GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels float64 0 2	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
P15173	P23409	1	transcriptional regulation	up-regulates quantity by expression	0.433	[...] confirming that myogenin binds to the E1 and E2 E boxes located in close proximity to the MRF4 transcription start site.	SIGNOR-255642
Q8TAP6	P53350	1	binding	down-regulates activity	0.433	Here, we found that centrosomal protein of 76 kDa (Cep76), previously shown to restrain centriole amplification, interacts with cyclin-dependent kinase 2 (CDK2) and is a bona fide substrate of this kinase. Cep76 is preferentially phosphorylated by cyclin A/CDK2 at a single site S83, and this event is crucial to suppress centriole amplification in S phase. Mechanistically, Cep76 phosphorylation inhibits activation of polo-like kinase 1 (Plk1), thereby blocking premature centriole disengagement and subsequent amplification.	SIGNOR-262731
Q12933	Q8IUC6	1	polyubiquitination	up-regulates	0.433	Here, we show that the TRAF family proteins directly bind TICAM-1 and demonstrate that TRAF2 and TRAF6 bind different sites of the N-terminal TICAM-1 and accelerate its polyubiquitination. we speculate that polyubiquitination of TICAM-1 by TRAF2 and TRAF6 is required for TICAM-1 to induce IRF-3 and NF-κB activation. This is supported by the observation that polyubiquitination of TICAM-1 was required for TRAF3-binding to TICAM-1	SIGNOR-271427
Q92905	Q13485	1	ubiquitination	down-regulates	0.433	We report a novel mechanism of smad4 degradation. Jab1 interacts directly with smad4 and induces its ubiquitylation for degradation	SIGNOR-114697
Q7Z3K3	P45973	1	binding	down-regulates activity	0.433	POGZ was found to bind to HP1alpha through a zinc-finger-like motif. Binding by POGZ, mediated through its zinc-finger-like motif, competed with PxVxL proteins and destabilized the HP1alpha-chromatin interaction.	SIGNOR-264487
P21452	O95837	1	binding	up-regulates activity	0.433	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-257131
Q9UBR4	Q96A47	1	binding	up-regulates activity	0.433	a direct NLI-independent interaction between Lhx3 and the related proteins Isl1 and Isl2 was observed. The combinatorial expression of the LIM homeodomain proteins Isl1, Isl2, Lhx1, and Lhx3 in subsets of developing motor neurons correlates with the future organization of these neurons into motor columns with distinct innervation targets, implying a functional role for LIM homeodomain protein combinations in the specification of neuronal identity	SIGNOR-236836
Q9C004	P04049	1	binding	down-regulates activity	0.433	Here we show that mammalian Sprouty4 suppresses vascular epithelial growth factor (VEGF)-induced, Ras-independent activation of Raf1 but does not affect epidermal growth factor (EGF)-induced, Ras-dependent activation of Raf1. Sprouty4 binds to Raf1 through its carboxy-terminal cysteine-rich domain, and this binding is necessary for the inhibitory activity of Sprouty4.	SIGNOR-253033
P17655	P10636	1	cleavage	down-regulates activity	0.433	Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains	SIGNOR-251611
P07949	P27361	1	phosphorylation	up-regulates	0.433	We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1).	SIGNOR-140298
O00141	P48764	1	phosphorylation	up-regulates activity	0.433	The NHE3 activation by SGK1 is dependent on their combined interaction with NHERF2 and then phosphorylation at S663 of NHE3 by SGK1 ( xref , xref ).	SIGNOR-279112
Q9H4P4	Q8N1B4	1	ubiquitination	down-regulates quantity by destabilization	0.433	RNF41 ubiquitinates and relocates VPS52 away from VPS53, another shared subunit of the GARP and EARP complexes, towards RNF41-positive structures.	SIGNOR-278597
Q04206	P18146	1	binding	up-regulates	0.433	The early growth response transcription factor egr-1 can also interact with rela in vitro and regulate nf-kappab transcriptional activity in vivo	SIGNOR-75001
Q06187	Q13422	1	phosphorylation	up-regulates activity	0.432	We demonstrate that BTK phosphorylates Ikaros at unique phosphorylation sites S214 and S215 in the close vicinity of its zinc finger 4 (ZF4) within the DNA binding domain, thereby augmenting its nuclear localization and sequence-specific DNA binding activity.	SIGNOR-279442
Q13627	Q13247	1	phosphorylation	up-regulates activity	0.432	These results suggest that Dyrk1A enhances SRp55 promoted cTnT exon 5 inclusion.\|These results supported the finding that phosphorylation of SRp55 by Dyrk1A promotes cTnT exon 5 inclusion.Alternative splicing of cTnT exon 5 is regulated developmentally.	SIGNOR-279166
P54829	Q12879	1	dephosphorylation	down-regulates activity	0.432	STEP inhibition by TC-2153 enhanced Tyr phosphorylation of GluN2A (XREF_FIG, 1 EGTA+TC-2153, n = 5, P < 0.05 compared with 1mM EGTA) without altering phosphorylation of Src (XREF_FIG, 1 EGTA+TC-2153, n = 5, P> 0.05 compared with 1 EGTA).\|These findings confirm that not only GluN2B and Fyn but also GluN2A are substrates of STEP.	SIGNOR-277089
P63211	P42336	1	binding	up-regulates	0.432	Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt	SIGNOR-154261
P17612	Q9Y698	1	phosphorylation	down-regulates activity	0.432	phosphorylation of stargazin at T321 by PKA inhibits its interaction with PSD-95.	SIGNOR-250342
Q9Y2Y9	Q96ST3	1	binding	up-regulates activity	0.432	detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A.	SIGNOR-222437
Q00987	Q02878	1	ubiquitination	down-regulates quantity by destabilization	0.432	Furthermore, we also demonstrated that RPL6 is a substrate for HDM2-mediated ubiquitination and proteasomal degradation.\|The interaction of RPL6 and HDM2 drives HDM2 mediated RPL6 polyubiquitination and proteasomal degradation.	SIGNOR-278630
Q13315	Q16665	1	phosphorylation	up-regulates	0.432	Here we show that hypoxia results in ataxia telangiectasia mutated (atm)-dependent phosphorylation of hypoxia-inducible factor 1-alpha (hif-1_) on serine(696) and mediates downregulation of mtorc1 signaling. phosphorylation of hif-1_ by atm is required for its stability	SIGNOR-169999
P17612	P46020	1	phosphorylation	up-regulates activity	0.432	Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme.	SIGNOR-267411
P49137	Q14457	1	phosphorylation	up-regulates activity	0.432	Beclin 1 S90 is phosphorylated by MAPKAPK2 (MK2) and MAPKAPK3 (MK3).	SIGNOR-278342
Q14669	Q13564	1	ubiquitination	down-regulates quantity by destabilization	0.432	Our data suggest that that TRIP12 promotes degradation of APP-BP1 by catalyzing its ubiquitination, which in turn modulates the neddylation pathway.	SIGNOR-266780
Q9UNY4	Q99459	1	binding	up-regulates quantity by stabilization	0.432	HLodestar/HuF2 associates with CDC5L in cell lysates and HeLa nuclear extracts. It is possible that during the cell division cycle, hLodestar/HuF2s associates with transcription/splicing complexes in order to inhibit transcription/splicing prior to the start of mitosis and/or functions in stabilizing nuclear complexes containing splicing factors (e.g., the CDC5L complex) so that these are available for re-initiation of splicing at the end of mitosis when gene expression is re-established in cells.	SIGNOR-224460
P28482	P33076	1	phosphorylation	up-regulates	0.432	We show in this study that the nuclear localized form of ciita is a predominantly phosphorylated form of the protein, whereas cytoplasmic ciita is predominantly unphosphorylated. Novel phosphorylation sites were determined to be located within a region that contains serine residues 286, 288, and 293. Double mutations of these residues increased nuclear ciita, indicating that these sites are not required for nuclear import. Erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation.	SIGNOR-160609
