGNOR-149993
P06213	Q8TCQ1	0	ubiquitination	down-regulates quantity by destabilization	0.2	MARCH1 ubiquitinates INSR to decrease cell surface INSR levels, but unlike other INSR ubiquitin ligases, MARCH1 acts in the basal state rather than after insulin stimulation.	SIGNOR-278819
P27361	P15923	1	phosphorylation	down-regulates quantity by destabilization	0.372	Notch-induced degradation requires phosphorylation of E47 by p42/p44 MAP kinases. \|Wild_type E47 but not the Mm mutant reacted to the antibodies, suggesting that E47 is at least phosphorylated at the M2 site (Figure 3A)\|anti_phospho_M2 peptide (SSPSpTPVGSPQG)	SIGNOR-249117
P40818	P56817	1	deubiquitination	up-regulates quantity by stabilization	0.45	Accordingly, we reported that BACE1 is ubiquitinated at lysine 501 and that lack of ubiquitination at lysine 501 produces BACE1 stabilization.Our findings demonstrate that USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating lysine 501.	SIGNOR-259101
O60216	Q14674	0	cleavage	down-regulates quantity by destabilization	0.78	In order to segregate sister chromatids to opposite poles in anaphase, cohesin has to be removed from chromosomes. In budding yeast, the prevalent mode of cohesin removal is by proteolytic cleavage of the Scc1 subunit at the onset of anaphase by the endopeptidase separase	SIGNOR-275537
Q5SW24	P36897	2	binding	down-regulates	0.392	Here, we provide evidence that unlike dpr1 that modulates wnt signaling, mdpr2 negatively regulates tgf-? Signaling and promotes tgf-? Receptor degradation in lysosomes. these results suggest that mdpr2 interferes with tgf-? By directly binding to and targeting the receptors for lysosomal inhibitor-sensitive degradation.	SIGNOR-151750
Q66GS9	Q9HC77	2	binding	up-regulates activity	0.808	In this study, we demonstrate that the human microcephaly protein, CEP135, directly interacts with hSAS-6 via its carboxyl-terminus and with MTs via its amino-terminus. Unexpectedly, CEP135 also interacts with another microcephaly protein CPAP via its amino terminal domain. Depletion of CEP135 not only perturbed the centriolar localization of CPAP, but also blocked CPAP-induced centriole elongation. We propose that CEP135 may serve as a linker protein that directly connects the central hub protein, hSAS-6, to the outer MTs, and suggest that this interaction stabilizes the proper cartwheel structure for further CPAP-mediated centriole elongation.	SIGNOR-269677
P31749	Q15257	0	dephosphorylation	down-regulates	0.2	Consistent with previous reports (2830), we found that expression of sv40st, suppression of either pp2a c or b resulted in elevated levels of akt phosphorylation (ser473)	SIGNOR-252607
Q9H0M0	O00308	2	binding	up-regulates activity	0.2	WWP1 in complex with WWP2 specifically regulates ΔNp73. In our study, we identified WWP2, an E3 ligase, as a novel p73-associated protein that ubiquitinates and degrades p73. In contrast, WWP2 heterodimerizes with another E3 ligase, WWP1, which specifically ubiquitinates and degrades ΔNp73.	SIGNOR-272231
Q9Y275	O14836	2	binding	up-regulates	0.781	Tumor necrosis factor (tnf) receptor superfamily member taci is a high affinity receptor for tnf family members april and blys.	SIGNOR-81360
Q96P70	Q13315	0	phosphorylation	up-regulates activity	0.2	In line with our previous results, IR exposure induced the nuclear accumulation of RanBP9, which was prevented by ATM inhibition using KU-55933.\|Taken together these data indicate that RanBP9 is a novel target of ATM and that ATM phosphorylates at least two different residues (S181 and S603) of RanBP9 following IR exposure.	SIGNOR-278910
P55211	Q13075	2	binding	down-regulates	0.459	These results demonstrate that naip is distinct from the other iaps, both in demonstrating a ligand-dependent caspase-9 interaction and in demonstrating a distinct mechanism of inhibition.	SIGNOR-127193
P31269	Q8NFU7	0	transcriptional regulation	up-regulates quantity by expression	0.306	Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9.	SIGNOR-259094
Q96KB5	O75385	1	phosphorylation	down-regulates activity	0.2	We found that TOPK could directly bind with and phosphorylate ULK1 at Ser469, Ser495, and Ser533. The phosphorylation of ULK1 at Ser469, Ser495, and Ser533 by TOPK decreased the activity and stability of ULK1.	SIGNOR-277473
Q13535	O43542	1	phosphorylation	up-regulates activity	0.464	HXRCC3 S225 phosphorylation is mediated by ATR via an ATM-dependent signaling pathway. These data clearly indicate that ATR mediates the late activation of XRCC3 following DSB accumulation.	SIGNOR-262666
P55072	Q8TAT6	2	binding	up-regulates activity	0.946	These findings ascribe specific functions to each of the components of the VCP-UFD1L-NPL4 complex in Vpu-mediated CD4 degradation: VCP energizes the process through ATP binding and hydrolysis, UFD1L binds ubiquitinated CD4 through recognition of K48 Ub chains, and NPL4 stabilizes UFD1L. VCP is thus likely to provide the energy required for extraction of CD4 from membranes.	SIGNOR-252423
P25116	P30679	2	binding	up-regulates activity	0.567	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-257353
O95721	P51956	0	phosphorylation	up-regulates activity	0.2	In the present study, we show that NEK3 (NIMA-never in mitosis gene A-related kinase 3)-mediated serine 105 (S105) phosphorylation of SNAP29 directs its membrane association, without which cells present defective focal adhesion formation, impaired Golgi structure and attenuated cellular recycling. Our results highlight the importance of NEK3-mediated S105 phosphorylation of SNAP29 for its membrane localization and for membrane fusion dependent processes.	SIGNOR-273708
Q8N9B8	P01116	1	guanine nucleotide exchange factor	up-regulates	0.427	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-183826
P18433	P07948	1	dephosphorylation	down-regulates activity	0.3	We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397\|Lyn expressed in CHO cells has a substantially higher specific activity than Lyn in RBL cells because of high levels of phosphorylation at its active site Tyr-397 (Fig. 1). Enhanced Lyn kinase activity in the CHO cells leads to spontaneous phosphorylation of multiple cellular proteins, including FcϵRI	SIGNOR-248436
O43379	P24941	1	relocalization	up-regulates activity	0.244	Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome.	SIGNOR-271726
Q9GZT9	Q13131	0	phosphorylation	down-regulates activity	0.373	Mechanistically, AMPKα1 directly phosphorylated prolyl hydroxylase domain-containing (PHD)2 at serines 61 and 136, which suppressed PHD2-dependent hydroxylation of hypoxia-inducible factor (HIF)1α and subsequent regulation of hepatic hepcidin-related iron signalling.	SIGNOR-277592
Q8WV44	Q02156	1	polyubiquitination	down-regulates quantity by destabilization	0.2	RINCK induces the ubiquitination of PKC both in vitro and in cells. Overexpression of RINCK reduces the levels of PKC in cells, whereas genetic knockdown of endogenous RINCK increases the levels of PKC. The RINCK-mediated ubiquitination is likely to be polyubiquitination, because the ubiquitinated PKCβII was detected as a high molecular weight smear.	SIGNOR-271668
Q13191	O00459	1	ubiquitination	down-regulates activity	0.499	Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells. it can be postulated that Cbl-b, as an E3 Ub ligase, may play a general role in functional regulation of its target proteins through ubiquitination in a protein degradation-independent manner.	SIGNOR-271424
P0C0S8	O76064	0	ubiquitination	up-regulates	0.2	Rnf8 and ubc13 ubiquitylate h2a and h2ax, but other substrates probably exist.	SIGNOR-166174
O75581	P34947	0	phosphorylation	up-regulates	0.548	we found that g protein-coupled receptor kinases 5 and 6 (grk5/6), traditionally known to phosphorylate and desensitize 7tm g protein-coupled receptors, directly phosphorylate the pppsp motifs on single transmembrane lrp6 and regulate wnt/lrp6 signaling	SIGNOR-23330
P11413	P68400	0	phosphorylation	up-regulates activity	0.2	CK2 phosphorylates G6PD T145 under ionizing radiation	SIGNOR-277890
O75469	P24941	0	phosphorylation	down-regulates quantity by destabilization	0.372	PXR Phosphorylation at S350 by CDK2 Triggers PXR Degradation via the Ubiquitin-Proteasome Pathway.	SIGNOR-279397
