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
P55212	P02545	1	cleavage	down-regulates	0.662	Lamin a breakdown is largely mediated by caspase-6 during the execution phase of apoptosis.	SIGNOR-83611
P01112	O00329	1	binding	up-regulates	0.662	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k	SIGNOR-175192
P01031	Q9P296	1	binding	up-regulates	0.662	Here we report that the orphan receptor c5l2/gpr77, which shares 35% amino acid identity with cd88, binds c5a with high affinity.	SIGNOR-113558
P42226	P23771	1	null	up-regulates	0.662	GATA-3 plays a central role in regulating Th1 and Th2 cell differentiation. Upon interleukin (IL)-4 binding to its receptor, GATA-3 is induced through the action of Stat6	SIGNOR-254299
Q9Y5K5	O15105	1	binding	up-regulates	0.662	Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases.	SIGNOR-138879
Q9UIC8	P62714	1	methylation	up-regulates activity	0.661	Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits \|The PP2A core enzyme was methylated by a PP2A-specific leucine carboxyl methyltransferase (LCMT1)	SIGNOR-265751
Q6ZN44	P43146	1	binding	down-regulates activity	0.661	In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists.	SIGNOR-268164
Q16539	Q02078	1	phosphorylation	up-regulates activity	0.661	We show that mef2a, but not mef2b or mef2d, is a substrate for p38. Threonines 312 and 319 are the key regulatory phosphorylation sites by p38 in mef2a. Phosphorylation at these sites enhances transcriptional activity of mef2a	SIGNOR-62780
P12931	P05106	1	phosphorylation	down-regulates activity	0.661	The phosphorylation level of beta(3) integrin was modulated using a temperature-sensitive v-Src kinase. Increased beta(3) phosphorylation abolished alpha(v)beta(3)- but not alpha(5)beta(1)-mediated adhesion to fibronectin. Thus, phosphorylation of the cytoplasmic domain of beta(3) is a negative regulator of alpha(v)beta(3)-fibronectin binding strength.	SIGNOR-247207
Q99835	P32121	1	binding	up-regulates	0.661	Grk2-mediated phosphorylation of vertebrate smo allows smo to bind to beta-arrestins 1 or 2	SIGNOR-132759
P13385	Q96S42	1	binding	up-regulates activity	0.661	Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors.	SIGNOR-251937
Q8IZQ1	O95166	1	binding	down-regulates quantity by destabilization	0.661	Here, we show that ALFY binds selectively to LC3C and the GABARAPs through a LIR in its WD40 domain. Binding of ALFY to GABARAP is indispensable for its recruitment to LC3B-positive structures and, thus, for the clearance of certain p62 structures by autophagy.	SIGNOR-266796
Q13233	Q02750	1	phosphorylation	up-regulates activity	0.661	Phosphorylation at ser-218 and ser-222 by map kinase kinase kinases (raf or mekk1) positively regulates mek1 kinase activity.	SIGNOR-235587
Q15173	P31749	1	dephosphorylation	down-regulates	0.661	Activation of pp2a is the intermediate step between the abeta-ceramide cascade and the subsequent inactivation of akt.	SIGNOR-252615
P52564	O15264	1	phosphorylation	up-regulates activity	0.661	p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation.	SIGNOR-273952
P42345	Q13542	1	phosphorylation	down-regulates	0.661	Here, we show that cancer cells acquire resistance to astori by downregulating eukaryotic translation initiation factor (eif4e)-binding proteins (4e-bps-eif4ebp1, eif4ebp2).	SIGNOR-122014
P35368	P29992	1	binding	up-regulates activity	0.661	In this report, we demonstrate that in transfected cos-7 cells Gal4 and Ga16, like Gaq and Ga11, can activate PIPLC j3l and that all three al-ARs, alA, alB and alC, can activate endogenous PI-PLC by coupling to Gaq or Ga11.	SIGNOR-278122
Q7Z569	Q8IVT5	1	ubiquitination	down-regulates quantity by destabilization	0.661	Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15.	SIGNOR-272028
O95433	P08238	1	binding	up-regulates activity	0.661	The N-terminal region of Aha1 interacts with the central domain of Hsp90 and stimulates Hsp90 ATPase activity	SIGNOR-252212
O75084	O14640	1	binding	up-regulates	0.661	In non-canonical Wnt signalling, Wnt proteins bind Fzd and glypican-4, to activate Dsh at the cell membrane, leading to activation of Rho and JNK	SIGNOR-255893
P0DP23	P48454	1	binding	up-regulates	0.661	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-114104
Q9HCE7	P36894	1	ubiquitination	down-regulates	0.66	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps.	SIGNOR-153399
P04049	Q92934	1	phosphorylation	down-regulates	0.66	The activation of several major anti-apoptotic signaling pathways correlates with an increase in the phosphorylation of bad on ser-112, ser-136, and ser-155. These phosphorylation events result in bad inactivation through sequestration by 14-3-3 proteins	SIGNOR-155293
