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
P49760	P18031	1	phosphorylation	up-regulates activity	0.322	The clk family kinases, clk1 and clk2, phosphorylate and activate the tyrosine phosphatase, ptp-1b.\|Phosphorylation of PTP-1B at Ser(50) by CLK1 or CLK2 is responsible for its enzymatic activation.	SIGNOR-70603
P17947	P17542	2	binding	down-regulates activity	0.439	PU.1/Spi-1 binds to the human TAL-1 silencer to mediate its activity.By expressing a mutant protein containing only the ETS domain of PU.1 in human erythroleukemic HEL cells, we demonstrated that PU.1 mediates the transcriptional repression activity of the silencer. Our data clearly demonstrate that PU.1 mediates TAL-1 silencer activity	SIGNOR-256048
Q6UN15	P51003	2	binding	up-regulates	0.791	Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna.	SIGNOR-121700
Q13233	P52564	1	phosphorylation	up-regulates	0.454	Both wild type and kinase-inactive mutant rip immunoprecipitates can active mkk6 in vitrohe sapks are activated by at least two meks, sapk/erk kinase-1 (sek1, also called mapk-kinase (mkk)) and mkk7	SIGNOR-59679
O14974	P04049	0	phosphorylation	down-regulates activity	0.274	In hESC, Raf-1 directly phosphorylates and inactivates MYPT1, and this process requires kinase active Raf-1 protein.	SIGNOR-278979
O14920	P19838	1	phosphorylation	down-regulates quantity by destabilization	0.853	Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway.	SIGNOR-70473
P08069	P12004	1	phosphorylation	up-regulates activity	0.2	In vitro MS analysis of PCNA co-incubated with the IGF-1R kinase indicated tyrosine residues 60, 133, and 250 in PCNA as IGF-1R targets, and PCNA phosphorylation was followed by mono- and polyubiquitination.	SIGNOR-277252
Q15751	P62195	1	ubiquitination	down-regulates quantity	0.2	HERC1 interacts with and ubiquitinates nascent PSMC5.\|PSMC5 produced in the absence of PAAF1 is presumably misfolded (consistent with its aggregation in the PURE system), triggering PSMC5 degradation by a HERC1-independent pathway.	SIGNOR-278812
Q9UIF8	Q5TEC6	2	binding	down-regulates activity	0.2	The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation.	SIGNOR-266618
P23946	P05305	1	cleavage	up-regulates activity	0.472	Chymase from human mast cells selectively cleaved big endothelins (ETs) at the Tyr31-Gly32 bond and produced novel trachea-constricting 31-amino acid-length endothelins, ETs(1-31), without any further degradation products.	SIGNOR-256356
P35222	Q14160	2	binding	up-regulates activity	0.434	Cadherins mediate the localization of vesicles to presynaptic compartments through multiple mechanisms. Cadherin-bound β-catenin then recruits scribble (Scrib) which acts as a scaffold for the further recruitment of proteins that mediate the localization of SVs.	SIGNOR-265826
P62993	P35968	0	relocalization	up-regulates activity	0.686	In a similar fashion, KDR associates with Grb2 and Nck in a ligand-dependent fashion, suggesting Shc, Grb2, and Nck as potential candidates involved in the regulation of endothelial function.	SIGNOR-261948
P42575	P36873	0	dephosphorylation	up-regulates activity	0.2	nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2.	SIGNOR-248503
P67870	O60763	1	phosphorylation	up-regulates activity	0.335	Phosphorylation is mediated by casein kinase II (CKII) or a CKII-like kinase. \| Serine 941 in the Acidic Domain of p115 Is Essential for Reassembly of Golgi Cisternae	SIGNOR-251082
P17655	P20810	2	binding	down-regulates activity	0.904	In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains\|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain	SIGNOR-251609
P46937	P42685	0	phosphorylation	down-regulates quantity by destabilization	0.275	Mechanistically, FRK interacted with and phosphorylated YAP on Tyr391/407/444, which recruited the classical E3 ubiquitin ligase Siah1 to catalyze ubiquitination and eventually degradation of YAP.	SIGNOR-275456
P12931	P00533	1	phosphorylation	up-regulates activity	0.625	Revealed that peptides derived from egfr residues y992, y1086, y1101, and y1148 bound directly to the sh2 domain of c-src (figure 8c). These experiments demonstrate that a specific subset of egfr receptor c-src phosphorylation sites are also ligands for the sh2 domain of c-src.Cellular src functions as a co-transducer of transmembrane signals emanating from a variety of growth factor receptors, including egfr	SIGNOR-44251
Q96D59	P05026	1	polyubiquitination	down-regulates quantity by destabilization	0.2	RNF183 promotes the degradation of Na, K-ATPas. We confirmed that RNF183 interacted with both α1 and β1 subunits; however, we found that RNF183 ubiquitinated only the β1 subunit, not the α1 subunit.	SIGNOR-272218
Q13043	P67775	0	dephosphorylation	down-regulates	0.367	Rassf1a apparently protects mst1/2 against inactivation by pp2a , the phosphatases that dephosphorylate the stimulatory thr-183 and thr-180 of mst1 andmst2, respectively.	SIGNOR-201270
P18031	Q8TD08	1	dephosphorylation	down-regulates	0.326	Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif. Dephosphorylation of the threonine residue by pp2a (protein serine/threonine phosphatase 2a) decreased erk8 activity by over 95% in vitro, whereas complete dephosphorylation of the tyrosine residue by ptp1b (protein tyrosine phosphatase 1b) decreased activity by only 15-20%	SIGNOR-142981
O75197	O14640	2	binding	up-regulates activity	0.688	The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization.	SIGNOR-262525
Q16539	Q9H1K0	1	phosphorylation	up-regulates	0.2	We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes	SIGNOR-140143
P53804	Q9HAU4	1	ubiquitination	down-regulates quantity	0.2	Tribbles homolog 3 ( TRB3 ) and Tetratricopeptide Repeat Domain 3 ( TTC3 ) directly ubiquitinate Smurf2 , thereby mediating Smurf2 degradation in a proteasome-dependent manner .\|Tribbles homolog 3 (TRB3) and Tetratricopeptide Repeat Domain 3 (TTC3) directly ubiquitinate Smurf2, thereby mediating Smurf2 degradation in a proteasome dependent manner.	SIGNOR-278739
Q16665	Q9UBF6	0	ubiquitination	down-regulates activity	0.2	SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase. by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes.	SIGNOR-271450
Q9Y297	P15336	1	ubiquitination	down-regulates quantity by destabilization	0.2	Our data suggest that mTORC1 promotes the binding of the E3 ligase, βTrCP, to CREB2 (Figure 4D), promoting CREB2 degradation by the proteasome (Figure 4E). Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2).	SIGNOR-267830