P23467	P27361	1	dephosphorylation	up-regulates	0.432	When cells are stimulated with various ligands such as growth factors, hormones, neurotransmitters, or tumor promoters, erk1/2 is activated through dualphosphorylation at the -ptepy-motif. Subsequently, p-erk1/2 translocates into the nucleus and phosphorylates elk-1, thereby acting as a transcription factor for cell proliferationthese data indicate that sa-p-erk1/2 might not only be regulated by mkp such as rvhr, but also by pp1 and ptp as well	SIGNOR-103165
Q15025	Q13114	1	binding	down-regulates activity	0.432	ABIN1 interacted with the A20 regulatory molecule TAX1BP1 and was essential for the recruitment of TAX1BP1 and A20 to the noncanonical IkappaB kinases TBK1 and IKKi in response to poly(I:C) transfection. ABIN1 and TAX1BP1 together disrupted the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKKi to attenuate lysine 63-linked polyubiquitination of TBK1/IKKi.	SIGNOR-275736
O14757	Q7Z2Z1	1	phosphorylation	down-regulates activity	0.432	In principle, phosphorylation of Treslin by Chk1 may alter its conformation or directly affect its interactions with other proteins to preclude helicase activation.\|The fact that the TRCT domain blocks the binding of Chk1 to Treslin suggests that Chk1 suppresses the initiating function of Treslin.	SIGNOR-278924
O00311	Q5FWF5	1	phosphorylation	down-regulates	0.432	We show here that eco1 degradation requires the sequential actions of cdk1 and two additional kinases, cdc7-dbf4 and the gsk-3 homolog mck1.	SIGNOR-200397
P67775	O96017	1	dephosphorylation	up-regulates activity	0.432	Protein phosphatase 2A interacts with Chk2 and regulates phosphorylation at Thr-68 after cisplatin treatment of human ovarian cancer cells\|In response to DNA damage, Chk2 is initially phosphorylated at Thr-68, which leads to its full activation.	SIGNOR-248617
P10276	P10827	2	binding	up-regulates	0.432	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs.	SIGNOR-133231
P10827	P10276	2	binding	up-regulates	0.432	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs.	SIGNOR-133240
Q9H1H9	Q6DKK2	1	binding	up-regulates activity	0.432	We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B.	SIGNOR-265540
Q9H9S0	P26358	1	transcriptional regulation	up-regulates quantity by expression	0.432	Oct4 and Nanog upregulate Dnmt1 through direct binding to its promoter, thereby leading to the repressed expression of p16 and p21 and genes associated with development and lineage differentiation	SIGNOR-253157
Q05655	Q9H257	1	phosphorylation	up-regulates activity	0.432	Here we demonstrated that protein kinase C-delta (PKCdelta) was activated upon Dectin-1-Syk signaling, mediated phosphorylation of Card9 at Thr231, and was responsible for Card9 and Bcl10 complex assembly and canonical NF-kappaB control.	SIGNOR-278383
P43378	P40763	1	dephosphorylation	down-regulates activity	0.432	Results are presented as mean \u00b1 SD from three independent experiments. (B) PTPMeg2 inhibits STAT3-mediated transcriptional activity in a dose dependent manner.\|These results indicate that PTPMeg2 inhibits STAT3 activation with certain specificity.\|In this study, we demonstrated that PTPMeg2 dephosphorylates STAT3 at the Tyr705 residue by a direct interaction.	SIGNOR-276976
Q5TG30	P61586	1	gtpase-activating protein	down-regulates activity	0.432	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260496
Q93009	Q96EP1	1	deubiquitination	up-regulates quantity by stabilization	0.432	In this study, we identified USP7 (also known as HAUSP), which is a member of a family of proteins that cleave polyubiquitin chains and/or ubiquitin precursors, as an interacting protein with Chfr by immunoaffinity purification and mass spectrometry, and their interaction greatly increases the stability of Chfr. In fact, USP7 can remove ubiquitin moiety from the autoubiquitinated Chfr both in vivo and in vitro, which results in the accumulation of Chfr in the cell. USP7 mediates deubiquitination of Chfr.	SIGNOR-271462
Q13651	O60674	1	phosphorylation	up-regulates activity	0.432	IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes.	SIGNOR-249545
Q9Y252	P53667	1	polyubiquitination	down-regulates quantity by destabilization	0.432	Consistent with a role in axonal growth, we found that Rnf6 binds to, polyubiquitinates, and targets LIMK1 for proteasomal degradation in growth cones of primary hippocampal neurons.	SIGNOR-271481
O43255	P55036	1	polyubiquitination	down-regulates quantity by destabilization	0.432	S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s.	SIGNOR-272748
Q9GZU7	P24928	1	dephosphorylation	up-regulates activity	0.431	Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. \| This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat.	SIGNOR-248785
P49841	Q9BPU6	1	phosphorylation	up-regulates activity	0.431	The T516 phosphorylation was achieved by the glycogen synthase kinase-3beta (GSK-3beta), which can phosphorylate the wildtype protein but not the non-phosphorylatable mutant. Furthermore, we have shown that T516 phosphorylation is essential for the tubulin-binding property of CRMP5. Therefore, CRMP5-induced growth inhibition is dependent on T516 phosphorylation through the GSK-3beta pathway.	SIGNOR-264835
Q96GD4	Q13315	1	phosphorylation	up-regulates	0.431	Aurora-b mediated atm serine 1403 phosphorylation is required for mitotic atm activation and the spindle checkpoint	SIGNOR-177280
Q9UHC7	P04637	1	polyubiquitination	down-regulates quantity by destabilization	0.431	Makorin Ring Finger Protein 1 (MKRN1) is a transcriptional co-regulator and an E3 ligase. Here, we show that MKRN1 simultaneously functions as a differentially negative regulator of p53 and p21. In normal conditions, MKRN1 could destabilize both p53 and p21 through ubiquitination and proteasome-dependent degradation. As a result, depletion of MKRN1 induced growth arrest through activation of p53 and p21. K291 and K292 of p53 are required for MKRN1-mediated degradation and ubiquitination of p53	SIGNOR-271846
Q99873	Q92804	1	methylation	up-regulates	0.431	The methylation of taf15 by prmt1 is required for the ability of taf15 to positively regulate the expression of the studied endogenous taf15-target genes.	SIGNOR-183137
Q96K19	Q14643	1	polyubiquitination	down-regulates activity	0.431	In summary, here we present evidence that RNF170 is an E3 ligase that mediates IP3 receptor ubiquitination and processing by the UPP and that it is recruited to activated IP3 receptors by the erlin1/2 complex to which it is constitutively bound.	SIGNOR-271913
P49841	Q9Y6K9	1	phosphorylation	down-regulates quantity	0.431	For analysis of phosphorylation of NEMO on Ser8 and Ser17 by GSK-3, we generated phospho-specific antibodies (anti-phospho-NEMO-Ser8 and anti-phospho-NEMO-Ser17) while anti-phospho-NEMO-Ser31 and anti-phospho-NEMO-Ser43 were commercially available. Indeed, GSK-3\u03b2 was able to phosphorylate all four serines of rhNEMO in a time-dependent manner in an in vitro kinase assay (Fig. 3a).\|In this study, we identified NEMO as a GSK-3\u03b2 substrate that is phosphorylated at several serine residues located within the N-terminal domain.\|The kinase forms a complex with wild-type NEMO while point mutations of NEMO at the specific serines abrogated GSK-3Œ≤ binding and subsequent phosphorylation of NEMO resulting in its destabilization	SIGNOR-279527