Q13546	Q9Y4K3	1	binding	up-regulates activity	0.66	Collectively, TRIF forms a multiprotein signaling complex along with TRAF6, TRADD, Pellino-1 and RIP1 for the activation of TAK1, which in turn activates the NF-_B and MAPK pathways.	SIGNOR-216325
Q9H4B4	O96017	1	phosphorylation	up-regulates activity	0.66	Plk3 phosphorylates Chk2 at two residues, serine 62 (S62) and serine 73 (S73) in vitro, and this phosphorylation facilitates subsequent phosphorylation of Chk2 on T68 by ATM in response to DNA damage. When the Chk2 mutant construct GFP-Chk2 S73A (serine 73 mutated to alanine) is transfected into cells, it no longer associates with a large complex in vivo, and manifests a significant reduction in kinase activity.	SIGNOR-276051
P24666	P29317	1	dephosphorylation	down-regulates activity	0.66	The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates	SIGNOR-246023
Q9Y6H6	P51787	1	binding	up-regulates activity	0.66	Sexual dimorphism and oestrogen regulation of KCNE3 expression modulates the functional properties of KCNQ1 K⁺ channels\|The KCNQ1 potassium channel associates with various KCNE ancillary subunits that drastically affect channel gating and pharmacology. Co-assembly with KCNE3 produces a current with nearly instantaneous activation	SIGNOR-275923
P06493	Q9GZM8	1	phosphorylation	up-regulates activity	0.66	In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites	SIGNOR-274074
P35125	P62330	1	relocalization	up-regulates	0.66	Here we show that tre17 (also called tre-2 and usp6), a founding member of the tbc family, targets the arf family gtpase arf6, which regulates plasma membrane-endosome trafficking. Surprisingly, tre17 does not function as a gap for arf6 but rather promotes its activation in vivo. Forced expression of tre17 promotes the localization of arf6 to the plasma membrane, leading to arf6 activation, presumably due to facilitated access to membrane-associated guanine nucleotide exchange factors (gefs).	SIGNOR-130019
P07550	P63092	1	binding	up-regulates activity	0.66	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-256809
P23443	Q8TB45	1	phosphorylation	down-regulates	0.66	Deptor is phosphorylated by s6k1 and rsk1 on the degron serine residues upon serum stimulation s6k1/rsk1 and _trcp are required for ubiquitination and degradation of endogenous deptor upon mitogen stimulation.	SIGNOR-176866
P18031	P35222	1	dephosphorylation	up-regulates activity	0.66	PTP1B modulates the association of beta-catenin with N-cadherin through binding to an adjacent and partially overlapping target site.\|The nonreceptor tyrosine phosphatase PTP1B associates with the cytoplasmic domain of N-cadherin and may regulate cadherin function through dephosphorylation of beta-catenin.\|Thus, interaction of PTP1B with N-cadherin is essential for its association with beta-catenin, stable expression at the cell surface, and consequently, cadherin function.	SIGNOR-277121
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
Q06124	P01116	1	dephosphorylation	up-regulates activity	0.66	Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling.	SIGNOR-255982
O75444	P10242	1	binding	down-regulates	0.66	Full-length c-maf binds to the c-myb and ets-1. / c-maf inhibits c-myb and ets-1 transcriptional activity.	SIGNOR-56811
Q00987	P08069	1	ubiquitination	down-regulates quantity by destabilization	0.66	We could prove that Mdm2 physically associates with IGF-1R and that Mdm2 causes IGF-1R ubiquitination in an in vitro assay.	SIGNOR-278571
P23458	P38484	1	phosphorylation	up-regulates activity	0.66	The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process.	SIGNOR-249491
Q13322	P06213	1	binding	down-regulates	0.66	Grb10 negatively regulates growth factor signaling. It binds the insulin and insulin-like growth factor 1 (igf-1) receptors;mice without grb10 are larger and exhibit enhanced insulin sensitivity.	SIGNOR-174065
P31749	P04792	1	phosphorylation	down-regulates	0.66	First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue.	SIGNOR-252526
P00519	O14746	1	phosphorylation	down-regulates activity	0.66	These findings indicate that phosphorylation of hTERT by c-Abl is associated with inhibition of telomerase activity.\|We also found that c-Abl phosphorylates hTERT and inhibits hTERT activity.	SIGNOR-279354
Q86WA8	Q2T9J0	1	cleavage	down-regulates quantity by destabilization	0.66	Self-cleavage of Tysnd1 in the active oligomer most likely inactivates its protease activity. Subsequently, the cleaved products are degraded by PsLon and removed from the Tysnd1 oligomer.	SIGNOR-261054