Q6EIG7	Q13191	0	ubiquitination	down-regulates quantity by destabilization	0.2	Furthermore, we found that Cbl-b, an E3 ubiquitin ligase, mediates the ubiquitination and degradation of the activated Dectin-2 and Dectin-3 to negatively regulate CLR mediated innate immune responses against fungal infections.	SIGNOR-278625
P12931	Q12774	1	phosphorylation	up-regulates activity	0.465	Arhgef5 was tyrosine-phosphorylated by Src and bound to Src to positively regulate its activity.\|Using an inducible system for Src activation, we found that Src induced podosome formation depends upon the Src SH3 domain, and identified Arhgef5 as a Src SH3 binding protein.	SIGNOR-279571
Q9H7Z6	Q13315	0	phosphorylation	up-regulates activity	0.469	In this study we present evidence that MOF is phosphorylated at the threonine 392 residue (pT392-MOF) by ATM subsequent to IR induced DNA damage.\|Interestingly, ATM dependent-MOF phosphorylation increases MOF retention on DNA post-irradiation in S/G2-phase cells.	SIGNOR-278350
O60674	Q06187	1	phosphorylation	up-regulates activity	0.447	Jak2 and Lyn coimmunoprecipitated with Btk and phosphorylated Btk on tyrosine (XREF_FIG C).	SIGNOR-279196
P06239	P16284	1	phosphorylation	up-regulates activity	0.588	We demonstrated that phosphorylation of PECAM-1 by Src or Csk family kinases was sufficient to trigger its association with SHP-2. Moreover, it was able to promote binding of PECAM-1 to SHP-1, a SHP-2-related protein-tyrosine phosphatase expressed in hemopoietic cells. Taken together, these findings indicated that the Src and Csk families of kinases are strong candidates for mediating tyrosine phosphorylation of PECAM-1 and triggering its association with SH2 domain-containing phosphatases under physiological circumstances.	SIGNOR-262742
P29992	Q9NQ66	2	binding	up-regulates activity	0.623	TRH-R1 receptor, which is coupled to Gq/11 protein, activates phospholipase C, mobilizes calcium and activates protein kinase C.	SIGNOR-267203
O15259	P12931	0	phosphorylation	up-regulates activity	0.297	Src-induced tyrosine phosphorylation could be prevented by mutating the tyrosine residue at position 721 to phenylalanine ( C, lane 12) suggesting that Src kinase phosphorylates NPHP1 at tyrosine 721.	SIGNOR-279122
Q9BQE3	Q5SQI0	0	acetylation	up-regulates quantity by stabilization	0.246	Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.\|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules	SIGNOR-272247
Q99704	P07949	2	binding	up-regulates	0.614	Dok proteins directly associate with tyrosine 1062 of ret and could be its substrates. Phosphorylation of dok1 is necessary for interaction with ras-gap in vitro and in vivo. Dok1 is a negative regulator for the ras/erk signaling pathway activated by ret.	SIGNOR-90158
Q9H211	P49736	2	binding	up-regulates activity	0.813	Chromosomal DNA replication requires the recruitment of the six-subunit minichromosome maintenance (Mcm) complex to chromatin through the action of Cdc6 and Cdt1.	SIGNOR-261681
P63096	O43193	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-256737
Q12929	P27361	0	phosphorylation	down-regulates activity	0.323	We further show that the actin barbed-end capping activity of Eps8 is inhibited by brain-derived neurotrophic factor (BDNF) treatment through MAPK-dependent phosphorylation of Eps8 residues S624 and T628. Additionally, an Eps8 mutant, impaired in the MAPK target sites (S624A/T628A), displays increased association to actin-rich structures, is resistant to BDNF-mediated release from microfilaments, and inhibits BDNF-induced filopodia. The opposite is observed for a phosphomimetic Eps8 (S624E/T628E) mutant. Thus, collectively, our data identify Eps8 as a critical capping protein in the regulation of axonal filopodia and delineate a molecular pathway by which BDNF, through MAPK-dependent phosphorylation of Eps8, stimulates axonal filopodia formation, a process with crucial impacts on neuronal development and synapse formation.	SIGNOR-263058
P53041	P04150	1	dephosphorylation	down-regulates activity	0.541	Estrogen inhibits glucocorticoid action via protein phosphatase 5 (PP5)-mediated glucocorticoid receptor dephosphorylation.\|Inhibition of GR phosphorylation at Ser-211 is associated with decreased nuclear retention of GR and decreased gene transcription.	SIGNOR-248538
P27986	Q12913	0	dephosphorylation	down-regulates	0.261	As reduction of pi3k activity by cd148 or shp-1 [32] is not large (2540%), it is likely that these ptps may function as modulators of the pi3k pathway rather than suppressors.	SIGNOR-178049
Q8NHY2	Q8NHY2	2	polyubiquitination	down-regulates quantity by destabilization	0.2	MTA1 destabilizes COP1 by promoting its autoubiquitination. in addition to polyubiquitination of its substrates, COP1 also catalyzes its autoubiquitination for degradation as a part of an autoregulatory mechanism	SIGNOR-271893
P62820	Q96LT7	2	binding	up-regulates activity	0.474	Thus, our data identify C9orf72 as a novel Rab1a effector in the regulation of autophagy and indicate that C9orf72 haploinsufficiency and associated reductions in autophagy might be the underlying cause of C9ALS/FTD-associated p62 pathology.	SIGNOR-261282
P49023	Q00535	0	phosphorylation	up-regulates activity	0.377	Thus, phosphorylation of paxillin is involved in NGF-induced neurite extension of PC-12 cells, probably through regulating focal adhesion organization.\|cdk5 and p38MAPK phosphorylates Ser 85 on paxillin in vitro.	SIGNOR-278921
Q9Y243	Q6ZVD8	0	dephosphorylation	down-regulates activity	0.683	The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.\|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells.	SIGNOR-248731
P46940	P63000	2	binding	down-regulates activity	0.715	Although the name implies that it functions as a GTPase-activating protein, IQGAP1 actually stabilizes Cdc42 and Rac1 in the active, GTP-bound form (5, 8, 17). Thus, IQGAP1 acts as an “anti-GTPase-activating protein” for Cdc42 and Rac1, with marked effects on the cytoskeleton.	SIGNOR-261889
Q9BRS2	P35579	1	phosphorylation	up-regulates activity	0.2	This study demonstrates that SPC25 acts as a molecular scaffold, mediating SPC25/RIOK1/MYH9 complex formation and triggering the RIOK1‐mediated phosphorylation of MYH9 at Ser1943.Taken together, these results suggested that SPC25 increases MYH9 phosphorylation at Ser1943, enhancing the nuclear accumulation of MYH9 and consequently modulating the transcription of CTNNB1.	SIGNOR-278895
P04049	P53350	0	phosphorylation	up-regulates activity	0.289	An in vitro kinase assay demonstrated that PLK1 directly phosphorylated CRAF at S338 and S339, but not at S621 (XREF_FIG).\|These results demonstrate that PLK1 increases the stability of CRAF protein by preventing proteasome degradation.	SIGNOR-278190