O14757	Q9UKI8	1	phosphorylation	down-regulates	0.431	Chk1 phosphorylates tlk1 on serine 695 (s695) these findings identify an unprecedented functional co- operation between atm and chk1 in propagation of a checkpoint response during s phase and suggest that, through transient inhibition of tlk kinases, the atm_chk1_tlk pathway may regulate processes involved in chromatin assembly.	SIGNOR-99653
O15297	O15151	1	dephosphorylation	up-regulates quantity by stabilization	0.431	PPM1D also inhibits p53 activity by dephosphorylating Ser395 and stabilizing MDM2 and by dephosphorylating Ser403 on MDMX	SIGNOR-275491
P06493	Q9BXS6	1	phosphorylation	down-regulates	0.431	We report here that cdk1 phosphorylates nusap at threonine 300 and 338 in early mitosis. Phosphorylation of nusap inhibits its microtubule-binding activity in vitro and in vivo.	SIGNOR-177549
P32249	P08754	1	binding	up-regulates activity	0.431	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-256858
P0DMV8	O14727	1	binding	down-regulates	0.431	Here we show that the documented anti-apoptotic effect of the principal heat-shock protein, hsp70, is mediated through its direct association with the caspase-recruitment domain (card) of apaf-1 and through apoptosome formation	SIGNOR-80451
Q06413	Q9UKX2	1	transcriptional regulation	up-regulates quantity by expression	0.431	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-238718
P51817	O43541	1	phosphorylation	up-regulates activity	0.431	In vitro phosphorylation assays demonstrated that PrKX phosphorylates Smad6 at a serine residue.	SIGNOR-279270
Q86YT6	Q9UPN4	1	ubiquitination	down-regulates	0.43	We demonstrate that the E3 ubiquitin ligase MIB1 is a new component of centriolar satellites, which interacts with and ubiquitylates AZI1 and PCM1 and suppresses primary cilium formation. Whereas these proteins are degraded prior to the ciliation process, MIB1 appears to maintain its targets in a latent state through inhibitory ubiquitylation that is reversed during ciliogenesis and in response to cell stress.The precise mechanism by which MIB1 inhibits primary cilium formation through ubiquitylation of ciliogenesis-promoting target proteins such as AZI1 and PCM1 remains to be determined.	SIGNOR-272876
P07948	P31994	1	phosphorylation	up-regulates activity	0.43	Therefore, we conclude that FcgammaRIIb1 phosphorylation upon BCR-FcgammaR coligation is most likely due to BCR-associated Lyn	SIGNOR-249380
P31749	Q05397	1	phosphorylation	up-regulates activity	0.43	In mouse embryonic fibroblasts, AKT1 phosphorylates S695 and T700 on FAK ( xref ) and in human colon cancer cells AKT1 phosphorylates S517, S601, and S695 on FAK ( xref , xref ).\|This suggests that further activation of FAK by AKT1 ( beyond that of Pten loss alone ) is required to promote FA turnover , increase tumor invasion , and ultimately elicit brain metastasis .	SIGNOR-279777
P17612	Q08289	1	phosphorylation	up-regulates activity	0.43	Voltage-dependent L-type calcium (Ca) channels are heteromultimeric proteins that are regulated through phosphorylation by cAMP-dependent protein kinase (PKA) Mutagenesis of a single residue at Ser459 resulted in the loss of one site of phosphorylation by PKA, and mutagenesis of two residues at Ser478/479 resulted in the loss of approximately two sites of PKA-mediated phosphorylation	SIGNOR-250341
O00635	Q9Y4K3	1	polyubiquitination	down-regulates quantity by destabilization	0.43	As an E3 ligase, TRIM38 bound to TRAF6 and promoted K48-linked polyubiquitination, which led to the proteasomal degradation of TRAF6.	SIGNOR-272009
P26045	P10912	1	dephosphorylation	down-regulates activity	0.43	PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates	SIGNOR-248459
P12931	P67775	2	phosphorylation	down-regulates	0.43	We found that ?-Syn gene overexpression in sk-n-sh cells and primary neurons led to pp2a/c phosphorylation at y307, a known target of src kinase, and consequent phosphatase inhibition.	SIGNOR-202192
P30559	P63092	1	binding	up-regulates activity	0.43	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-256793
Q16671	O00238	1	binding	up-regulates	0.43	See table2	SIGNOR-121596
P01106	P11166	1	transcriptional regulation	up-regulates quantity	0.43	C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway.	SIGNOR-259987
P78527	Q14653	1	phosphorylation	up-regulates	0.43	Phosphorylation of irf-3 by dna-pk after virus infection results in its nuclear retention and delayed proteolysis	SIGNOR-115331
Q9UHC7	P60484	1	ubiquitination	down-regulates quantity by destabilization	0.43	EGFR/PI3K/AKT-mediated ubiquitination and degradation of PTEN are dependent on the MKRN1 E3 ligase.\|In fact, epidermal growth factor-stimulated pAKT phosphorylates and subsequently stabilizes MKRN1, which then ubiquitinates and induces the degradation of PTEN.	SIGNOR-278830
P08246	P25116	1	cleavage	up-regulates activity	0.43	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases \| The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II\|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.\|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.\|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus	SIGNOR-263565
P67775	P12931	2	dephosphorylation	down-regulates activity	0.43	We show that PR55gamma binds c-SRC and modulates the phosphorylation of serine 12 of c-SRC, a residue we demonstrate to be required for JNK activation by c-SRC	SIGNOR-247970
P33981	Q02224	1	phosphorylation	up-regulates activity	0.43	Strikingly, phosphorylation of Cenp-E C tail by wild-type (WT) MPS1 or CDK1-cyclin B completely reverses its inhibitory effect toward Cenp-E motor ATPase in solution.	SIGNOR-278999
Q15418	Q16821	1	phosphorylation	up-regulates activity	0.43	The protein G(M), which targets protein phosphatase 1 (PP1) to the glycogen particles and sarcoplasmic reticulum (SR) of striated muscles, is known to be phosphorylated at Ser48 and Ser67 in vitro by adenosine 3',5' cyclic monophosphate-dependent protein kinase (PKA) and at Ser48 by MAP kinase-activated protein kinase-1 (MAPKAP-K1, also called p90 RSK). The phosphorylation of Ser48 increases the rate at which the glycogen-associated PP1.G(M) complex dephosphorylates (activates) glycogen synthase, but the phosphorylation of Ser67 has the opposite effect, suppressing the activity of PP1 toward glycogen-bound substrates.	SIGNOR-249036
Q9C040	P07196	1	ubiquitination	down-regulates quantity by destabilization	0.43	Here, we show that TRIM RING finger protein TRIM2, highly expressed in the nervous system, is an UbcH5a-dependent ubiquitin ligase. We further demonstrate that TRIM2 binds to neurofilament light subunit (NF-L) and regulates NF-L ubiquitination.	SIGNOR-271776
Q9P227	P63000	1	gtpase-activating protein	down-regulates activity	0.43	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260480
Q16539	O60381	1	phosphorylation	up-regulates	0.43	A mutation of the p38 map kinase phosphorylation site at aa 401 [(s-a)401hbp1] also triggered hbp1 protein instability. While protein stability was compromised by mutation, the specific activities of (s-a)401hbp1 and of wild-type hbp1 appeared comparable for transcriptional repression.	SIGNOR-119138
Q96KB5	P05412	1	phosphorylation	up-regulates activity	0.43	TOPK promotes lung cancer resistance to EGFR tyrosine kinase inhibitors by phosphorylating and activating c-Jun.\|These data confirm the phosphorylation of c-Jun by TOPK at serine 63 and 73 during the development of resistance to EGFR-targeted TKIs.	SIGNOR-278156