Q9BQL6	Q8IWT3	0	ubiquitination	down-regulates quantity by destabilization	0.2	M-phase-specific CDK1–cyclin B1 complex directly binds KIND1 and KIND2 and phosphorylates a conserved proline-directed CDK1 consensus motif in the flexible and intrinsically disordered loop of the F1 domain. This then results in the recruitment of the CUL9–FBXL10 complex, modification with K48-linked polyubiquitin chains and proteasomal degradation of KIND1 and KIND2.	SIGNOR-276718
Q13557	Q13557	2	phosphorylation	up-regulates	0.2	Upon binding of the Ca2+/calmodulin complex to the binding domain of CaMKII, it is activated via autophosphorylation, then remaining active independent of of Ca2+ levels.	SIGNOR-255954
P53355	P09493	1	phosphorylation	up-regulates activity	0.277	We identified, for the first time, death-associated protein kinase 1 (DAP kinase 1) as the kinase that phosphorylates tropomyosin-1 in response to ERK activation by hydrogen peroxide (H(2)O(2)). We also report that the phosphorylation of tropomyosin-1 mediated by DAP kinase occurs on Ser283. Our finding that tropomyosin-1 is phosphorylated downstream of ERK and DAP kinase and that it helps regulate the formation of stress fibers will aid understanding the role of this protein in regulating the endothelial functions associated with cytoskeletal remodeling.	SIGNOR-262845
P62714	Q9Y570	0	demethylation	down-regulates activity	0.716	Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits \|Demethylation and negative regulation of PP2A is mediated by a PP2A-specific methylesterase PME-1, which is conserved from yeast to humans.	SIGNOR-265750
Q9Y490	P18564	2	binding	up-regulates activity	0.577	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257631
Q8N122	P28482	0	phosphorylation	up-regulates activity	0.518	We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1.	SIGNOR-188916
Q15366	Q96J02	2	binding	up-regulates activity	0.615	Only AIP4 associated with PCBP2 and caused MAVS degradation. The interaction between PCBP2 and AIP4 was abrogated when the linker region or WB2 of PCBP2 was deleted, which confirmed our previous data indicating that this region was critical for PCBP2-mediated degradation of MAVS	SIGNOR-260361
Q9H237	P56704	1	palmitoylation	up-regulates activity	0.7	And WNT3A binding to WLS requires PORCN-dependent lipid modification of WNT3A at serine 209. Inhibition of vacuolar acidification results in accumulation of the WNT3A-WLS complex both in cells and at the plasma membrane.	SIGNOR-256598
Q99626	P24941	0	phosphorylation	down-regulates quantity by destabilization	0.476	Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation\|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo.	SIGNOR-250729
P53350	P06748	1	phosphorylation	up-regulates	0.425	Phosphorylated at ser-4 by plk1 and plk2. Phosphorylation at ser-4 by plk2 in s phase is required for centriole duplication and is sufficient to trigger centriole replication. Phosphorylation at ser-4 by plk1 takes place during mitosis.	SIGNOR-125666
P49840	P13807	1	phosphorylation	down-regulates	0.411	Glycogen synthase kinase-3 (gsk-3) phosphorylates four serine residues in the cooh terminus of glycogen synthase. Phosphorylation of one of these residues, ser640 (site 3a), causes strong inactivation of glycogen synthase	SIGNOR-118927
P45984	Q9Y2Y9	1	phosphorylation	down-regulates quantity by destabilization	0.2	TGF-β-mediated downregulation of KLF13 by HDAC-mediated epigenetic silencing and JNK-induced phosphorylation abrogates the latter’s inhibitory effect on TGF-β signaling.	SIGNOR-277809
Q92793	O75177	0	relocalization	up-regulates	0.397	The calcium-responsive transactivator recruits creb binding protein to nuclear bodies.	SIGNOR-129926
Q15418	P01100	1	phosphorylation	up-regulates activity	0.529	We now provide evidence that two growth-regulated, nucleus- and cytoplasm-localized protein kinases, 90-kda ribosomal s6 kinase (rsk) and mitogen-activated protein kinase (map kinase), contribute to the serum-induced phosphorylation of c-fos. The major phosphopeptides derived from biosynthetically labeled c-fos correspond to phosphopeptides generated after phosphorylation of c-fos in vitro with both rsk and map kinase. The phosphorylation sites identified for rsk (ser-362) and map kinase (ser-374) are in the transrepression domain. Cooperative phosphorylation at these sites by both enzymes was observed in vitro and reflected in vivo by the predominance of the peptide phosphorylated on both sites, as opposed to singly phosphorylated peptides. This study suggests a role for nuclear rsk and map kinase in modulating newly synthesized c-fos phosphorylation and downstream signaling.	SIGNOR-37154
Q5JTC6	Q9HCP0	2	binding	up-regulates	0.2	Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6.	SIGNOR-171889
Q05639	P59595	2	binding	down-regulates activity	0.2	The nucleocapsid protein of severe acute respiratory syndrome coronavirus inhibits cell cytokinesis and proliferation by interacting with translation elongation factor 1alpha	SIGNOR-260260
O14649	P51812	0	phosphorylation	up-regulates activity	0.2	The chaperone protein, 14-3-3, binds to a critical phosphorylated serine in the channel c termini of k2p3.1 and k2p9.1 (ser(393) and ser(373), respectively) and overcomes retention in the endoplasmic reticulum by ?COP. We sought to identify the kinase responsible for phosphorylation of the terminal serine in human and rat variants of k2p3.1 and k2p9.1. Adopting a bioinformatic approach, three candidate protein kinases were identified: camp-dependent protein kinase, ribosomal s6 kinase, and protein kinase c.	SIGNOR-172470
O14965	Q96R06	1	phosphorylation	up-regulates activity	0.511	We report here that Astrin acts as a mitotic phosphoprotein, and Aurora-A phosphorylates Astrin at Ser(115). The phosphorylation-deficient mutant Astrin S115A abnormally activates spindle assembly checkpoint and delays mitosis progression, decreases spindle stability, and induces chromosome misalignment. Mechanistic analyses reveal that Astrin phosphorylation mimicking mutant S115D, instead of S115A, binds and induces ubiquitination and degradation of securin, which sequentially activates Separase, an enzyme required for the separation of sister chromatids.	SIGNOR-276648
P14859	P12882	1	transcriptional regulation	up-regulates quantity by expression	0.2	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238760
O75084	P63092	2	binding	up-regulates activity	0.2	Wnt7a binding to fzd7 activates pi3k through a g protein alpha s- dependent mechanism.	SIGNOR-198831
P29274	O95837	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-257413
Q13263	P12931	0	phosphorylation	down-regulates activity	0.2	Among SFKs, Src strongly induces tyrosine phosphorylation of KAP1.\|Immunostaining and chromatin fractionation show that Src and Lyn decrease the association of KAP1 with heterochromatin in a kinase activity-dependent manner.	SIGNOR-280137
O43791	Q13618	2	binding	up-regulates activity	0.921	Here we show that the CULLIN3 E3 ubiquitin ligase adaptor protein SPOP binds Geminin at endogenous level and regulates DNA replication. SPOP promotes K27-linked non-degradative poly-ubiquitination of Geminin at lysine residues 100 and 127.	SIGNOR-268927
P23381	Q2TAL8	0	transcriptional regulation	up-regulates quantity by expression	0.2	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269410
Q9NTX7	Q9NTX7	2	ubiquitination	down-regulates quantity	0.2	We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation.	SIGNOR-260006
Q8TBB1	Q9UMX1	1	ubiquitination	down-regulates quantity	0.2	Indeed, they target different lysine residues in the SuFu protein, as LNX1 ubiquitinates SuFu at K59 and K470, and SCF Fbxl17 acts at K257, while Itch ubiquitinates at K321 and K457.\|XREF_FIG, ectopic LNX1 expression reduced SuFu protein levels in HEK-293T cells, while shRNA mediated knockdown of LNX1 increased these levels.	SIGNOR-278626
Q9UK53	Q8IXJ6	2	binding	down-regulates activity	0.451	We found that p33(ING1b) physically interacts with hSIR2, reverses its ability to induce the AFP promoter, and induces acetylation of p53 residues at Lys(373) and/or Lys(382).	SIGNOR-254486