Q99538	P78362	0	phosphorylation	up-regulates activity	0.2	Here we report that serine-arginine protein kinase 2 (SRPK2) phosphorylates delta-secretase and enhances its enzymatic activity. SRPK2 phosphorylates serine 226 on delta-secretase and accelerates its autocatalytic cleavage, leading to its cytoplasmic translocation and escalated enzymatic activities.	SIGNOR-273569
P23769	P04839	1	transcriptional regulation	down-regulates quantity	0.25	These results suggest that GATA-1 is an activator and that GATA-2 is a relative competitive inhibitor of GATA-1 in the expression of the gp91(phox) gene in human eosinophils.	SIGNOR-259948
P24394	P42229	1	null	up-regulates	0.556	Several cytokine receptors share subchains and targets. For example, the common gamma chain (CGC) is shared by IL2, IL4, IL7, IL9 and IL15 receptors that lead to the activation of STAT5	SIGNOR-254298
P50750	Q96PM5	1	phosphorylation	down-regulates	0.46	We showed that cdk9 phosphorylates pirh2 on ser-211 and thr-217 residues through their physical interaction. Phosphorylation of pirh2 renders it inactive and may contribute to p53-inhibition of transcriptional elongation of the hiv-1 ltr.	SIGNOR-201923
P49841	P30279	1	phosphorylation	down-regulates	0.454	Glycogen synthase kinase-3beta and p38 phosphorylate cyclin d2 on thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells	SIGNOR-154668
Q92918	O75791	1	phosphorylation	down-regulates activity	0.834	Serine/threonine phosphorylation of the T cell adaptor proteins SLP76 and GADS by HPK1 induces their release from signaling microclusters and subsequent termination of the T cell response.	SIGNOR-279421
Q13490	Q14249	1	ubiquitination	up-regulates activity	0.468	Alternatively, cIAP1 may mediate a vital function of EndoG other than cell death.\|Cellular inhibitor of apoptosis protein 1 ubiquitinates endonuclease G but does not affect endonuclease G-mediated cell death.	SIGNOR-278605
P21728	P50148	2	binding	up-regulates activity	0.495	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-257335
P60709	P17600	2	binding	up-regulates activity	0.299	Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner.	SIGNOR-269184
Q92730	P45983	2	binding	up-regulates	0.321	In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor	SIGNOR-152811
P32004	Q15349	0	phosphorylation	up-regulates activity	0.515	Western blot analysis demonstrated that the L1 kinase activity from PC12 cells that phosphorylated this site was co-eluted with the S6 kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity co-immunoprecipitate with L1 from brain, and metabolic labeling studies have demonstrated that Ser1152 is phosphorylated in vivo in the developing rat brain. \| These data demonstrate that the membrane-proximal 15 amino acids of the cytoplasmic domain of L1 are important for neurite outgrowth on L1, and the interactions it mediates may be regulated by phosphorylation of Ser1152.	SIGNOR-248949
P20339	P53611	0	lipidation	up-regulates activity	0.491	Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional	SIGNOR-265573
P05556	Q9Y5H5	2	binding	up-regulates activity	0.2	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion.	SIGNOR-265662
Q13535	Q01094	1	phosphorylation	up-regulates quantity by stabilization	0.377	These results thus suggest that this serine 31 residue is indeed an atm/atr phosphorylation site and in fact is the major site for atm/atr-mediated phosphorylation within e2f1. Thus, it is possible that the atm/atr-mediated phosphorylation inhibits the binding and function of skp2 and thus prevents the normal degradation of e2f1	SIGNOR-109420
Q96J92	O00141	0	phosphorylation	up-regulates activity	0.415	In addition, we identified a novel SGK1 phosphorylation site (S1201) in WNK4, and phosphorylation at this site is reduced by Ca(2+)/CaM.	SIGNOR-276421
Q16665	P48730	0	phosphorylation	down-regulates	0.324	In this work, we investigate the phosphorylation of the n-terminal heterodimerization (pas) domain of hif-1alpha and identify ser247 as a major site of in vitro modification by casein kinase 1delta (ck1delta). Mutation of this site to alanine, surprisingly, enhanced the transcriptional activity of hif-1alpha	SIGNOR-167476
P19525	P78563	2	binding	up-regulates activity	0.459	Both forms of ADAR1 show enhanced interactions with PKR at the peak of HIV infection, suggesting a role for this protein in the regulation of PKR activation.	SIGNOR-266359
P78317	Q9UGL1	1	sumoylation	down-regulates quantity by destabilization	0.3	Hendriks and coworkers showed that, in response to alkylation damage by methyl methanesulfonate (MMS), SUMOylated JARID1B (KDM5B) is ubiquitylated by the SUMOtargeted ubiquitin ligase RNF4 and degraded by the proteasome, whereas JARID1C (KDM5C) is SUMOylated and recruited to the chromatin to demethylate histone H3K4 (Hendriks et al., 2015).	SIGNOR-271575
P04049	O75914	0	phosphorylation	up-regulates	0.556	The protein kinase pak3 positively regulates raf-1 activity through phosphorylation of serine 338.	SIGNOR-62043
O00418	P0DP25	2	binding	up-regulates	0.461	The calmodulin-binding region is located between amino acids 51 and 96	SIGNOR-266337
P09619	P18031	0	dephosphorylation	down-regulates	0.691	Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr.	SIGNOR-179064
P12931	P04049	1	phosphorylation	up-regulates	0.605	We also show that phosphorylation of raf-1 on serine 338 by pak1 and tyrosines 340 and 341 by src relieves autoinhibition and that this occurs through a specific decrease in the binding of the raf-1 regulatory domain to its catalytic domain.	SIGNOR-97639
P30305	O14965	0	phosphorylation	up-regulates	0.722	We show that bypass of the g2/m checkpoint by the chk1 kinase inhibitor ucn-01 results in the activation of aurora-a and phosphorylation of cdc25b on s353	SIGNOR-139396
Q9Y297	Q13315	0	phosphorylation	up-regulates quantity by stabilization	0.299	ATM phosphorylates and stabilizes β-TrCP1 upon DNA damage.	SIGNOR-277549
P12882	Q02078	0	transcriptional regulation	up-regulates quantity by expression	0.355	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-238748
Q96GD4	Q8NG31	1	phosphorylation	down-regulates	0.2	To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant).	SIGNOR-165502
Q04724	Q96QT6	2	binding	up-regulates activity	0.2	We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE.	SIGNOR-266994
Q13131	O43524	1	phosphorylation	up-regulates activity	0.517	Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.	SIGNOR-249684