P30530	P00533	2	phosphorylation	up-regulates activity	0.43	AXL trans-actives EGFR in a ligand independent manner and induces phosphorylation of EGFR on tyrosine 1173.\|In our models AXL seems to induce a re-wiring of the EGFR signaling towards the PLCgamma-PKC axis by receptor phosphorylation at tyrosine 1173.	SIGNOR-279141
Q13332	P00533	1	dephosphorylation	down-regulates activity	0.43	Similarly, Pestana et al. (89) have reported that overexpression of RPTPsigma in human A431 carcinoma cells partially inhibits EGFR activation, whereas antisense mediated suppression of RPTPsigma expression enhances EGFR activation, substrate phosphorylation, and signalling.\|These data indicate that LAR and RPTPsigma may have a significant role in GPCR induced EGFR signalling.Whereas in A431 cells LAR and RPTPsigma may act to suppress the EGFR in response to GPCR activation, it is possible that the converse may also be true in other cell types.	SIGNOR-277145
Q9UBC7	O43603	1	binding	up-regulates	0.43	Galp is therefore an endogenous ligand that preferentially binds the galr2 receptor	SIGNOR-73143
P23769	O00321	1	binding	up-regulates activity	0.43	Transcriptional assays with the Spi1 promoter-reporter demonstrated that Gata2 cooperates with Etv2 and augments the transcriptional activity of Etv2.The protein-protein interaction between Etv2 and Gata2 is mediated by the Ets and Gata domains. Using the embryoid body differentiation system, we demonstrate that co-expression of Gata2 augments the activity of Etv2 in promoting endothelial and hematopoietic lineage differentiation.	SIGNOR-256008
P00533	P30530	2	phosphorylation	up-regulates activity	0.43	In this study, we have identified for the first time a direct interaction between EGFR and Axl RTKs, with EGF and EGFR induced activation of Axl as a novel signalling pathway to invasion in cancer cells.\|The activation of Axl was shown to occur through direct phosphorylation by EGFR of Axl tyrosine 779, one of the key residues within Axl that serves as a multi-substrate docking site for further downstream signalling.	SIGNOR-279734
P31749	O14757	1	phosphorylation	down-regulates	0.43	The chk1 protein phosphorylated by pkb on serine 280 does not enter into protein complexes after replication arrest. Moreover, chk1 phosphorylated by pkb fails to undergo activating phosphorylation on serine 345 by atm/atr. Phosphorylation by atm/atr and association with other checkpoint proteins are essential steps in activation of chk1.	SIGNOR-124365
O94901	P49790	1	binding	up-regulates activity	0.43	The NXF1:NXT1 complex and NUP153 interact with the amino terminus of SUN1 \|In analogy to a proposal made by Chang et al.4, Nesprins could help anchoring SUN1 near the NPC to enable it to fulfill its task in mRNA export.	SIGNOR-263294
Q9Y6Y1	P01160	1	transcriptional regulation	up-regulates quantity by expression	0.429	CAMTA1 itself stimulates the expression of the anti-proliferative peptide NPPA.	SIGNOR-261570
P49840	P10636	1	phosphorylation	down-regulates	0.429	Tau is phosphorylated by gsk-3 at several sites found in alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by a-kinase.	SIGNOR-60651
O60603	Q86XR7	1	binding	up-regulates activity	0.429	To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group	SIGNOR-266747
Q9UQM7	Q96PV0	1	phosphorylation	up-regulates activity	0.429	Here we show that phosphorylation of synGAP by Ca(2+)/calmodulin-dependent protein kinase II increases its Ras GTPase-activating activity by 70-95%. The Major Phosphorylation Sites, Serines 764/765, 1058, and 1123, All Contribute to Regulation of GAP Activity of synGAP by CaMKII	SIGNOR-262687
P53350	Q9BVS4	1	phosphorylation	up-regulates activity	0.429	Here, we report that the atypical protein kinase Rio2 is a novel substrate of Plk1 and can be phosphorylated by Plk1 at Ser-335, Ser-380, and Ser-548. Overexpression of Rio2 causes a prolonged mitotic exit whereas knockdown of Rio2 accelerates mitotic progression, suggesting that Rio2 is required for the proper mitotic progression. F urthermore, time-lapse imaging data show that overexpression of Rio2 but not Rio2 S3A results in a slowed metaphase-anaphase transition. Collectively, these findings strongly indicate that the Plk1-mediated phosphorylation of Rio2 regulates metaphase-anaphase transition during mitotic progression.	SIGNOR-262937
Q96RI0	O95837	1	binding	up-regulates activity	0.429	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-257419
O15111	P20749	1	phosphorylation	up-regulates activity	0.429	Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.	SIGNOR-277362
P68400	Q01892	1	phosphorylation	down-regulates	0.429	Serine residues 37 in the transactivation domain and 129, 144 and 146 in the pest domain of spi-b are phosphorylated by ckii in vitro. The ckii phosphorylation sites mapped in vitro are phosphorylated in vivo. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability	SIGNOR-73891
P22694	Q92934	1	phosphorylation	down-regulates	0.429	Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136.	SIGNOR-81141
Q9P0L2	P10636	1	phosphorylation	down-regulates activity	0.429	We have studied the relationship between the phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. MARK and PKA phosphorylate several sites within the repeats (notably the KXGS motifs including Ser262, Ser324, and Ser356, plus Ser320). This type of phosphorylation strongly reduces tau's affinity for microtubules, and at the same time inhibits tau's assembly into PHFs.	SIGNOR-250173
Q8NBJ5	P08123	1	glycosylation	up-regulates activity	0.429	Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues.	SIGNOR-261153
Q9BXM7	Q9UJA2	1	phosphorylation	down-regulates quantity	0.429	In vitro kinase assays using recombinant proteins under various control conditions indicated that PINK1 directly phosphorylates CLS1 (XREF_FIG).\|Similar to Fbxo15, knockdown of PINK1 kinase using shRNA increased CLS1 levels, whereas overexpression of PINK1 plasmid decreased CLS1 levels .	SIGNOR-280065
O15105	P62136	1	binding	up-regulates	0.429	Smad7, induced by alk1 activation, recruits pp1? To alk1 and thereby inhibits tgf-?/Alk1-induced smad1/5 phosphorylation in ecs	SIGNOR-145389
Q99835	P04899	1	binding	up-regulates activity	0.429	it was proposed that Smo might signal through activation of Gi proteins to reduce PKA activity.	SIGNOR-199162
P31751	Q15365	1	phosphorylation	down-regulates activity	0.429	We show that heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) binds a structural, 33-nucleotide TGF-beta-activated translation (BAT) element in the 3' untranslated region of disabled-2 (Dab2) and interleukin-like EMT inducer (ILEI) transcripts, and represses their translation.TGF-beta activation leads to phosphorylation at Ser 43 of hnRNP E1 by protein kinase Bbeta/Akt2, inducing its release from the BAT element and translational activation of Dab2 and ILEI messenger RNAs.	SIGNOR-262625
P06493	P55211	1	phosphorylation	down-regulates	0.429	Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, thr125. This site is phosphorylated by cdk1/cyclin b1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle.	SIGNOR-141621
Q99986	Q96GD4	1	phosphorylation	up-regulates activity	0.429	In the VRK1 overexpression of experiment, VRK1 caused a significant stabilization of AURKB, with no change in level after 24h, which is consistent with protection of AURKB against its known degradation by ubiquitylation .\|The phosphorylation of AURKB by VRK1 and VRK1 by AURKB was tested using a kinase-dead form as substrate.	SIGNOR-280160