O95863	Q9UKA1	2	binding	down-regulates quantity by destabilization	0.509	FBXL5 is located in the nucleus where it interacts with Snail1 promoting its polyubiquitination and affecting Snail1 protein stability and function by impairing DNA binding. Snail1 is ubiquitinated by the SCFFBXL5 complex. Snail1 downregulation by FBXL5 is prevented by Lats2, a protein kinase that phosphorylates Snail1 precluding its nuclear export but not its polyubiquitination. To demonstrate that FBXL5 has a direct activity on Snail1, we carried out polyubiquitination reactions in vitro. For this we purified Snail1 and the SCFFBXL5 complex from Sf9 insect cells infected with different baculoviruses corresponding to Flag-FBXL5, His-Skp1, HA-Cullin1 and Rbx1 (Supplementary Figure S3C).	SIGNOR-272135
P78527	Q9GZU7	0	dephosphorylation	up-regulates activity	0.2	CTDSP1 activates DNA-PKcs and enhances DNA-PKcs dependent topoI degradation in response to irinotecan .\|Our novel finding indicates that CTDSP1 dephosphorylates DNA-PKcs, changes its kinase activity, and regulates irinotecan-induced topoI degradation.	SIGNOR-277101
Q13976	P10644	1	phosphorylation	up-regulates activity	0.234	In this study, we further examined the potential of RIα phosphorylation to regulate physiologically relevant "desensitization" of PKAc activity. First, the serine 101 site of RIα was validated as a target of PKGIα phosphorylation both in vitro and in cells.These findings suggest that RIα phosphorylation may be a novel mechanism to circumvent the requirement of cAMP stimulus to activate type I PKA in cells.	SIGNOR-277383
P62714	P05771	1	dephosphorylation	down-regulates activity	0.469	Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme.	SIGNOR-248585
P04155	O00170	0	transcriptional regulation	down-regulates quantity by repression	0.2	We show that XAP2 is recruited to the promoter of ERα regulated genes like the breast cancer marker gene pS2 or GREB1 and negatively regulate the expression of these genes in MCF-7 cells.	SIGNOR-259911
P05107	P12931	0	phosphorylation	down-regulates activity	0.449	PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role.	SIGNOR-254740
P61086	Q8WVD3	2	binding	up-regulates activity	0.536	NARF exhibits E3 ubiquitin-ligase activity in cooperation with the ubiquitin conjugating enzyme, E2-25K. These data show that the auto-ubiquitylating activity of NARF is coordinated with E2-25K, and that the RING finger domain of NARF is indispensable for this reaction.	SIGNOR-271594
Q00535	P35611	1	phosphorylation	up-regulates activity	0.255	We found that Cdk5 directly phosphorylated the actin-binding protein adducin-1 (ADD1) at T724 in vitro and in intact cells.	SIGNOR-277487
Q15392	Q9UBM7	2	binding	up-regulates activity	0.653	DHCR7 coimmunoprecipitates DHCR24. Overexpression of functional DHCR24 increases DHCR7 activity. Because knockdown of DHCR24 has no effect on DHCR7 mRNA (Fig. 3A), this implies that this phenomenon is occurring posttranscriptionally. Thus, the interaction between the two terminal steps of cholesterol synthesis appears to have functional consequences.	SIGNOR-267249
Q7Z5G4	P01111	1	palmitoylation	up-regulates activity	0.396	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-261354
P16070	O14672	0	cleavage	up-regulates activity	0.346	The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin.	SIGNOR-259847
O94953	Q99814	0	transcriptional regulation	up-regulates quantity by expression	0.2	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271584
P06241	Q13094	1	phosphorylation	down-regulates	0.755	P59fyn_phosphorylated slp-76 at intermediate levels but, significantly, this phosphorylation failed to induce vav?SLP-76 complex formation	SIGNOR-46851
O75170	P06493	0	phosphorylation	down-regulates activity	0.261	We found that many interactions were abolished upon kinase inhibition; however, a subset was protected from phosphatase opposition or was unopposed, resulting in persistent interaction of the substrate with Plk1. This subset includes phosphoprotein phosphatase 6 (PP6), whose activity toward Aurora kinase A (Aurora A) was inhibited by Plk1. Our data suggest that this Plk1-PP6 interaction generates a feedback loop that coordinates and reinforces the activities of Plk1 and Aurora A during mitotic entry and is terminated by the degradation of Plk1 during mitotic exit.	SIGNOR-273587
Q5T447	P55211	1	polyubiquitination	down-regulates activity	0.2	HECTD3 binds and ubiquitinates caspase-9.HECTD3 inhibits caspase-9 oligomerization and association with Apaf-1. HECTD3 suppressing caspase-9 activation is dependent on T157 phosphorylation by ERK.	SIGNOR-272329
Q96SN8	P23258	2	binding	up-regulates activity	0.652	Immunoprecipitation of CDK5RAP2 specifically coprecipitated _TuRC components, as detected on immunoblots of _-tubulin and GCP3 (Figure 3A).\| Perturbing CDK5RAP2 function delocalized gamma-tubulin from the centrosomes and inhibited centrosomal microtubule nucleation, thus leading to disorganization of interphase microtubule arrays and formation of anastral mitotic spindles. Together, CDK5RAP2 is a pericentriolar structural component that functions in gammaTuRC attachment and therefore in the microtubule organizing function of the centrosome.	SIGNOR-260310
Q9Y4I1	P60709	2	binding	up-regulates activity	0.409	Myosin Va regulates exocytosis of large dense-core vesicles (LDCVs). interestingly, inhibition of myosin Va potentiates LDCV exocytosis to the same extent as F-actin depolymerization does, suggesting that myosin Va cooperates with the actin cytoskeleton to impede or control LDCV exocytosis	SIGNOR-269280
Q66K89	P52926	2	binding	down-regulates	0.371	Here we show that hmga2 associates with the e1a-regulated transcriptional repressor p120(e4f), interfering with p120(e4f) binding to the cyclin a promoter	SIGNOR-119537
P06241	A8K4G0	1	phosphorylation	up-regulates activity	0.308	As CD300b phosphorylation was occurring only in the presence of both c-Fyn and DAP-12, we addressed whether tyrosine phosphorylation was required for association of CD300b and DAP-12. For this purpose, we generated a set of HA-tagged CD300b mutants affecting the transmembrane lysine (K158L), the cytoplasmic tyrosine (Y188F) or both residues.\|As expected, the CD300b double mutant could neither recruit DAP-12 nor become phosphorylated in the presence of c-Fyn kinase (Fig. 5⇑C). Association between CD300b and DAP-12 was maintained in absence of the c-Fyn kinase, indicating that phosphorylation of the adaptor was not essential for the formation of the complex (data not shown)	SIGNOR-264771
P50221	P23760	2	binding	up-regulates activity	0.422	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-222235
Q02241	O43663	2	binding	up-regulates activity	0.572	These data indicate that PRC1 binds to KIF4, MKLP1 and CENP-E during late mitosis; however, it apparently does not interact simultaneously with more than one of these motor proteins.	SIGNOR-265989
P04908	Q9H3R0	0	demethylation	down-regulates activity	0.2	As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation	SIGNOR-263862
Q53ET0	P35575	1	transcriptional regulation	up-regulates quantity	0.2	Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB	SIGNOR-256103
P62136	P55211	1	dephosphorylation	up-regulates	0.2	Pp1 dephosphorylated thr125 site of caspase-9 and activated caspase-9 to mediate il-2 deprivation-induced apoptosis.	SIGNOR-195992
Q9BPV8	P50148	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-256892
Q16620	P52735	1	phosphorylation	up-regulates activity	0.302	Finally, the TrkB kinase dependent increase in P-Y172 Vav2 was largely independent of the Vav2 SH2 domain (XREF_FIG, right), which was previously shown to be important for activation by Eph receptors.\|These findings reveal a strong kinase independent binding mechanism between Vav and TrkB in cells, and suggest that activation of TrkB kinase activity stimulates Vav2 tyrosine phosphorylation and GEF activity.	SIGNOR-280050
P51812	O15530	0	phosphorylation	up-regulates	0.655	We characterize two monoclonal antibodies raised against phosphorylated forms of the n- and c-terminal domain of rsk2 (p-s227 and p-t577, respectively). Using these two antibodies, we show that stress signals, such as uv light, induce phosphorylation and activation of the three rsks.	SIGNOR-70612
P17612	Q14978	1	phosphorylation	up-regulates	0.307	Here we demonstrate that protein kinase a (pka)-dependent phosphorylation of nopp140 at ser 627, together with c/ebpbeta, induces agp gene expression synergistically.	SIGNOR-91186