Q9H469	Q9HCE7-2	2	binding	down-regulates quantity by destabilization	0.56	Here, we report that F-box and LRR domain-containing protein 15 (FBXL15), an F-box protein of the FBXL family, forms an Skp1-Cullin1-F-box protein-Roc1 (SCF)(FBXL15) ubiquitin ligase complex and targets Smurf1 for ubiquitination and proteasomal degradation. FBXL15, through its leucine-rich repeat domain, specifically recognizes the large subdomain within the N-lobe of the Smurf1 HECT domain and promotes the ubiquitination of Smurf1 on K355 and K357 within the WW-HECT linker region. In this way, FBXL15 positively regulates BMP signalling in mammalian cells.	SIGNOR-271909
P78347	P54821	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
Q9UPX8	Q9P1A6	0	relocalization	up-regulates activity	0.849	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264590
P53350	Q8N4N8	1	phosphorylation	up-regulates activity	0.66	We show that Plk1 directly phosphorylates Kif2b at threonine 125 (T125) and serine 204 (S204), and that these two sites differentially regulate Kif2b function. Phosphorylation of S204 is required for the kinetochore localization and activity of Kif2b in prometaphase, and phosphorylation of T125 is required for Kif2b activity in the correction of k-MT attachment errors.	SIGNOR-252049
P46527	P00519	0	phosphorylation	down-regulates quantity	0.595	A conserved tyrosine residue (Y88) in the Cdk-binding domain of p27 can be phosphorylated by the Src-family kinase Lyn and the oncogene product BCR-ABL	SIGNOR-245293
O00429	P49841	0	phosphorylation	up-regulates activity	0.388	We identified glycogen synthase kinase (GSK)3β-dependent Drp1 phosphorylation at Ser(40) and Ser(44), which increases Drp1 GTPase activity and its mitochondrial distribution and could induce mitochondrial fragmentation.	SIGNOR-276849
P08754	Q13639	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-257154
Q96EB6	P46531	1	deacetylation	down-regulates	0.423	The acetylation marks on notch1-icd are removed by the deacetylase sirt1, suggesting that both deacetylation of notch1-icd and of histones inhibit notch signaling.	SIGNOR-195333
Q14164	P10914	1	phosphorylation	down-regulates activity	0.35	We demonstrated that IKK-ε phosphorylated the transcription factor IFN regulatory factor 1 (IRF-1) at amino acid (aa) 215/219/221 in primary CD4(+) T cells and blocked its transcriptional activity.	SIGNOR-276480
Q06124	P35221	1	dephosphorylation	down-regulates	0.435	Tyr148 of beta-catenin is an shp2 target dephosphorylation site. Together, these results suggest that beta-catenin plays a suppressor role in cell transformation and that shp2, by dephosphorylating beta-catenin, promotes mitogenic, cell survival and transformation signals.	SIGNOR-147075
P46934	P37840	1	ubiquitination	down-regulates quantity by destabilization	0.372	Here we show that the ubiquitin ligase Nedd4, which functions in the endosomal-lysosomal pathway, robustly ubiquitinates alpha-synuclein, unlike ligases previously implicated in its degradation.	SIGNOR-278611
Q9HCK8	P04818	1	transcriptional regulation	up-regulates quantity by expression	0.283	In order to identify CHD8 target genes, we performed a transcriptomic analysis of CHD8-depleted cells, finding out that CHD8 controls the expression of cyclin E2 (CCNE2) and thymidylate synthetase (TYMS), two genes expressed in the G1/S transition of the cell cycle. CHD8 was also able to co-activate the CCNE2 promoter in transient transfection experiments. Chromatin immunoprecipitation experiments demonstrated that CHD8 binds directly to the 5' region of both CCNE2 and TYMS genes.	SIGNOR-268805
Q15759	O75928	1	phosphorylation	up-regulates activity	0.264	The switch between the coactivating and inhibitory actions of PIASxα is controlled, at least in part, through PIASxα phosphorylation. PIASxα is itself phosphorylated by p38 in vitro and in vivo in response to the activation of stress signaling pathways (Figure 2, Figure 3, Figure 4). We identify Ser113 and Ser 116 as two residues that are phosphorylated by p38 and have important functional roles	SIGNOR-262947
Q86TM6	Q99574	1	polyubiquitination	down-regulates quantity by destabilization	0.2	In this study, we demonstrate that two ER-associated E3 ligases, Hrd1 and gp78, are involved in the ubiquitination and degradation of mutant neuroserpin.	SIGNOR-272757
P24928	O60885	0	phosphorylation	up-regulates	0.448	We report that brd4 is an atypical kinase that binds to the carboxyl-terminal domain (ctd) of rna polymerase ii and directly phosphorylates its serine 2 (ser2) sites both in vitro and in vivo under conditions where other ctd kinases are inactive. our findings may provide a mechanistic basis for several functional studies that showed that loss of brd4 causes transcription termination and embryonic lethality	SIGNOR-197012
P48736	Q01105	1	phosphorylation	up-regulates activity	0.336	We show that PI3Kgamma phosphorylates I2PP2A on serine 9 and 93 residues resulting in enhanced interaction of I2PP2A with PP2A.	SIGNOR-278320
Q14493	P06899	1	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265381
Q03164	P23759	2	binding	up-regulates	0.2	Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5.	SIGNOR-198626
P60953	Q9ULL1	0	guanine nucleotide exchange factor	up-regulates activity	0.323	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-260563
Q86Y07	P04637	1	phosphorylation	up-regulates activity	0.383	Endogenous p53 is also phosphorylated in Thr18 by VRK2B, promoting its stabilization and transcriptional activation in A549 cells.\|Only overexpression of the nuclear VRK2B isoform induces p53 stabilization by post-translational modification, largely due to Thr18 phosphorylation.	SIGNOR-280162
P41221	Q14938	0	transcriptional regulation	down-regulates quantity	0.2	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268889
P35398	P20393	2	binding	down-regulates activity	0.461	Direct Regulation of the NPAS2 Promoter by RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding.	SIGNOR-267979
P15336	Q13315	0	phosphorylation	up-regulates	0.566	Here, we demonstrate that the protein kinase atm phosphorylates atf2 on serines 490 and 498 following ionizing radiation (ir). dose- and time-dependent phosphorylation of atf2 by atm that results in its rapid colocalization with gamma-h2ax and mrn components into ir-induced foci (irif)	SIGNOR-137619
Q969R5	Q8IYW5	2	binding	down-regulates quantity	0.246	L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling.	SIGNOR-266788
P31785	Q9HBE4	2	binding	up-regulates	0.61	The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, and il-15 as well as il-2. Here we show that the gamma(c) is also shared with the il-21r complex	SIGNOR-108858
P60568	P01589	2	binding	up-regulates	0.927	Il-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits il-2r alpha, il-2r beta, and gamma(c).	SIGNOR-144537