P15173

P23409

1

transcriptional regulation

up-regulates quantity by expression

0.433

[...] confirming that myogenin binds to the E1 and E2 E boxes located in close proximity to the MRF4 transcription start site.

SIGNOR-255642

Q8TAP6

P53350

1

binding

down-regulates activity

0.433

Here, we found that centrosomal protein of 76 kDa (Cep76), previously shown to restrain centriole amplification, interacts with cyclin-dependent kinase 2 (CDK2) and is a bona fide substrate of this kinase. Cep76 is preferentially phosphorylated by cyclin A/CDK2 at a single site S83, and this event is crucial to suppress centriole amplification in S phase. Mechanistically, Cep76 phosphorylation inhibits activation of polo-like kinase 1 (Plk1), thereby blocking premature centriole disengagement and subsequent amplification.

SIGNOR-262731

Q12933

Q8IUC6

1

polyubiquitination

up-regulates

0.433

Here, we show that the TRAF family proteins directly bind TICAM-1 and demonstrate that TRAF2 and TRAF6 bind different sites of the N-terminal TICAM-1 and accelerate its polyubiquitination. we speculate that polyubiquitination of TICAM-1 by TRAF2 and TRAF6 is required for TICAM-1 to induce IRF-3 and NF-κB activation. This is supported by the observation that polyubiquitination of TICAM-1 was required for TRAF3-binding to TICAM-1

SIGNOR-271427

Q92905

Q13485

1

ubiquitination

down-regulates

0.433

We report a novel mechanism of smad4 degradation. Jab1 interacts directly with smad4 and induces its ubiquitylation for degradation

SIGNOR-114697

Q7Z3K3

P45973

1

binding

down-regulates activity

0.433

POGZ was found to bind to HP1alpha through a zinc-finger-like motif. Binding by POGZ, mediated through its zinc-finger-like motif, competed with PxVxL proteins and destabilized the HP1alpha-chromatin interaction.

SIGNOR-264487

P21452

O95837

1

binding

up-regulates activity

0.433

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-257131

Q9UBR4

Q96A47

1

binding

up-regulates activity

0.433

a direct NLI-independent interaction between Lhx3 and the related proteins Isl1 and Isl2 was observed. The combinatorial expression of the LIM homeodomain proteins Isl1, Isl2, Lhx1, and Lhx3 in subsets of developing motor neurons correlates with the future organization of these neurons into motor columns with distinct innervation targets, implying a functional role for LIM homeodomain protein combinations in the specification of neuronal identity

SIGNOR-236836

Q9C004

P04049

1

binding

down-regulates activity

0.433

Here we show that mammalian Sprouty4 suppresses vascular epithelial growth factor (VEGF)-induced, Ras-independent activation of Raf1 but does not affect epidermal growth factor (EGF)-induced, Ras-dependent activation of Raf1. Sprouty4 binds to Raf1 through its carboxy-terminal cysteine-rich domain, and this binding is necessary for the inhibitory activity of Sprouty4.

SIGNOR-253033

P17655

P10636

1

cleavage

down-regulates activity

0.433

Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains

SIGNOR-251611

P07949

P27361

1

phosphorylation

up-regulates

0.433

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

SIGNOR-140298

O00141

P48764

1

phosphorylation

up-regulates activity

0.433

The NHE3 activation by SGK1 is dependent on their combined interaction with NHERF2 and then phosphorylation at S663 of NHE3 by SGK1 ( xref , xref ).

SIGNOR-279112

Q9H4P4

Q8N1B4

1

ubiquitination

down-regulates quantity by destabilization

0.433

RNF41 ubiquitinates and relocates VPS52 away from VPS53, another shared subunit of the GARP and EARP complexes, towards RNF41-positive structures.

SIGNOR-278597

Q04206

P18146

1

binding

up-regulates

0.433

The early growth response transcription factor egr-1 can also interact with rela in vitro and regulate nf-kappab transcriptional activity in vivo

SIGNOR-75001

Q06187

Q13422

1

phosphorylation

up-regulates activity

0.432

We demonstrate that BTK phosphorylates Ikaros at unique phosphorylation sites S214 and S215 in the close vicinity of its zinc finger 4 (ZF4) within the DNA binding domain, thereby augmenting its nuclear localization and sequence-specific DNA binding activity.

SIGNOR-279442

Q13627

Q13247

1

phosphorylation

up-regulates activity

0.432

These results suggest that Dyrk1A enhances SRp55 promoted cTnT exon 5 inclusion.|These results supported the finding that phosphorylation of SRp55 by Dyrk1A promotes cTnT exon 5 inclusion.Alternative splicing of cTnT exon 5 is regulated developmentally.

SIGNOR-279166

P54829

Q12879

1

dephosphorylation

down-regulates activity

0.432

STEP inhibition by TC-2153 enhanced Tyr phosphorylation of GluN2A (XREF_FIG, 1 EGTA+TC-2153, n = 5, P < 0.05 compared with 1mM EGTA) without altering phosphorylation of Src (XREF_FIG, 1 EGTA+TC-2153, n = 5, P> 0.05 compared with 1 EGTA).|These findings confirm that not only GluN2B and Fyn but also GluN2A are substrates of STEP.

SIGNOR-277089

P63211

P42336

1

binding

up-regulates

0.432

Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt

SIGNOR-154261

P17612

Q9Y698

1

phosphorylation

down-regulates activity

0.432

phosphorylation of stargazin at T321 by PKA inhibits its interaction with PSD-95.

SIGNOR-250342

Q9Y2Y9

Q96ST3

1

binding

up-regulates activity

0.432

detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A.

SIGNOR-222437

Q00987

Q02878

1

ubiquitination

down-regulates quantity by destabilization

0.432

Furthermore, we also demonstrated that RPL6 is a substrate for HDM2-mediated ubiquitination and proteasomal degradation.|The interaction of RPL6 and HDM2 drives HDM2 mediated RPL6 polyubiquitination and proteasomal degradation.

SIGNOR-278630

Q13315

Q16665

1

phosphorylation

up-regulates

0.432

Here we show that hypoxia results in ataxia telangiectasia mutated (atm)-dependent phosphorylation of hypoxia-inducible factor 1-alpha (hif-1_) on serine(696) and mediates downregulation of mtorc1 signaling. phosphorylation of hif-1_ by atm is required for its stability

SIGNOR-169999

P17612

P46020

1

phosphorylation

up-regulates activity

0.432

Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme.

SIGNOR-267411

P49137

Q14457

1

phosphorylation

up-regulates activity

0.432

Beclin 1 S90 is phosphorylated by MAPKAPK2 (MK2) and MAPKAPK3 (MK3).

SIGNOR-278342

Q14669

Q13564

1

ubiquitination

down-regulates quantity by destabilization

0.432

Our data suggest that that TRIP12 promotes degradation of APP-BP1 by catalyzing its ubiquitination, which in turn modulates the neddylation pathway.

SIGNOR-266780

Q9UNY4

Q99459

1

binding

up-regulates quantity by stabilization

0.432

HLodestar/HuF2 associates with CDC5L in cell lysates and HeLa nuclear extracts. It is possible that during the cell division cycle, hLodestar/HuF2s associates with transcription/splicing complexes in order to inhibit transcription/splicing prior to the start of mitosis and/or functions in stabilizing nuclear complexes containing splicing factors (e.g., the CDC5L complex) so that these are available for re-initiation of splicing at the end of mitosis when gene expression is re-established in cells.