Q12933

Q13077

2

binding

up-regulates

0.636

Our analysis indicates that traf1 and traf2 are associated with the cytoplasmic domain of tnf-r2 in a heterodimeric complex in which traf2 contacts the receptor directly. Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2.

SIGNOR-35881

P49841

P31751

0

phosphorylation

down-regulates activity

0.623

Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1

SIGNOR-245420

P00519

Q04912

0

phosphorylation

up-regulates activity

0.272

This suggests that by interacting with Sdc4, either directly or indirectly, RON is activated via transphosphorylation when clustered, engages the ABL1 SH2 domain, and activates ABL1 by phosphorylation.

SIGNOR-272999

Q15796

P10398

0

phosphorylation

down-regulates quantity by destabilization

0.37

Araf promotes Smad2 linker phosphorylation through S253.|In this study, we demonstrate that Araf can directly bind to and phosphorylate the linker of Smad2, leading to degradation of activated Smad2.

SIGNOR-279391

P28482

Q9GZM8

1

phosphorylation

up-regulates activity

0.287

In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites

SIGNOR-274076

Q13882

P49023

1

phosphorylation

up-regulates activity

0.63

It was also observed that the attenuation of BRK phosphorylation in turn inhibits BRK mediated activation of its direct targets, STAT3, SAM68, and Paxillin.|The EGF pathway also stimulates BRK 's phosphorylation of paxillin to promote migratory and invasive characteristics in breast cancer cells.

SIGNOR-280102

P09471

P49683

2

binding

up-regulates activity

0.306

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-256973

P84022

P55317

2

binding

down-regulates activity

0.331

TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. Repression is mediated by SMAD3 through interactions with NKX2.1 and FOXA1, two key transcription factors that are positive regulators of SpB transcription. In this study, we found that SMAD3 interacts through its MAD domains, MH1 and MH2 with NKX2.1 and FOXA1 proteins. The sites of interaction on NKX2.1 are located within the NH2 and COOH domains, known to be involved in transactivation function.