P49760

P18031

1

phosphorylation

up-regulates activity

0.322

The clk family kinases, clk1 and clk2, phosphorylate and activate the tyrosine phosphatase, ptp-1b.|Phosphorylation of PTP-1B at Ser(50) by CLK1 or CLK2 is responsible for its enzymatic activation.

SIGNOR-70603

P17947

P17542

2

binding

down-regulates activity

0.439

PU.1/Spi-1 binds to the human TAL-1 silencer to mediate its activity.By expressing a mutant protein containing only the ETS domain of PU.1 in human erythroleukemic HEL cells, we demonstrated that PU.1 mediates the transcriptional repression activity of the silencer. Our data clearly demonstrate that PU.1 mediates TAL-1 silencer activity

SIGNOR-256048

Q6UN15

P51003

2

binding

up-regulates

0.791

Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna.

SIGNOR-121700

Q13233

P52564

1

phosphorylation

up-regulates

0.454

Both wild type and kinase-inactive mutant rip immunoprecipitates can active mkk6 in vitrohe sapks are activated by at least two meks, sapk/erk kinase-1 (sek1, also called mapk-kinase (mkk)) and mkk7

SIGNOR-59679

O14974

P04049

0

phosphorylation

down-regulates activity

0.274

In hESC, Raf-1 directly phosphorylates and inactivates MYPT1, and this process requires kinase active Raf-1 protein.

SIGNOR-278979

O14920

P19838

1

phosphorylation

down-regulates quantity by destabilization

0.853

Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway.

SIGNOR-70473

P08069

P12004

1

phosphorylation

up-regulates activity

0.2

In vitro MS analysis of PCNA co-incubated with the IGF-1R kinase indicated tyrosine residues 60, 133, and 250 in PCNA as IGF-1R targets, and PCNA phosphorylation was followed by mono- and polyubiquitination.

SIGNOR-277252

Q15751

P62195

1

ubiquitination

down-regulates quantity

0.2

HERC1 interacts with and ubiquitinates nascent PSMC5.|PSMC5 produced in the absence of PAAF1 is presumably misfolded (consistent with its aggregation in the PURE system), triggering PSMC5 degradation by a HERC1-independent pathway.

SIGNOR-278812

Q9UIF8

Q5TEC6

2

binding

down-regulates activity

0.2

The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation.

SIGNOR-266618

P23946

P05305

1

cleavage

up-regulates activity

0.472

Chymase from human mast cells selectively cleaved big endothelins (ETs) at the Tyr31-Gly32 bond and produced novel trachea-constricting 31-amino acid-length endothelins, ETs(1-31), without any further degradation products.

SIGNOR-256356

P35222

Q14160

2

binding

up-regulates activity

0.434

Cadherins mediate the localization of vesicles to presynaptic compartments through multiple mechanisms. Cadherin-bound β-catenin then recruits scribble (Scrib) which acts as a scaffold for the further recruitment of proteins that mediate the localization of SVs.

SIGNOR-265826

P62993

P35968

0

relocalization

up-regulates activity

0.686

In a similar fashion, KDR associates with Grb2 and Nck in a ligand-dependent fashion, suggesting Shc, Grb2, and Nck as potential candidates involved in the regulation of endothelial function.

SIGNOR-261948

P42575

P36873

0

dephosphorylation

up-regulates activity

0.2

nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2.

SIGNOR-248503

P67870

O60763

1

phosphorylation

up-regulates activity

0.335

Phosphorylation is mediated by casein kinase II (CKII) or a CKII-like kinase. | Serine 941 in the Acidic Domain of p115 Is Essential for Reassembly of Golgi Cisternae

SIGNOR-251082

P17655

P20810

2

binding

down-regulates activity

0.904

In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain

SIGNOR-251609

P46937

P42685

0

phosphorylation

down-regulates quantity by destabilization

0.275

Mechanistically, FRK interacted with and phosphorylated YAP on Tyr391/407/444, which recruited the classical E3 ubiquitin ligase Siah1 to catalyze ubiquitination and eventually degradation of YAP.

SIGNOR-275456

P12931

P00533

1

phosphorylation

up-regulates activity

0.625

Revealed that peptides derived from egfr residues y992, y1086, y1101, and y1148 bound directly to the sh2 domain of c-src (figure 8c). These experiments demonstrate that a specific subset of egfr receptor c-src phosphorylation sites are also ligands for the sh2 domain of c-src.Cellular src functions as a co-transducer of transmembrane signals emanating from a variety of growth factor receptors, including egfr

SIGNOR-44251

Q96D59

P05026

1

polyubiquitination

down-regulates quantity by destabilization

0.2

RNF183 promotes the degradation of Na, K-ATPas. We confirmed that RNF183 interacted with both α1 and β1 subunits; however, we found that RNF183 ubiquitinated only the β1 subunit, not the α1 subunit.

SIGNOR-272218

Q13043

P67775

0

dephosphorylation

down-regulates

0.367

Rassf1a apparently protects mst1/2 against inactivation by pp2a , the phosphatases that dephosphorylate the stimulatory thr-183 and thr-180 of mst1 andmst2, respectively.

SIGNOR-201270

P18031

Q8TD08

1

dephosphorylation

down-regulates

0.326

Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif. Dephosphorylation of the threonine residue by pp2a (protein serine/threonine phosphatase 2a) decreased erk8 activity by over 95% in vitro, whereas complete dephosphorylation of the tyrosine residue by ptp1b (protein tyrosine phosphatase 1b) decreased activity by only 15-20%

SIGNOR-142981

O75197

O14640

2

binding

up-regulates activity

0.688

The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization.

SIGNOR-262525

Q16539

Q9H1K0

1

phosphorylation

up-regulates

0.2

We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes

SIGNOR-140143

P53804

Q9HAU4

1

ubiquitination

down-regulates quantity

0.2

Tribbles homolog 3 ( TRB3 ) and Tetratricopeptide Repeat Domain 3 ( TTC3 ) directly ubiquitinate Smurf2 , thereby mediating Smurf2 degradation in a proteasome-dependent manner .|Tribbles homolog 3 (TRB3) and Tetratricopeptide Repeat Domain 3 (TTC3) directly ubiquitinate Smurf2, thereby mediating Smurf2 degradation in a proteasome dependent manner.

SIGNOR-278739

Q16665

Q9UBF6

0

ubiquitination

down-regulates activity

0.2

SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase. by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes.

SIGNOR-271450

Q9Y297

P15336

1

ubiquitination

down-regulates quantity by destabilization

0.2

Our data suggest that mTORC1 promotes the binding of the E3 ligase, βTrCP, to CREB2 (Figure 4D), promoting CREB2 degradation by the proteasome (Figure 4E). Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2).