P52564	P53778	1	phosphorylation	up-regulates	0.659	Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily . the p38 mapkinasekinasemkk6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma mapkinaseisoforms . p38mapks are activated by dual phosphorylation on a t-x-y motif in the activation loop through the action of map kinase kinases	SIGNOR-184134
P28482	Q13541	1	phosphorylation	down-regulates activity	0.659	The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.\|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 \|phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding	SIGNOR-249390
Q13467	O14640	1	binding	up-regulates activity	0.659	Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.	SIGNOR-258957
P63000	P45983	1	binding	up-regulates	0.659	The mechanism by which pak1 induced cancer growth might involve activation of jnk 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-152808
Q8IXL6	Q13316	1	phosphorylation	up-regulates quantity	0.659	Fam20c knockdown decreased Dmp1 mRNA and increased Fgf23 mRNA in UMR-106 cells.\|Relative migration distances of OPN and DMP1, which were the ratio of the migration distances of OPN or DMP1 co-expressed with mutant FAM20C to that with WT FAM20C, showed that only WT FAM20C could fully phosphorylate OPN and DMP1.	SIGNOR-280011
P07948	P40763	1	phosphorylation	up-regulates activity	0.659	An in vitro phosphorylation assay showed that Lyn directly phosphorylates STAT3.	SIGNOR-279062
Q13309	Q9H211	1	binding	down-regulates quantity by destabilization	0.659	Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCF(Skp2) ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators. Skp2 was associated with Cul1, but not Cul3.	SIGNOR-272565
Q9NPG1	O14640	1	binding	up-regulates activity	0.659	When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp.	SIGNOR-134288
Q06124	Q15116	1	dephosphorylation	down-regulates activity	0.659	Related to the latter notion, we recently showed that SHP2 dephosphorylates PD-1 to disassemble the PD-1:SHP2 complex ( xref ).	SIGNOR-277052
O60907	P35222	1	binding	up-regulates activity	0.659	TBL1 appears to serve two roles in regulating the activity of β-catenin. Besides the initially identified role of TBL1 in recruiting β-catenin to the SCF(TBL1) complex, it has also been shown to function as a transcriptional co-activator of β-catenin in recruiting it to the promoter site of Wnt target genes. Our results indicated that TBL1 can inhibit the polyubiquitination of β-catenin by Siah-1 in vitro (Fig. 3) and stabilize β-catenin in cells by protecting it from Siah-1-mediated ubiquitination and proteasomal degradation (Fig. 4).	SIGNOR-271954
P60604	Q86TM6	1	ubiquitination	up-regulates activity	0.659	We show that human HRD1 is a non-glycosylated, stable ER protein with a cytosolic RING-H2 finger domain. In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation.	SIGNOR-272593
P09619	P29353	1	phosphorylation	up-regulates	0.659	In this study, we have characterized the interaction between the pdgf beta-receptor and shc. multiple autophosphorylation sites in the pdgf beta-receptor are responsible for the binding of shc.	SIGNOR-36906
P18850	P35638	1	transcriptional regulation	up-regulates quantity by expression	0.658	Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network	SIGNOR-260180
P12931	P01116	1	phosphorylation	up-regulates activity	0.658	Src phosphorylation promotes the intrinsic exchange rate of KRAS Q61H.\|Wild-type and Q61H-mutant KRAS are both phosphorylated by Src on Tyr32 and Tyr64 and dephosphorylated by SHP2, however, SHP2i does not reduce ERK phosphorylation in KRAS Q61H cells.	SIGNOR-278990
Q9NWZ3	Q96FA3	1	phosphorylation	up-regulates activity	0.658	The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites.	SIGNOR-276128
P18433	P06241	1	dephosphorylation	up-regulates	0.658	Ptpalpha is a more widely expressed transmembrane ptp that has been shown to regulate the src family kinases, src and fyn, and is also present in t cells.	SIGNOR-154796
Q6ZTQ3	Q13188	1	binding	down-regulates	0.658	When rassf 6 is bound to mst2, rassf 6 inhibits mst2 activity, thus, inhibiting its role in the hippo pathway.	SIGNOR-198463
Q9P2J9	P08559	1	dephosphorylation	up-regulates activity	0.658	Pyruvate dehydrogenase phosphatase (PDP) is a mitochondrial serine phosphatase that activates phosphorylated pyruvate dehydrogenase complex by dephosphorylation	SIGNOR-251665