SIGNOR-254168

Q5NUL3

P63096

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-257045

Q14766

P01137

2

binding

up-regulates activity

0.638

Together these data form strong support for the hypothesis that the LTBP plays an essential role in the activation of latent TGF-b in heterotypic cultures.

SIGNOR-235754

P54821

P78347

2

binding

up-regulates

0.345

Spin binds specifically to multiple sequences in the c-fos promoter and interacts cooperatively withphox1to promote serum-inducible transcription of a reporter gene driven by the c-fos serum response element (sre).

SIGNOR-52654

P10451

Q8IXL6

0

phosphorylation

down-regulates quantity

0.683

OPN phosphorylation by Fam20C decreased OPN secretion, and OPN neutralization reduced Fam20C-deficiency-induced osteoclast differentiation and bone metastasis.

SIGNOR-278936

P35580

P14859

0

transcriptional regulation

up-regulates quantity by expression

0.2

Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation

SIGNOR-238772

P62993

P36888

2

binding

up-regulates activity

0.604

FL stimulation induces association of Grb2 with Flt3, SHP-2,and Shc

SIGNOR-245060

P07947

O15524

1

phosphorylation

up-regulates quantity by stabilization

0.2

Samples from human lymphomas that often overexpress SOCS1 also displayed SRC family kinase activation, constitutive phosphorylation of SOCS1 on Y80, and SOCS1 cytoplasmic localization.

SIGNOR-277453

P05412

Q00534

0

phosphorylation

up-regulates quantity

0.423

CDK6 additionally induced c-Jun phosphorylation, but did not activate JNK, as determined by examining JNK phosphorylation at various time-points.|CDK6 upregulates c-Jun expression.

SIGNOR-280222

P0DP25

O00418

2

binding

up-regulates

0.461

The calmodulin-binding region is located between amino acids 51 and 96

SIGNOR-266337

Q14012

P49757

1

phosphorylation

down-regulates

0.334

Based on experiments using numb mutants, both the initial phosphorylation of ser(264) and the subsequent phosphorylation of ser(283) are sufficient to abolish the binding of numb to ap-2.

SIGNOR-149993

P06213

Q8TCQ1

0

ubiquitination

down-regulates quantity by destabilization

0.2

MARCH1 ubiquitinates INSR to decrease cell surface INSR levels, but unlike other INSR ubiquitin ligases, MARCH1 acts in the basal state rather than after insulin stimulation.

SIGNOR-278819

P27361

P15923

1

phosphorylation

down-regulates quantity by destabilization

0.372

Notch-induced degradation requires phosphorylation of E47 by p42/p44 MAP kinases. |Wild_type E47 but not the Mm mutant reacted to the antibodies, suggesting that E47 is at least phosphorylated at the M2 site (Figure 3A)|anti_phospho_M2 peptide (SSPSpTPVGSPQG)

SIGNOR-249117

P40818

P56817

1

deubiquitination

up-regulates quantity by stabilization

0.45

Accordingly, we reported that BACE1 is ubiquitinated at lysine 501 and that lack of ubiquitination at lysine 501 produces BACE1 stabilization.Our findings demonstrate that USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating lysine 501.

SIGNOR-259101

O60216

Q14674

0

cleavage

down-regulates quantity by destabilization

0.78

In order to segregate sister chromatids to opposite poles in anaphase, cohesin has to be removed from chromosomes. In budding yeast, the prevalent mode of cohesin removal is by proteolytic cleavage of the Scc1 subunit at the onset of anaphase by the endopeptidase separase

SIGNOR-275537

Q5SW24

P36897

2

binding

down-regulates

0.392

Here, we provide evidence that unlike dpr1 that modulates wnt signaling, mdpr2 negatively regulates tgf-? Signaling and promotes tgf-? Receptor degradation in lysosomes. these results suggest that mdpr2 interferes with tgf-? By directly binding to and targeting the receptors for lysosomal inhibitor-sensitive degradation.

SIGNOR-151750

Q66GS9

Q9HC77

2

binding

up-regulates activity

0.808

In this study, we demonstrate that the human microcephaly protein, CEP135, directly interacts with hSAS-6 via its carboxyl-terminus and with MTs via its amino-terminus. Unexpectedly, CEP135 also interacts with another microcephaly protein CPAP via its amino terminal domain. Depletion of CEP135 not only perturbed the centriolar localization of CPAP, but also blocked CPAP-induced centriole elongation. We propose that CEP135 may serve as a linker protein that directly connects the central hub protein, hSAS-6, to the outer MTs, and suggest that this interaction stabilizes the proper cartwheel structure for further CPAP-mediated centriole elongation.

SIGNOR-269677

P31749

Q15257

0

dephosphorylation

down-regulates

0.2

Consistent with previous reports (2830), we found that expression of sv40st, suppression of either pp2a c or b resulted in elevated levels of akt phosphorylation (ser473)

SIGNOR-252607

Q9H0M0

O00308

2

binding

up-regulates activity

0.2

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

SIGNOR-272231

Q9Y275

O14836

2

binding

up-regulates

0.781

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

SIGNOR-81360

Q96P70

Q13315

0

phosphorylation

up-regulates activity

0.2

In line with our previous results, IR exposure induced the nuclear accumulation of RanBP9, which was prevented by ATM inhibition using KU-55933.|Taken together these data indicate that RanBP9 is a novel target of ATM and that ATM phosphorylates at least two different residues (S181 and S603) of RanBP9 following IR exposure.

SIGNOR-278910

P55211

Q13075

2

binding

down-regulates

0.459

These results demonstrate that naip is distinct from the other iaps, both in demonstrating a ligand-dependent caspase-9 interaction and in demonstrating a distinct mechanism of inhibition.

SIGNOR-127193

P31269

Q8NFU7

0

transcriptional regulation

up-regulates quantity by expression

0.306

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

SIGNOR-259094

Q96KB5

O75385

1

phosphorylation

down-regulates activity

0.2

We found that TOPK could directly bind with and phosphorylate ULK1 at Ser469, Ser495, and Ser533. The phosphorylation of ULK1 at Ser469, Ser495, and Ser533 by TOPK decreased the activity and stability of ULK1.

SIGNOR-277473

Q13535

O43542

1

phosphorylation

up-regulates activity

0.464

HXRCC3 S225 phosphorylation is mediated by ATR via an ATM-dependent signaling pathway. These data clearly indicate that ATR mediates the late activation of XRCC3 following DSB accumulation.