SIGNOR-267830

Q6EIG7

Q13191

0

ubiquitination

down-regulates quantity by destabilization

0.2

Furthermore, we found that Cbl-b, an E3 ubiquitin ligase, mediates the ubiquitination and degradation of the activated Dectin-2 and Dectin-3 to negatively regulate CLR mediated innate immune responses against fungal infections.

SIGNOR-278625

P12931

Q12774

1

phosphorylation

up-regulates activity

0.465

Arhgef5 was tyrosine-phosphorylated by Src and bound to Src to positively regulate its activity.|Using an inducible system for Src activation, we found that Src induced podosome formation depends upon the Src SH3 domain, and identified Arhgef5 as a Src SH3 binding protein.

SIGNOR-279571

Q9H7Z6

Q13315

0

phosphorylation

up-regulates activity

0.469

In this study we present evidence that MOF is phosphorylated at the threonine 392 residue (pT392-MOF) by ATM subsequent to IR induced DNA damage.|Interestingly, ATM dependent-MOF phosphorylation increases MOF retention on DNA post-irradiation in S/G2-phase cells.

SIGNOR-278350

O60674

Q06187

1

phosphorylation

up-regulates activity

0.447

Jak2 and Lyn coimmunoprecipitated with Btk and phosphorylated Btk on tyrosine (XREF_FIG C).

SIGNOR-279196

P06239

P16284

1

phosphorylation

up-regulates activity

0.588

We demonstrated that phosphorylation of PECAM-1 by Src or Csk family kinases was sufficient to trigger its association with SHP-2. Moreover, it was able to promote binding of PECAM-1 to SHP-1, a SHP-2-related protein-tyrosine phosphatase expressed in hemopoietic cells. Taken together, these findings indicated that the Src and Csk families of kinases are strong candidates for mediating tyrosine phosphorylation of PECAM-1 and triggering its association with SH2 domain-containing phosphatases under physiological circumstances.

SIGNOR-262742

P29992

Q9NQ66

2

binding

up-regulates activity

0.623

TRH-R1 receptor, which is coupled to Gq/11 protein, activates phospholipase C, mobilizes calcium and activates protein kinase C.

SIGNOR-267203

O15259

P12931

0

phosphorylation

up-regulates activity

0.297

Src-induced tyrosine phosphorylation could be prevented by mutating the tyrosine residue at position 721 to phenylalanine ( C, lane 12) suggesting that Src kinase phosphorylates NPHP1 at tyrosine 721.

SIGNOR-279122

Q9BQE3

Q5SQI0

0

acetylation

up-regulates quantity by stabilization

0.246

Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules

SIGNOR-272247

Q99704

P07949

2

binding

up-regulates

0.614

Dok proteins directly associate with tyrosine 1062 of ret and could be its substrates. Phosphorylation of dok1 is necessary for interaction with ras-gap in vitro and in vivo. Dok1 is a negative regulator for the ras/erk signaling pathway activated by ret.

SIGNOR-90158

Q9H211

P49736

2

binding

up-regulates activity

0.813

Chromosomal DNA replication requires the recruitment of the six-subunit minichromosome maintenance (Mcm) complex to chromatin through the action of Cdc6 and Cdt1.

SIGNOR-261681

P63096

O43193

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-256737

Q12929

P27361

0

phosphorylation

down-regulates activity

0.323

We further show that the actin barbed-end capping activity of Eps8 is inhibited by brain-derived neurotrophic factor (BDNF) treatment through MAPK-dependent phosphorylation of Eps8 residues S624 and T628. Additionally, an Eps8 mutant, impaired in the MAPK target sites (S624A/T628A), displays increased association to actin-rich structures, is resistant to BDNF-mediated release from microfilaments, and inhibits BDNF-induced filopodia. The opposite is observed for a phosphomimetic Eps8 (S624E/T628E) mutant. Thus, collectively, our data identify Eps8 as a critical capping protein in the regulation of axonal filopodia and delineate a molecular pathway by which BDNF, through MAPK-dependent phosphorylation of Eps8, stimulates axonal filopodia formation, a process with crucial impacts on neuronal development and synapse formation.

SIGNOR-263058

P53041

P04150

1

dephosphorylation

down-regulates activity

0.541

Estrogen inhibits glucocorticoid action via protein phosphatase 5 (PP5)-mediated glucocorticoid receptor dephosphorylation.|Inhibition of GR phosphorylation at Ser-211 is associated with decreased nuclear retention of GR and decreased gene transcription.

SIGNOR-248538

P27986

Q12913

0

dephosphorylation

down-regulates

0.261

As reduction of pi3k activity by cd148 or shp-1 [32] is not large (2540%), it is likely that these ptps may function as modulators of the pi3k pathway rather than suppressors.

SIGNOR-178049

Q8NHY2

2

polyubiquitination

down-regulates quantity by destabilization

0.2

MTA1 destabilizes COP1 by promoting its autoubiquitination. in addition to polyubiquitination of its substrates, COP1 also catalyzes its autoubiquitination for degradation as a part of an autoregulatory mechanism

SIGNOR-271893

P62820

Q96LT7

2

binding

up-regulates activity

0.474

Thus, our data identify C9orf72 as a novel Rab1a effector in the regulation of autophagy and indicate that C9orf72 haploinsufficiency and associated reductions in autophagy might be the underlying cause of C9ALS/FTD-associated p62 pathology.

SIGNOR-261282

P49023

Q00535

0

phosphorylation

up-regulates activity

0.377

Thus, phosphorylation of paxillin is involved in NGF-induced neurite extension of PC-12 cells, probably through regulating focal adhesion organization.|cdk5 and p38MAPK phosphorylates Ser 85 on paxillin in vitro.

SIGNOR-278921

Q9Y243

Q6ZVD8

0

dephosphorylation

down-regulates activity

0.683

The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells.

SIGNOR-248731

P46940

P63000

2

binding

down-regulates activity

0.715

Although the name implies that it functions as a GTPase-activating protein, IQGAP1 actually stabilizes Cdc42 and Rac1 in the active, GTP-bound form (5, 8, 17). Thus, IQGAP1 acts as an “anti-GTPase-activating protein” for Cdc42 and Rac1, with marked effects on the cytoskeleton.

SIGNOR-261889

Q9BRS2

P35579

1

phosphorylation

up-regulates activity

0.2

This study demonstrates that SPC25 acts as a molecular scaffold, mediating SPC25/RIOK1/MYH9 complex formation and triggering the RIOK1‐mediated phosphorylation of MYH9 at Ser1943.Taken together, these results suggested that SPC25 increases MYH9 phosphorylation at Ser1943, enhancing the nuclear accumulation of MYH9 and consequently modulating the transcription of CTNNB1.

SIGNOR-278895

P04049

P53350

0

phosphorylation

up-regulates activity

0.289

An in vitro kinase assay demonstrated that PLK1 directly phosphorylated CRAF at S338 and S339, but not at S621 (XREF_FIG).|These results demonstrate that PLK1 increases the stability of CRAF protein by preventing proteasome degradation.