SIGNOR-224460

P28482

P33076

1

phosphorylation

up-regulates

0.432

We show in this study that the nuclear localized form of ciita is a predominantly phosphorylated form of the protein, whereas cytoplasmic ciita is predominantly unphosphorylated. Novel phosphorylation sites were determined to be located within a region that contains serine residues 286, 288, and 293. Double mutations of these residues increased nuclear ciita, indicating that these sites are not required for nuclear import. Erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation.

SIGNOR-160609

P23467

P27361

1

dephosphorylation

up-regulates

0.432

When cells are stimulated with various ligands such as growth factors, hormones, neurotransmitters, or tumor promoters, erk1/2 is activated through dualphosphorylation at the -ptepy-motif. Subsequently, p-erk1/2 translocates into the nucleus and phosphorylates elk-1, thereby acting as a transcription factor for cell proliferationthese data indicate that sa-p-erk1/2 might not only be regulated by mkp such as rvhr, but also by pp1 and ptp as well

SIGNOR-103165

Q15025

Q13114

1

binding

down-regulates activity

0.432

ABIN1 interacted with the A20 regulatory molecule TAX1BP1 and was essential for the recruitment of TAX1BP1 and A20 to the noncanonical IkappaB kinases TBK1 and IKKi in response to poly(I:C) transfection. ABIN1 and TAX1BP1 together disrupted the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKKi to attenuate lysine 63-linked polyubiquitination of TBK1/IKKi.

SIGNOR-275736

O14757

Q7Z2Z1

1

phosphorylation

down-regulates activity

0.432

In principle, phosphorylation of Treslin by Chk1 may alter its conformation or directly affect its interactions with other proteins to preclude helicase activation.|The fact that the TRCT domain blocks the binding of Chk1 to Treslin suggests that Chk1 suppresses the initiating function of Treslin.

SIGNOR-278924

O00311

Q5FWF5

1

phosphorylation

down-regulates

0.432

We show here that eco1 degradation requires the sequential actions of cdk1 and two additional kinases, cdc7-dbf4 and the gsk-3 homolog mck1.

SIGNOR-200397

P67775

O96017

1

dephosphorylation

up-regulates activity

0.432

Protein phosphatase 2A interacts with Chk2 and regulates phosphorylation at Thr-68 after cisplatin treatment of human ovarian cancer cells|In response to DNA damage, Chk2 is initially phosphorylated at Thr-68, which leads to its full activation.

SIGNOR-248617

P10276

P10827

2

binding

up-regulates

0.432

We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs.

SIGNOR-133231

P10827

P10276

2

binding

up-regulates

0.432

We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs.

SIGNOR-133240

Q9H1H9

Q6DKK2

1

binding

up-regulates activity

0.432

We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B.

SIGNOR-265540

Q9H9S0

P26358

1

transcriptional regulation

up-regulates quantity by expression

0.432

Oct4 and Nanog upregulate Dnmt1 through direct binding to its promoter, thereby leading to the repressed expression of p16 and p21 and genes associated with development and lineage differentiation

SIGNOR-253157

Q05655

Q9H257

1

phosphorylation

up-regulates activity

0.432

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

SIGNOR-278383

P43378

P40763

1

dephosphorylation

down-regulates activity

0.432

Results are presented as mean \u00b1 SD from three independent experiments. (B) PTPMeg2 inhibits STAT3-mediated transcriptional activity in a dose dependent manner.|These results indicate that PTPMeg2 inhibits STAT3 activation with certain specificity.|In this study, we demonstrated that PTPMeg2 dephosphorylates STAT3 at the Tyr705 residue by a direct interaction.

SIGNOR-276976

Q5TG30

P61586

1

gtpase-activating protein

down-regulates activity

0.432

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260496

Q93009

Q96EP1

1

deubiquitination

up-regulates quantity by stabilization

0.432

In this study, we identified USP7 (also known as HAUSP), which is a member of a family of proteins that cleave polyubiquitin chains and/or ubiquitin precursors, as an interacting protein with Chfr by immunoaffinity purification and mass spectrometry, and their interaction greatly increases the stability of Chfr. In fact, USP7 can remove ubiquitin moiety from the autoubiquitinated Chfr both in vivo and in vitro, which results in the accumulation of Chfr in the cell. USP7 mediates deubiquitination of Chfr.

SIGNOR-271462

Q13651

O60674

1

phosphorylation

up-regulates activity

0.432

IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes.

SIGNOR-249545

Q9Y252

P53667

1

polyubiquitination

down-regulates quantity by destabilization

0.432

Consistent with a role in axonal growth, we found that Rnf6 binds to, polyubiquitinates, and targets LIMK1 for proteasomal degradation in growth cones of primary hippocampal neurons.

SIGNOR-271481

O43255

P55036

1

polyubiquitination

down-regulates quantity by destabilization

0.432

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

SIGNOR-272748

Q9GZU7

P24928

1

dephosphorylation

up-regulates activity

0.431

Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat.

SIGNOR-248785

P49841

Q9BPU6

1

phosphorylation

up-regulates activity

0.431

The T516 phosphorylation was achieved by the glycogen synthase kinase-3beta (GSK-3beta), which can phosphorylate the wildtype protein but not the non-phosphorylatable mutant. Furthermore, we have shown that T516 phosphorylation is essential for the tubulin-binding property of CRMP5. Therefore, CRMP5-induced growth inhibition is dependent on T516 phosphorylation through the GSK-3beta pathway.

SIGNOR-264835

Q96GD4

Q13315

1

phosphorylation

up-regulates

0.431

Aurora-b mediated atm serine 1403 phosphorylation is required for mitotic atm activation and the spindle checkpoint

SIGNOR-177280

Q9UHC7

P04637

1

polyubiquitination

down-regulates quantity by destabilization

0.431

Makorin Ring Finger Protein 1 (MKRN1) is a transcriptional co-regulator and an E3 ligase. Here, we show that MKRN1 simultaneously functions as a differentially negative regulator of p53 and p21. In normal conditions, MKRN1 could destabilize both p53 and p21 through ubiquitination and proteasome-dependent degradation. As a result, depletion of MKRN1 induced growth arrest through activation of p53 and p21. K291 and K292 of p53 are required for MKRN1-mediated degradation and ubiquitination of p53

SIGNOR-271846

Q99873

Q92804

1

methylation

up-regulates

0.431

The methylation of taf15 by prmt1 is required for the ability of taf15 to positively regulate the expression of the studied endogenous taf15-target genes.

SIGNOR-183137

Q96K19

Q14643

1

polyubiquitination

down-regulates activity

0.431

In summary, here we present evidence that RNF170 is an E3 ligase that mediates IP3 receptor ubiquitination and processing by the UPP and that it is recruited to activated IP3 receptors by the erlin1/2 complex to which it is constitutively bound.

SIGNOR-271913

P49841

Q9Y6K9

1

phosphorylation

down-regulates quantity

0.431

For analysis of phosphorylation of NEMO on Ser8 and Ser17 by GSK-3, we generated phospho-specific antibodies (anti-phospho-NEMO-Ser8 and anti-phospho-NEMO-Ser17) while anti-phospho-NEMO-Ser31 and anti-phospho-NEMO-Ser43 were commercially available. Indeed, GSK-3\u03b2 was able to phosphorylate all four serines of rhNEMO in a time-dependent manner in an in vitro kinase assay (Fig. 3a).|In this study, we identified NEMO as a GSK-3\u03b2 substrate that is phosphorylated at several serine residues located within the N-terminal domain.|The kinase forms a complex with wild-type NEMO while point mutations of NEMO at the specific serines abrogated GSK-3Œ≤ binding and subsequent phosphorylation of NEMO resulting in its destabilization

SIGNOR-279527

O14757

Q9UKI8

1

phosphorylation

down-regulates

0.431

Chk1 phosphorylates tlk1 on serine 695 (s695) these findings identify an unprecedented functional co- operation between atm and chk1 in propagation of a checkpoint response during s phase and suggest that, through transient inhibition of tlk kinases, the atm_chk1_tlk pathway may regulate processes involved in chromatin assembly.