SIGNOR-262666

P55072

Q8TAT6

2

binding

up-regulates activity

0.946

These findings ascribe specific functions to each of the components of the VCP-UFD1L-NPL4 complex in Vpu-mediated CD4 degradation: VCP energizes the process through ATP binding and hydrolysis, UFD1L binds ubiquitinated CD4 through recognition of K48 Ub chains, and NPL4 stabilizes UFD1L. VCP is thus likely to provide the energy required for extraction of CD4 from membranes.

SIGNOR-252423

P25116

P30679

2

binding

up-regulates activity

0.567

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-257353

O95721

P51956

0

phosphorylation

up-regulates activity

0.2

In the present study, we show that NEK3 (NIMA-never in mitosis gene A-related kinase 3)-mediated serine 105 (S105) phosphorylation of SNAP29 directs its membrane association, without which cells present defective focal adhesion formation, impaired Golgi structure and attenuated cellular recycling. Our results highlight the importance of NEK3-mediated S105 phosphorylation of SNAP29 for its membrane localization and for membrane fusion dependent processes.

SIGNOR-273708

Q8N9B8

P01116

1

guanine nucleotide exchange factor

up-regulates

0.427

Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.

SIGNOR-183826

P18433

P07948

1

dephosphorylation

down-regulates activity

0.3

We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397|Lyn expressed in CHO cells has a substantially higher specific activity than Lyn in RBL cells because of high levels of phosphorylation at its active site Tyr-397 (Fig. 1). Enhanced Lyn kinase activity in the CHO cells leads to spontaneous phosphorylation of multiple cellular proteins, including FcϵRI

SIGNOR-248436

O43379

P24941

1

relocalization

up-regulates activity

0.244

Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome.

SIGNOR-271726

Q9GZT9

Q13131

0

phosphorylation

down-regulates activity

0.373

Mechanistically, AMPKα1 directly phosphorylated prolyl hydroxylase domain-containing (PHD)2 at serines 61 and 136, which suppressed PHD2-dependent hydroxylation of hypoxia-inducible factor (HIF)1α and subsequent regulation of hepatic hepcidin-related iron signalling.

SIGNOR-277592

Q8WV44

Q02156

1

polyubiquitination

down-regulates quantity by destabilization

0.2

RINCK induces the ubiquitination of PKC both in vitro and in cells. Overexpression of RINCK reduces the levels of PKC in cells, whereas genetic knockdown of endogenous RINCK increases the levels of PKC. The RINCK-mediated ubiquitination is likely to be polyubiquitination, because the ubiquitinated PKCβII was detected as a high molecular weight smear.

SIGNOR-271668

Q13191

O00459

1

ubiquitination

down-regulates activity

0.499

Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells. it can be postulated that Cbl-b, as an E3 Ub ligase, may play a general role in functional regulation of its target proteins through ubiquitination in a protein degradation-independent manner.

SIGNOR-271424

P0C0S8

O76064

0

ubiquitination

up-regulates

0.2

Rnf8 and ubc13 ubiquitylate h2a and h2ax, but other substrates probably exist.

SIGNOR-166174

O75581

P34947

0

phosphorylation

up-regulates

0.548

we found that g protein-coupled receptor kinases 5 and 6 (grk5/6), traditionally known to phosphorylate and desensitize 7tm g protein-coupled receptors, directly phosphorylate the pppsp motifs on single transmembrane lrp6 and regulate wnt/lrp6 signaling

SIGNOR-23330

P11413

P68400

0

phosphorylation

up-regulates activity

0.2

CK2 phosphorylates G6PD T145 under ionizing radiation

SIGNOR-277890

O75469

P24941

0

phosphorylation

down-regulates quantity by destabilization

0.372

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

SIGNOR-279397

Q9BQL6

Q8IWT3

0

ubiquitination

down-regulates quantity by destabilization

0.2

M-phase-specific CDK1–cyclin B1 complex directly binds KIND1 and KIND2 and phosphorylates a conserved proline-directed CDK1 consensus motif in the flexible and intrinsically disordered loop of the F1 domain. This then results in the recruitment of the CUL9–FBXL10 complex, modification with K48-linked polyubiquitin chains and proteasomal degradation of KIND1 and KIND2.

SIGNOR-276718

Q13557

2

phosphorylation

up-regulates

0.2

Upon binding of the Ca2+/calmodulin complex to the binding domain of CaMKII, it is activated via autophosphorylation, then remaining active independent of of Ca2+ levels.

SIGNOR-255954

P53355

P09493

1

phosphorylation

up-regulates activity

0.277

We identified, for the first time, death-associated protein kinase 1 (DAP kinase 1) as the kinase that phosphorylates tropomyosin-1 in response to ERK activation by hydrogen peroxide (H(2)O(2)). We also report that the phosphorylation of tropomyosin-1 mediated by DAP kinase occurs on Ser283. Our finding that tropomyosin-1 is phosphorylated downstream of ERK and DAP kinase and that it helps regulate the formation of stress fibers will aid understanding the role of this protein in regulating the endothelial functions associated with cytoskeletal remodeling.

SIGNOR-262845

P62714

Q9Y570

0

demethylation

down-regulates activity

0.716

Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits |Demethylation and negative regulation of PP2A is mediated by a PP2A-specific methylesterase PME-1, which is conserved from yeast to humans.

SIGNOR-265750

Q9Y490

P18564

2

binding

up-regulates activity

0.577

Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.

SIGNOR-257631

Q8N122

P28482

0

phosphorylation

up-regulates activity

0.518

We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1.

SIGNOR-188916

Q15366

Q96J02

2

binding

up-regulates activity

0.615

Only AIP4 associated with PCBP2 and caused MAVS degradation. The interaction between PCBP2 and AIP4 was abrogated when the linker region or WB2 of PCBP2 was deleted, which confirmed our previous data indicating that this region was critical for PCBP2-mediated degradation of MAVS

SIGNOR-260361

Q9H237

P56704

1

palmitoylation

up-regulates activity

0.7

And WNT3A binding to WLS requires PORCN-dependent lipid modification of WNT3A at serine 209. Inhibition of vacuolar acidification results in accumulation of the WNT3A-WLS complex both in cells and at the plasma membrane.

SIGNOR-256598

Q99626

P24941

0

phosphorylation

down-regulates quantity by destabilization

0.476

Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo.

SIGNOR-250729

P53350

P06748

1

phosphorylation

up-regulates

0.425

Phosphorylated at ser-4 by plk1 and plk2. Phosphorylation at ser-4 by plk2 in s phase is required for centriole duplication and is sufficient to trigger centriole replication. Phosphorylation at ser-4 by plk1 takes place during mitosis.

SIGNOR-125666

P49840

P13807

1

phosphorylation

down-regulates

0.411

Glycogen synthase kinase-3 (gsk-3) phosphorylates four serine residues in the cooh terminus of glycogen synthase. Phosphorylation of one of these residues, ser640 (site 3a), causes strong inactivation of glycogen synthase

SIGNOR-118927

P45984

Q9Y2Y9

1

phosphorylation

down-regulates quantity by destabilization

0.2

TGF-β-mediated downregulation of KLF13 by HDAC-mediated epigenetic silencing and JNK-induced phosphorylation abrogates the latter’s inhibitory effect on TGF-β signaling.