SIGNOR-278190

Q99538

P78362

0

phosphorylation

up-regulates activity

0.2

Here we report that serine-arginine protein kinase 2 (SRPK2) phosphorylates delta-secretase and enhances its enzymatic activity. SRPK2 phosphorylates serine 226 on delta-secretase and accelerates its autocatalytic cleavage, leading to its cytoplasmic translocation and escalated enzymatic activities.

SIGNOR-273569

P23769

P04839

1

transcriptional regulation

down-regulates quantity

0.25

These results suggest that GATA-1 is an activator and that GATA-2 is a relative competitive inhibitor of GATA-1 in the expression of the gp91(phox) gene in human eosinophils.

SIGNOR-259948

P24394

P42229

1

null

up-regulates

0.556

Several cytokine receptors share subchains and targets. For example, the common gamma chain (CGC) is shared by IL2, IL4, IL7, IL9 and IL15 receptors that lead to the activation of STAT5

SIGNOR-254298

P50750

Q96PM5

1

phosphorylation

down-regulates

0.46

We showed that cdk9 phosphorylates pirh2 on ser-211 and thr-217 residues through their physical interaction. Phosphorylation of pirh2 renders it inactive and may contribute to p53-inhibition of transcriptional elongation of the hiv-1 ltr.

SIGNOR-201923

P49841

P30279

1

phosphorylation

down-regulates

0.454

Glycogen synthase kinase-3beta and p38 phosphorylate cyclin d2 on thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells

SIGNOR-154668

Q92918

O75791

1

phosphorylation

down-regulates activity

0.834

Serine/threonine phosphorylation of the T cell adaptor proteins SLP76 and GADS by HPK1 induces their release from signaling microclusters and subsequent termination of the T cell response.

SIGNOR-279421

Q13490

Q14249

1

ubiquitination

up-regulates activity

0.468

Alternatively, cIAP1 may mediate a vital function of EndoG other than cell death.|Cellular inhibitor of apoptosis protein 1 ubiquitinates endonuclease G but does not affect endonuclease G-mediated cell death.

SIGNOR-278605

P21728

P50148

2

binding

up-regulates activity

0.495

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-257335

P60709

P17600

2

binding

up-regulates activity

0.299

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

SIGNOR-269184

Q92730

P45983

2

binding

up-regulates

0.321

In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor

SIGNOR-152811

P32004

Q15349

0

phosphorylation

up-regulates activity

0.515

Western blot analysis demonstrated that the L1 kinase activity from PC12 cells that phosphorylated this site was co-eluted with the S6 kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity co-immunoprecipitate with L1 from brain, and metabolic labeling studies have demonstrated that Ser1152 is phosphorylated in vivo in the developing rat brain. | These data demonstrate that the membrane-proximal 15 amino acids of the cytoplasmic domain of L1 are important for neurite outgrowth on L1, and the interactions it mediates may be regulated by phosphorylation of Ser1152.

SIGNOR-248949

P20339

P53611

0

lipidation

up-regulates activity

0.491

Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional

SIGNOR-265573

P05556

Q9Y5H5

2

binding

up-regulates activity

0.2

The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion.

SIGNOR-265662

Q13535

Q01094

1

phosphorylation

up-regulates quantity by stabilization

0.377

These results thus suggest that this serine 31 residue is indeed an atm/atr phosphorylation site and in fact is the major site for atm/atr-mediated phosphorylation within e2f1. Thus, it is possible that the atm/atr-mediated phosphorylation inhibits the binding and function of skp2 and thus prevents the normal degradation of e2f1

SIGNOR-109420

Q96J92

O00141

0

phosphorylation

up-regulates activity

0.415

In addition, we identified a novel SGK1 phosphorylation site (S1201) in WNK4, and phosphorylation at this site is reduced by Ca(2+)/CaM.

SIGNOR-276421

Q16665

P48730

0

phosphorylation

down-regulates

0.324

In this work, we investigate the phosphorylation of the n-terminal heterodimerization (pas) domain of hif-1alpha and identify ser247 as a major site of in vitro modification by casein kinase 1delta (ck1delta). Mutation of this site to alanine, surprisingly, enhanced the transcriptional activity of hif-1alpha

SIGNOR-167476

P19525

P78563

2

binding

up-regulates activity

0.459

Both forms of ADAR1 show enhanced interactions with PKR at the peak of HIV infection, suggesting a role for this protein in the regulation of PKR activation.

SIGNOR-266359

P78317

Q9UGL1

1

sumoylation

down-regulates quantity by destabilization

0.3

Hendriks and coworkers showed that, in response to alkylation damage by methyl methanesulfonate (MMS), SUMOylated JARID1B (KDM5B) is ubiquitylated by the SUMOtargeted ubiquitin ligase RNF4 and degraded by the proteasome, whereas JARID1C (KDM5C) is SUMOylated and recruited to the chromatin to demethylate histone H3K4 (Hendriks et al., 2015).

SIGNOR-271575

P04049

O75914

0

phosphorylation

up-regulates

0.556

The protein kinase pak3 positively regulates raf-1 activity through phosphorylation of serine 338.

SIGNOR-62043

O00418

P0DP25

2

binding

up-regulates

0.461

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

SIGNOR-266337

P09619

P18031

0

dephosphorylation

down-regulates

0.691

Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr.

SIGNOR-179064

P12931

P04049

1

phosphorylation

up-regulates

0.605

We also show that phosphorylation of raf-1 on serine 338 by pak1 and tyrosines 340 and 341 by src relieves autoinhibition and that this occurs through a specific decrease in the binding of the raf-1 regulatory domain to its catalytic domain.

SIGNOR-97639

P30305

O14965

0

phosphorylation

up-regulates

0.722

We show that bypass of the g2/m checkpoint by the chk1 kinase inhibitor ucn-01 results in the activation of aurora-a and phosphorylation of cdc25b on s353

SIGNOR-139396

Q9Y297

Q13315

0

phosphorylation

up-regulates quantity by stabilization

0.299

ATM phosphorylates and stabilizes β-TrCP1 upon DNA damage.

SIGNOR-277549

P12882

Q02078

0

transcriptional regulation

up-regulates quantity by expression

0.355

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-238748

Q96GD4

Q8NG31

1

phosphorylation

down-regulates

0.2

To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant).

SIGNOR-165502

Q04724

Q96QT6

2

binding

up-regulates activity

0.2

We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE.

SIGNOR-266994

Q13131

O43524

1

phosphorylation

up-regulates activity

0.517

Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.