SIGNOR-99653

O15297

O15151

1

dephosphorylation

up-regulates quantity by stabilization

0.431

PPM1D also inhibits p53 activity by dephosphorylating Ser395 and stabilizing MDM2 and by dephosphorylating Ser403 on MDMX

SIGNOR-275491

P06493

Q9BXS6

1

phosphorylation

down-regulates

0.431

We report here that cdk1 phosphorylates nusap at threonine 300 and 338 in early mitosis. Phosphorylation of nusap inhibits its microtubule-binding activity in vitro and in vivo.

SIGNOR-177549

P32249

P08754

1

binding

up-regulates activity

0.431

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-256858

P0DMV8

O14727

1

binding

down-regulates

0.431

Here we show that the documented anti-apoptotic effect of the principal heat-shock protein, hsp70, is mediated through its direct association with the caspase-recruitment domain (card) of apaf-1 and through apoptosome formation

SIGNOR-80451

Q06413

Q9UKX2

1

transcriptional regulation

up-regulates quantity by expression

0.431

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-238718

P51817

O43541

1

phosphorylation

up-regulates activity

0.431

In vitro phosphorylation assays demonstrated that PrKX phosphorylates Smad6 at a serine residue.

SIGNOR-279270

Q86YT6

Q9UPN4

1

ubiquitination

down-regulates

0.43

We demonstrate that the E3 ubiquitin ligase MIB1 is a new component of centriolar satellites, which interacts with and ubiquitylates AZI1 and PCM1 and suppresses primary cilium formation. Whereas these proteins are degraded prior to the ciliation process, MIB1 appears to maintain its targets in a latent state through inhibitory ubiquitylation that is reversed during ciliogenesis and in response to cell stress.The precise mechanism by which MIB1 inhibits primary cilium formation through ubiquitylation of ciliogenesis-promoting target proteins such as AZI1 and PCM1 remains to be determined.

SIGNOR-272876

P07948

P31994

1

phosphorylation

up-regulates activity

0.43

Therefore, we conclude that FcgammaRIIb1 phosphorylation upon BCR-FcgammaR coligation is most likely due to BCR-associated Lyn

SIGNOR-249380

P31749

Q05397

1

phosphorylation

up-regulates activity

0.43

In mouse embryonic fibroblasts, AKT1 phosphorylates S695 and T700 on FAK ( xref ) and in human colon cancer cells AKT1 phosphorylates S517, S601, and S695 on FAK ( xref , xref ).|This suggests that further activation of FAK by AKT1 ( beyond that of Pten loss alone ) is required to promote FA turnover , increase tumor invasion , and ultimately elicit brain metastasis .

SIGNOR-279777

P17612

Q08289

1

phosphorylation

up-regulates activity

0.43

Voltage-dependent L-type calcium (Ca) channels are heteromultimeric proteins that are regulated through phosphorylation by cAMP-dependent protein kinase (PKA) Mutagenesis of a single residue at Ser459 resulted in the loss of one site of phosphorylation by PKA, and mutagenesis of two residues at Ser478/479 resulted in the loss of approximately two sites of PKA-mediated phosphorylation

SIGNOR-250341

O00635

Q9Y4K3

1

polyubiquitination

down-regulates quantity by destabilization

0.43

As an E3 ligase, TRIM38 bound to TRAF6 and promoted K48-linked polyubiquitination, which led to the proteasomal degradation of TRAF6.

SIGNOR-272009

P26045

P10912

1

dephosphorylation

down-regulates activity

0.43

PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates

SIGNOR-248459

P12931

P67775

2

phosphorylation

down-regulates

0.43

We found that ?-Syn gene overexpression in sk-n-sh cells and primary neurons led to pp2a/c phosphorylation at y307, a known target of src kinase, and consequent phosphatase inhibition.

SIGNOR-202192

P30559

P63092

1

binding

up-regulates activity

0.43

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

SIGNOR-256793

Q16671

O00238

1

binding

up-regulates

0.43

See table2

SIGNOR-121596

P01106

P11166

1

transcriptional regulation

up-regulates quantity

0.43

C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway.

SIGNOR-259987

P78527

Q14653

1

phosphorylation

up-regulates

0.43

Phosphorylation of irf-3 by dna-pk after virus infection results in its nuclear retention and delayed proteolysis

SIGNOR-115331

Q9UHC7

P60484

1

ubiquitination

down-regulates quantity by destabilization

0.43

EGFR/PI3K/AKT-mediated ubiquitination and degradation of PTEN are dependent on the MKRN1 E3 ligase.|In fact, epidermal growth factor-stimulated pAKT phosphorylates and subsequently stabilizes MKRN1, which then ubiquitinates and induces the degradation of PTEN.

SIGNOR-278830

P08246

P25116

1

cleavage

up-regulates activity

0.43

PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus

SIGNOR-263565

P67775

P12931

2

dephosphorylation

down-regulates activity

0.43

We show that PR55gamma binds c-SRC and modulates the phosphorylation of serine 12 of c-SRC, a residue we demonstrate to be required for JNK activation by c-SRC

SIGNOR-247970

P33981

Q02224

1

phosphorylation

up-regulates activity

0.43

Strikingly, phosphorylation of Cenp-E C tail by wild-type (WT) MPS1 or CDK1-cyclin B completely reverses its inhibitory effect toward Cenp-E motor ATPase in solution.

SIGNOR-278999

Q15418

Q16821

1

phosphorylation

up-regulates activity

0.43

The protein G(M), which targets protein phosphatase 1 (PP1) to the glycogen particles and sarcoplasmic reticulum (SR) of striated muscles, is known to be phosphorylated at Ser48 and Ser67 in vitro by adenosine 3',5' cyclic monophosphate-dependent protein kinase (PKA) and at Ser48 by MAP kinase-activated protein kinase-1 (MAPKAP-K1, also called p90 RSK). The phosphorylation of Ser48 increases the rate at which the glycogen-associated PP1.G(M) complex dephosphorylates (activates) glycogen synthase, but the phosphorylation of Ser67 has the opposite effect, suppressing the activity of PP1 toward glycogen-bound substrates.

SIGNOR-249036

Q9C040

P07196

1

ubiquitination

down-regulates quantity by destabilization

0.43

Here, we show that TRIM RING finger protein TRIM2, highly expressed in the nervous system, is an UbcH5a-dependent ubiquitin ligase. We further demonstrate that TRIM2 binds to neurofilament light subunit (NF-L) and regulates NF-L ubiquitination.

SIGNOR-271776

Q9P227

P63000

1

gtpase-activating protein

down-regulates activity

0.43

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260480

Q16539

O60381

1

phosphorylation

up-regulates

0.43

A mutation of the p38 map kinase phosphorylation site at aa 401 [(s-a)401hbp1] also triggered hbp1 protein instability. While protein stability was compromised by mutation, the specific activities of (s-a)401hbp1 and of wild-type hbp1 appeared comparable for transcriptional repression.

SIGNOR-119138

Q96KB5

P05412

1

phosphorylation

up-regulates activity

0.43

TOPK promotes lung cancer resistance to EGFR tyrosine kinase inhibitors by phosphorylating and activating c-Jun.|These data confirm the phosphorylation of c-Jun by TOPK at serine 63 and 73 during the development of resistance to EGFR-targeted TKIs.