SIGNOR-277809

Q92793

O75177

0

relocalization

up-regulates

0.397

The calcium-responsive transactivator recruits creb binding protein to nuclear bodies.

SIGNOR-129926

Q15418

P01100

1

phosphorylation

up-regulates activity

0.529

We now provide evidence that two growth-regulated, nucleus- and cytoplasm-localized protein kinases, 90-kda ribosomal s6 kinase (rsk) and mitogen-activated protein kinase (map kinase), contribute to the serum-induced phosphorylation of c-fos. The major phosphopeptides derived from biosynthetically labeled c-fos correspond to phosphopeptides generated after phosphorylation of c-fos in vitro with both rsk and map kinase. The phosphorylation sites identified for rsk (ser-362) and map kinase (ser-374) are in the transrepression domain. Cooperative phosphorylation at these sites by both enzymes was observed in vitro and reflected in vivo by the predominance of the peptide phosphorylated on both sites, as opposed to singly phosphorylated peptides. This study suggests a role for nuclear rsk and map kinase in modulating newly synthesized c-fos phosphorylation and downstream signaling.

SIGNOR-37154

Q5JTC6

Q9HCP0

2

binding

up-regulates

0.2

Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6.

SIGNOR-171889

Q05639

P59595

2

binding

down-regulates activity

0.2

The nucleocapsid protein of severe acute respiratory syndrome coronavirus inhibits cell cytokinesis and proliferation by interacting with translation elongation factor 1alpha

SIGNOR-260260

O14649

P51812

0

phosphorylation

up-regulates activity

0.2

The chaperone protein, 14-3-3, binds to a critical phosphorylated serine in the channel c termini of k2p3.1 and k2p9.1 (ser(393) and ser(373), respectively) and overcomes retention in the endoplasmic reticulum by ?COP. We sought to identify the kinase responsible for phosphorylation of the terminal serine in human and rat variants of k2p3.1 and k2p9.1. Adopting a bioinformatic approach, three candidate protein kinases were identified: camp-dependent protein kinase, ribosomal s6 kinase, and protein kinase c.

SIGNOR-172470

O14965

Q96R06

1

phosphorylation

up-regulates activity

0.511

We report here that Astrin acts as a mitotic phosphoprotein, and Aurora-A phosphorylates Astrin at Ser(115). The phosphorylation-deficient mutant Astrin S115A abnormally activates spindle assembly checkpoint and delays mitosis progression, decreases spindle stability, and induces chromosome misalignment. Mechanistic analyses reveal that Astrin phosphorylation mimicking mutant S115D, instead of S115A, binds and induces ubiquitination and degradation of securin, which sequentially activates Separase, an enzyme required for the separation of sister chromatids.

SIGNOR-276648

P14859

P12882

1

transcriptional regulation

up-regulates quantity by expression

0.2

Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation

SIGNOR-238760

O75084

P63092

2

binding

up-regulates activity

0.2

Wnt7a binding to fzd7 activates pi3k through a g protein alpha s- dependent mechanism.

SIGNOR-198831

P29274

O95837

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-257413

Q13263

P12931

0

phosphorylation

down-regulates activity

0.2

Among SFKs, Src strongly induces tyrosine phosphorylation of KAP1.|Immunostaining and chromatin fractionation show that Src and Lyn decrease the association of KAP1 with heterochromatin in a kinase activity-dependent manner.

SIGNOR-280137

O43791

Q13618

2

binding

up-regulates activity

0.921

Here we show that the CULLIN3 E3 ubiquitin ligase adaptor protein SPOP binds Geminin at endogenous level and regulates DNA replication. SPOP promotes K27-linked non-degradative poly-ubiquitination of Geminin at lysine residues 100 and 127.

SIGNOR-268927

P23381

Q2TAL8

0

transcriptional regulation

up-regulates quantity by expression

0.2

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

SIGNOR-269410

Q9NTX7

2

ubiquitination

down-regulates quantity

0.2

We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation.

SIGNOR-260006

Q8TBB1

Q9UMX1

1

ubiquitination

down-regulates quantity

0.2

Indeed, they target different lysine residues in the SuFu protein, as LNX1 ubiquitinates SuFu at K59 and K470, and SCF Fbxl17 acts at K257, while Itch ubiquitinates at K321 and K457.|XREF_FIG, ectopic LNX1 expression reduced SuFu protein levels in HEK-293T cells, while shRNA mediated knockdown of LNX1 increased these levels.

SIGNOR-278626

Q9UK53

Q8IXJ6

2

binding

down-regulates activity

0.451

We found that p33(ING1b) physically interacts with hSIR2, reverses its ability to induce the AFP promoter, and induces acetylation of p53 residues at Lys(373) and/or Lys(382).

SIGNOR-254486

O95863

Q9UKA1

2

binding

down-regulates quantity by destabilization

0.509

FBXL5 is located in the nucleus where it interacts with Snail1 promoting its polyubiquitination and affecting Snail1 protein stability and function by impairing DNA binding. Snail1 is ubiquitinated by the SCFFBXL5 complex. Snail1 downregulation by FBXL5 is prevented by Lats2, a protein kinase that phosphorylates Snail1 precluding its nuclear export but not its polyubiquitination. To demonstrate that FBXL5 has a direct activity on Snail1, we carried out polyubiquitination reactions in vitro. For this we purified Snail1 and the SCFFBXL5 complex from Sf9 insect cells infected with different baculoviruses corresponding to Flag-FBXL5, His-Skp1, HA-Cullin1 and Rbx1 (Supplementary Figure S3C).

SIGNOR-272135

P78527

Q9GZU7

0

dephosphorylation

up-regulates activity

0.2

CTDSP1 activates DNA-PKcs and enhances DNA-PKcs dependent topoI degradation in response to irinotecan .|Our novel finding indicates that CTDSP1 dephosphorylates DNA-PKcs, changes its kinase activity, and regulates irinotecan-induced topoI degradation.

SIGNOR-277101

Q13976

P10644

1

phosphorylation

up-regulates activity

0.234

In this study, we further examined the potential of RIα phosphorylation to regulate physiologically relevant "desensitization" of PKAc activity. First, the serine 101 site of RIα was validated as a target of PKGIα phosphorylation both in vitro and in cells.These findings suggest that RIα phosphorylation may be a novel mechanism to circumvent the requirement of cAMP stimulus to activate type I PKA in cells.

SIGNOR-277383

P62714

P05771

1

dephosphorylation

down-regulates activity

0.469

Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme.