SIGNOR-249684

Q9H469

Q9HCE7-2

2

binding

down-regulates quantity by destabilization

0.56

Here, we report that F-box and LRR domain-containing protein 15 (FBXL15), an F-box protein of the FBXL family, forms an Skp1-Cullin1-F-box protein-Roc1 (SCF)(FBXL15) ubiquitin ligase complex and targets Smurf1 for ubiquitination and proteasomal degradation. FBXL15, through its leucine-rich repeat domain, specifically recognizes the large subdomain within the N-lobe of the Smurf1 HECT domain and promotes the ubiquitination of Smurf1 on K355 and K357 within the WW-HECT linker region. In this way, FBXL15 positively regulates BMP signalling in mammalian cells.

SIGNOR-271909

P78347

P54821

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

Q9UPX8

Q9P1A6

0

relocalization

up-regulates activity

0.849

SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).

SIGNOR-264590

P53350

Q8N4N8

1

phosphorylation

up-regulates activity

0.66

We show that Plk1 directly phosphorylates Kif2b at threonine 125 (T125) and serine 204 (S204), and that these two sites differentially regulate Kif2b function. Phosphorylation of S204 is required for the kinetochore localization and activity of Kif2b in prometaphase, and phosphorylation of T125 is required for Kif2b activity in the correction of k-MT attachment errors.

SIGNOR-252049

P46527

P00519

0

phosphorylation

down-regulates quantity

0.595

A conserved tyrosine residue (Y88) in the Cdk-binding domain of p27 can be phosphorylated by the Src-family kinase Lyn and the oncogene product BCR-ABL

SIGNOR-245293

O00429

P49841

0

phosphorylation

up-regulates activity

0.388

We identified glycogen synthase kinase (GSK)3β-dependent Drp1 phosphorylation at Ser(40) and Ser(44), which increases Drp1 GTPase activity and its mitochondrial distribution and could induce mitochondrial fragmentation.

SIGNOR-276849

P08754

Q13639

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-257154

Q96EB6

P46531

1

deacetylation

down-regulates

0.423

The acetylation marks on notch1-icd are removed by the deacetylase sirt1, suggesting that both deacetylation of notch1-icd and of histones inhibit notch signaling.

SIGNOR-195333

Q14164

P10914

1

phosphorylation

down-regulates activity

0.35

We demonstrated that IKK-ε phosphorylated the transcription factor IFN regulatory factor 1 (IRF-1) at amino acid (aa) 215/219/221 in primary CD4(+) T cells and blocked its transcriptional activity.

SIGNOR-276480

Q06124

P35221

1

dephosphorylation

down-regulates

0.435

Tyr148 of beta-catenin is an shp2 target dephosphorylation site. Together, these results suggest that beta-catenin plays a suppressor role in cell transformation and that shp2, by dephosphorylating beta-catenin, promotes mitogenic, cell survival and transformation signals.

SIGNOR-147075

P46934

P37840

1

ubiquitination

down-regulates quantity by destabilization

0.372

Here we show that the ubiquitin ligase Nedd4, which functions in the endosomal-lysosomal pathway, robustly ubiquitinates alpha-synuclein, unlike ligases previously implicated in its degradation.

SIGNOR-278611

Q9HCK8

P04818

1

transcriptional regulation

up-regulates quantity by expression

0.283

In order to identify CHD8 target genes, we performed a transcriptomic analysis of CHD8-depleted cells, finding out that CHD8 controls the expression of cyclin E2 (CCNE2) and thymidylate synthetase (TYMS), two genes expressed in the G1/S transition of the cell cycle. CHD8 was also able to co-activate the CCNE2 promoter in transient transfection experiments. Chromatin immunoprecipitation experiments demonstrated that CHD8 binds directly to the 5' region of both CCNE2 and TYMS genes.

SIGNOR-268805

Q15759

O75928

1

phosphorylation

up-regulates activity

0.264

The switch between the coactivating and inhibitory actions of PIASxα is controlled, at least in part, through PIASxα phosphorylation. PIASxα is itself phosphorylated by p38 in vitro and in vivo in response to the activation of stress signaling pathways (Figure 2, Figure 3, Figure 4). We identify Ser113 and Ser 116 as two residues that are phosphorylated by p38 and have important functional roles

SIGNOR-262947

Q86TM6

Q99574

1

polyubiquitination

down-regulates quantity by destabilization

0.2

In this study, we demonstrate that two ER-associated E3 ligases, Hrd1 and gp78, are involved in the ubiquitination and degradation of mutant neuroserpin.

SIGNOR-272757

P24928

O60885

0

phosphorylation

up-regulates

0.448

We report that brd4 is an atypical kinase that binds to the carboxyl-terminal domain (ctd) of rna polymerase ii and directly phosphorylates its serine 2 (ser2) sites both in vitro and in vivo under conditions where other ctd kinases are inactive. our findings may provide a mechanistic basis for several functional studies that showed that loss of brd4 causes transcription termination and embryonic lethality

SIGNOR-197012

P48736

Q01105

1

phosphorylation

up-regulates activity

0.336

We show that PI3Kgamma phosphorylates I2PP2A on serine 9 and 93 residues resulting in enhanced interaction of I2PP2A with PP2A.

SIGNOR-278320

Q14493

P06899

1

translation regulation

up-regulates quantity by expression

0.2

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

SIGNOR-265381

Q03164

P23759

2

binding

up-regulates

0.2

Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5.

SIGNOR-198626

P60953

Q9ULL1

0

guanine nucleotide exchange factor

up-regulates activity

0.323

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-260563

Q86Y07

P04637

1

phosphorylation

up-regulates activity

0.383

Endogenous p53 is also phosphorylated in Thr18 by VRK2B, promoting its stabilization and transcriptional activation in A549 cells.|Only overexpression of the nuclear VRK2B isoform induces p53 stabilization by post-translational modification, largely due to Thr18 phosphorylation.

SIGNOR-280162

P41221

Q14938

0

transcriptional regulation

down-regulates quantity

0.2

By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development

SIGNOR-268889

P35398

P20393

2

binding

down-regulates activity

0.461

Direct Regulation of the NPAS2 Promoter by RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding.

SIGNOR-267979

P15336

Q13315

0

phosphorylation

up-regulates

0.566

Here, we demonstrate that the protein kinase atm phosphorylates atf2 on serines 490 and 498 following ionizing radiation (ir). dose- and time-dependent phosphorylation of atf2 by atm that results in its rapid colocalization with gamma-h2ax and mrn components into ir-induced foci (irif)

SIGNOR-137619

Q969R5

Q8IYW5

2

binding

down-regulates quantity

0.246

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

SIGNOR-266788

P31785

Q9HBE4

2

binding

up-regulates

0.61

The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, and il-15 as well as il-2. Here we show that the gamma(c) is also shared with the il-21r complex

SIGNOR-108858

P60568

P01589

2

binding

up-regulates

0.927

Il-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits il-2r alpha, il-2r beta, and gamma(c).

SIGNOR-144537