SIGNOR-278156

P30530

P00533

2

phosphorylation

up-regulates activity

0.43

AXL trans-actives EGFR in a ligand independent manner and induces phosphorylation of EGFR on tyrosine 1173.|In our models AXL seems to induce a re-wiring of the EGFR signaling towards the PLCgamma-PKC axis by receptor phosphorylation at tyrosine 1173.

SIGNOR-279141

Q13332

P00533

1

dephosphorylation

down-regulates activity

0.43

Similarly, Pestana et al. (89) have reported that overexpression of RPTPsigma in human A431 carcinoma cells partially inhibits EGFR activation, whereas antisense mediated suppression of RPTPsigma expression enhances EGFR activation, substrate phosphorylation, and signalling.|These data indicate that LAR and RPTPsigma may have a significant role in GPCR induced EGFR signalling.Whereas in A431 cells LAR and RPTPsigma may act to suppress the EGFR in response to GPCR activation, it is possible that the converse may also be true in other cell types.

SIGNOR-277145

Q9UBC7

O43603

1

binding

up-regulates

0.43

Galp is therefore an endogenous ligand that preferentially binds the galr2 receptor

SIGNOR-73143

P23769

O00321

1

binding

up-regulates activity

0.43

Transcriptional assays with the Spi1 promoter-reporter demonstrated that Gata2 cooperates with Etv2 and augments the transcriptional activity of Etv2.The protein-protein interaction between Etv2 and Gata2 is mediated by the Ets and Gata domains. Using the embryoid body differentiation system, we demonstrate that co-expression of Gata2 augments the activity of Etv2 in promoting endothelial and hematopoietic lineage differentiation.

SIGNOR-256008

P00533

P30530

2

phosphorylation

up-regulates activity

0.43

In this study, we have identified for the first time a direct interaction between EGFR and Axl RTKs, with EGF and EGFR induced activation of Axl as a novel signalling pathway to invasion in cancer cells.|The activation of Axl was shown to occur through direct phosphorylation by EGFR of Axl tyrosine 779, one of the key residues within Axl that serves as a multi-substrate docking site for further downstream signalling.

SIGNOR-279734

P31749

O14757

1

phosphorylation

down-regulates

0.43

The chk1 protein phosphorylated by pkb on serine 280 does not enter into protein complexes after replication arrest. Moreover, chk1 phosphorylated by pkb fails to undergo activating phosphorylation on serine 345 by atm/atr. Phosphorylation by atm/atr and association with other checkpoint proteins are essential steps in activation of chk1.

SIGNOR-124365

O94901

P49790

1

binding

up-regulates activity

0.43

The NXF1:NXT1 complex and NUP153 interact with the amino terminus of SUN1 |In analogy to a proposal made by Chang et al.4, Nesprins could help anchoring SUN1 near the NPC to enable it to fulfill its task in mRNA export.

SIGNOR-263294

Q9Y6Y1

P01160

1

transcriptional regulation

up-regulates quantity by expression

0.429

CAMTA1 itself stimulates the expression of the anti-proliferative peptide NPPA.

SIGNOR-261570

P49840

P10636

1

phosphorylation

down-regulates

0.429

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

SIGNOR-60651

O60603

Q86XR7

1

binding

up-regulates activity

0.429

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

SIGNOR-266747

Q9UQM7

Q96PV0

1

phosphorylation

up-regulates activity

0.429

Here we show that phosphorylation of synGAP by Ca(2+)/calmodulin-dependent protein kinase II increases its Ras GTPase-activating activity by 70-95%. The Major Phosphorylation Sites, Serines 764/765, 1058, and 1123, All Contribute to Regulation of GAP Activity of synGAP by CaMKII

SIGNOR-262687

P53350

Q9BVS4

1

phosphorylation

up-regulates activity

0.429

Here, we report that the atypical protein kinase Rio2 is a novel substrate of Plk1 and can be phosphorylated by Plk1 at Ser-335, Ser-380, and Ser-548. Overexpression of Rio2 causes a prolonged mitotic exit whereas knockdown of Rio2 accelerates mitotic progression, suggesting that Rio2 is required for the proper mitotic progression. F urthermore, time-lapse imaging data show that overexpression of Rio2 but not Rio2 S3A results in a slowed metaphase-anaphase transition. Collectively, these findings strongly indicate that the Plk1-mediated phosphorylation of Rio2 regulates metaphase-anaphase transition during mitotic progression.

SIGNOR-262937

Q96RI0

O95837

1

binding

up-regulates activity

0.429

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-257419

O15111

P20749

1

phosphorylation

up-regulates activity

0.429

Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.

SIGNOR-277362

P68400

Q01892

1

phosphorylation

down-regulates

0.429

Serine residues 37 in the transactivation domain and 129, 144 and 146 in the pest domain of spi-b are phosphorylated by ckii in vitro. The ckii phosphorylation sites mapped in vitro are phosphorylated in vivo. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability

SIGNOR-73891

P22694

Q92934

1

phosphorylation

down-regulates

0.429

Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136.

SIGNOR-81141

Q9P0L2

P10636

1

phosphorylation

down-regulates activity

0.429

We have studied the relationship between the phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. MARK and PKA phosphorylate several sites within the repeats (notably the KXGS motifs including Ser262, Ser324, and Ser356, plus Ser320). This type of phosphorylation strongly reduces tau's affinity for microtubules, and at the same time inhibits tau's assembly into PHFs.

SIGNOR-250173

Q8NBJ5

P08123

1

glycosylation

up-regulates activity

0.429

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

SIGNOR-261153

Q9BXM7

Q9UJA2

1

phosphorylation

down-regulates quantity

0.429

In vitro kinase assays using recombinant proteins under various control conditions indicated that PINK1 directly phosphorylates CLS1 (XREF_FIG).|Similar to Fbxo15, knockdown of PINK1 kinase using shRNA increased CLS1 levels, whereas overexpression of PINK1 plasmid decreased CLS1 levels .

SIGNOR-280065

O15105

P62136

1

binding

up-regulates

0.429

Smad7, induced by alk1 activation, recruits pp1? To alk1 and thereby inhibits tgf-?/Alk1-induced smad1/5 phosphorylation in ecs

SIGNOR-145389

Q99835

P04899

1

binding

up-regulates activity

0.429

it was proposed that Smo might signal through activation of Gi proteins to reduce PKA activity.

SIGNOR-199162

P31751

Q15365

1

phosphorylation

down-regulates activity

0.429

We show that heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) binds a structural, 33-nucleotide TGF-beta-activated translation (BAT) element in the 3' untranslated region of disabled-2 (Dab2) and interleukin-like EMT inducer (ILEI) transcripts, and represses their translation.TGF-beta activation leads to phosphorylation at Ser 43 of hnRNP E1 by protein kinase Bbeta/Akt2, inducing its release from the BAT element and translational activation of Dab2 and ILEI messenger RNAs.

SIGNOR-262625

P06493

P55211

1

phosphorylation

down-regulates

0.429

Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, thr125. This site is phosphorylated by cdk1/cyclin b1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle.

SIGNOR-141621

Q99986

Q96GD4

1

phosphorylation

up-regulates activity

0.429

In the VRK1 overexpression of experiment, VRK1 caused a significant stabilization of AURKB, with no change in level after 24h, which is consistent with protection of AURKB against its known degradation by ubiquitylation .|The phosphorylation of AURKB by VRK1 and VRK1 by AURKB was tested using a kinase-dead form as substrate.

SIGNOR-280160