SIGNOR-248585

P04155

O00170

0

transcriptional regulation

down-regulates quantity by repression

0.2

We show that XAP2 is recruited to the promoter of ERα regulated genes like the breast cancer marker gene pS2 or GREB1 and negatively regulate the expression of these genes in MCF-7 cells.

SIGNOR-259911

P05107

P12931

0

phosphorylation

down-regulates activity

0.449

PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role.

SIGNOR-254740

P61086

Q8WVD3

2

binding

up-regulates activity

0.536

NARF exhibits E3 ubiquitin-ligase activity in cooperation with the ubiquitin conjugating enzyme, E2-25K. These data show that the auto-ubiquitylating activity of NARF is coordinated with E2-25K, and that the RING finger domain of NARF is indispensable for this reaction.

SIGNOR-271594

Q00535

P35611

1

phosphorylation

up-regulates activity

0.255

We found that Cdk5 directly phosphorylated the actin-binding protein adducin-1 (ADD1) at T724 in vitro and in intact cells.

SIGNOR-277487

Q15392

Q9UBM7

2

binding

up-regulates activity

0.653

DHCR7 coimmunoprecipitates DHCR24. Overexpression of functional DHCR24 increases DHCR7 activity. Because knockdown of DHCR24 has no effect on DHCR7 mRNA (Fig. 3A), this implies that this phenomenon is occurring posttranscriptionally. Thus, the interaction between the two terminal steps of cholesterol synthesis appears to have functional consequences.

SIGNOR-267249

Q7Z5G4

P01111

1

palmitoylation

up-regulates activity

0.396

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-261354

P16070

O14672

0

cleavage

up-regulates activity

0.346

The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin.

SIGNOR-259847

O94953

Q99814

0

transcriptional regulation

up-regulates quantity by expression

0.2

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

SIGNOR-271584

P06241

Q13094

1

phosphorylation

down-regulates

0.755

P59fyn_phosphorylated slp-76 at intermediate levels but, significantly, this phosphorylation failed to induce vav?SLP-76 complex formation

SIGNOR-46851

O75170

P06493

0

phosphorylation

down-regulates activity

0.261

We found that many interactions were abolished upon kinase inhibition; however, a subset was protected from phosphatase opposition or was unopposed, resulting in persistent interaction of the substrate with Plk1. This subset includes phosphoprotein phosphatase 6 (PP6), whose activity toward Aurora kinase A (Aurora A) was inhibited by Plk1. Our data suggest that this Plk1-PP6 interaction generates a feedback loop that coordinates and reinforces the activities of Plk1 and Aurora A during mitotic entry and is terminated by the degradation of Plk1 during mitotic exit.

SIGNOR-273587

Q5T447

P55211

1

polyubiquitination

down-regulates activity

0.2

HECTD3 binds and ubiquitinates caspase-9.HECTD3 inhibits caspase-9 oligomerization and association with Apaf-1. HECTD3 suppressing caspase-9 activation is dependent on T157 phosphorylation by ERK.

SIGNOR-272329

Q96SN8

P23258

2

binding

up-regulates activity

0.652

Immunoprecipitation of CDK5RAP2 specifically coprecipitated _TuRC components, as detected on immunoblots of _-tubulin and GCP3 (Figure 3A).| Perturbing CDK5RAP2 function delocalized gamma-tubulin from the centrosomes and inhibited centrosomal microtubule nucleation, thus leading to disorganization of interphase microtubule arrays and formation of anastral mitotic spindles. Together, CDK5RAP2 is a pericentriolar structural component that functions in gammaTuRC attachment and therefore in the microtubule organizing function of the centrosome.

SIGNOR-260310

Q9Y4I1

P60709

2

binding

up-regulates activity

0.409

Myosin Va regulates exocytosis of large dense-core vesicles (LDCVs). interestingly, inhibition of myosin Va potentiates LDCV exocytosis to the same extent as F-actin depolymerization does, suggesting that myosin Va cooperates with the actin cytoskeleton to impede or control LDCV exocytosis

SIGNOR-269280

Q66K89

P52926

2

binding

down-regulates

0.371

Here we show that hmga2 associates with the e1a-regulated transcriptional repressor p120(e4f), interfering with p120(e4f) binding to the cyclin a promoter

SIGNOR-119537

P06241

A8K4G0

1

phosphorylation

up-regulates activity

0.308

As CD300b phosphorylation was occurring only in the presence of both c-Fyn and DAP-12, we addressed whether tyrosine phosphorylation was required for association of CD300b and DAP-12. For this purpose, we generated a set of HA-tagged CD300b mutants affecting the transmembrane lysine (K158L), the cytoplasmic tyrosine (Y188F) or both residues.|As expected, the CD300b double mutant could neither recruit DAP-12 nor become phosphorylated in the presence of c-Fyn kinase (Fig. 5⇑C). Association between CD300b and DAP-12 was maintained in absence of the c-Fyn kinase, indicating that phosphorylation of the adaptor was not essential for the formation of the complex (data not shown)

SIGNOR-264771

P50221

P23760

2

binding

up-regulates activity

0.422

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-222235

Q02241

O43663

2

binding

up-regulates activity

0.572

These data indicate that PRC1 binds to KIF4, MKLP1 and CENP-E during late mitosis; however, it apparently does not interact simultaneously with more than one of these motor proteins.

SIGNOR-265989

P04908

Q9H3R0

0

demethylation

down-regulates activity

0.2

As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation

SIGNOR-263862

Q53ET0

P35575

1

transcriptional regulation

up-regulates quantity

0.2

Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB

SIGNOR-256103

P62136

P55211

1

dephosphorylation

up-regulates

0.2

Pp1 dephosphorylated thr125 site of caspase-9 and activated caspase-9 to mediate il-2 deprivation-induced apoptosis.

SIGNOR-195992

Q9BPV8

P50148

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-256892

Q16620

P52735

1

phosphorylation

up-regulates activity

0.302

Finally, the TrkB kinase dependent increase in P-Y172 Vav2 was largely independent of the Vav2 SH2 domain (XREF_FIG, right), which was previously shown to be important for activation by Eph receptors.|These findings reveal a strong kinase independent binding mechanism between Vav and TrkB in cells, and suggest that activation of TrkB kinase activity stimulates Vav2 tyrosine phosphorylation and GEF activity.

SIGNOR-280050

P51812

O15530

0

phosphorylation

up-regulates

0.655

We characterize two monoclonal antibodies raised against phosphorylated forms of the n- and c-terminal domain of rsk2 (p-s227 and p-t577, respectively). Using these two antibodies, we show that stress signals, such as uv light, induce phosphorylation and activation of the three rsks.

SIGNOR-70612

P17612

Q14978

1

phosphorylation

up-regulates

0.307

Here we demonstrate that protein kinase a (pka)-dependent phosphorylation of nopp140 at ser 627, together with c/ebpbeta, induces agp gene expression synergistically.

SIGNOR-91186