P31751	Q12778	1	phosphorylation	down-regulates activity	0.658	Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus.	SIGNOR-68652
P06241	Q13291	1	phosphorylation	up-regulates activity	0.658	All 3 tyrosines of CD150 (Tyr281, Tyr307, Tyr327) are phosphorylated by the src kinase Fyn. CD150 is unique among its homologues in the immunoglobulin superfamily in that it is able to bind SAP, a floating SH2 domain, in the absence of tyrosine phosphorylation. In this study, using a detailed mutagenesis mapping approach we have shown that SAP binding to CD150 is in fact bimodal. Prior to tyrosine phosphorylation, SAP binds the membrane-proximal motif surrounding Tyr281. Following tyrosine phosphorylation by tyrosine kinases such as Fyn, SAP binds additionally to the distal motif surrounding Tyr327.	SIGNOR-251182
Q8IZJ1	P43146	1	binding	down-regulates activity	0.658	In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists.	SIGNOR-268166
P27361	P47712	1	phosphorylation	up-regulates	0.658	Activated map kinase phosphorylates cpla2 at ser-505, causing increased enzymatic activity of cpla2, which is only realized upon translocation of cpla2 to the membrane.	SIGNOR-38434
O14904	O75197	1	binding	up-regulates	0.658	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-132073
Q9BXY4	O75473	1	binding	up-regulates	0.657	Here we demonstrate that lgr4 and lgr5 bind the r-spondins with high affinity and mediate the potentiation of wnt/betBeta-catenin signaling by enhancing wnt-induced lrp6 phosphorylation	SIGNOR-174535
P49674	P35222	1	phosphorylation	down-regulates activity	0.657	Using mass spectrometry and phosphopeptide-specific antibodies, we show that a complex of axin and casein kinase I (CKI) induces Beta-catenin phosphorylation at a single site: serine 45 (S45).	SIGNOR-244102
Q9Y6R4	P52564	1	phosphorylation	up-regulates activity	0.657	When truncated mapkkk4 (deltamapkkk4) was overexpressed in hek293 cells, it was constitutively activeco-expressed map kinase kinase (mkk)-1, mkk-4, mkk-3 and mkk-6 were activated in vivo by deltamapkkk4. All of the above mkks purified from escherichia coli were phosphorylated and activated by deltamapkkk4 immunoprecipitates in vitro.	SIGNOR-62372
P08069	O14654	1	phosphorylation	up-regulates	0.657	Insulin-like growth factor i acting through its receptor was as effective as insulin in eliciting tyrosine phosphorylation of irs-4.	SIGNOR-56604
Q13535	Q9UBU7	1	phosphorylation	down-regulates	0.657	Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication.	SIGNOR-177809
Q9Y5J3	Q06330	1	binding	down-regulates	0.657	These findings suggest a novel mechanism for negative feedback on notch signaling that requires rbp-jkappa to interact physically with hrt and hes.	SIGNOR-146687
P12931	Q13009	1	phosphorylation	up-regulates	0.657	Tiam1 cooperated with src to induce activation of rac1 in vivo and the formation of membrane ruffles.	SIGNOR-102354
Q16829	Q16539	1	dephosphorylation	down-regulates	0.657	The activity of mapks can be also regulated by a family of dusps, which dephosphorylates bot phosphotyrosine and phopsphothreonine residues	SIGNOR-166577
Q9NTG7	P48735	1	deacetylation	up-regulates	0.657	Site-specific, genetic incorporation of n(_)-acetyllysine into position 413 of idh2 revealed that acetylated idh2 displays a dramatic 44-fold loss in activity. Deacetylation by sirt3 fully restored maximum idh2 activity.	SIGNOR-196617
Q9UP38	Q92997	1	binding	up-regulates activity	0.657	Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.	SIGNOR-258953
P04626	Q05397	1	phosphorylation	up-regulates activity	0.657	HER2, EGFR, and additional RTKs directly phosphorylate FAK FERM at Y397.\|To further confirm the mechanism of direct FAK activation by HER2, we performed a series of GST pull-down assays with purified recombinant proteins.	SIGNOR-278475
P18848	O75807	1	transcriptional regulation	up-regulates quantity by expression	0.657	ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress.	SIGNOR-260172
P01008	P03951	1	cleavage	down-regulates activity	0.657	Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1	SIGNOR-264137
P31749	Q07352	1	phosphorylation	down-regulates	0.657	Here we report that protein kinase b (pkb/akt) stabilizes are transcripts by phosphorylating brf1 at serine 92 (s92). Recombinant brf1 promoted in vitro decay of are-containing mrna (are-mrna), yet phosphorylation by pkb impaired this activity.	SIGNOR-130376
Q96EQ8	Q9BYX4	1	polyubiquitination	down-regulates quantity by destabilization	0.657	Here, we found that RIG-I undergoes proteasomal degradation after conjugation to ubiquitin by RNF125. Further, RNF125 conjugates ubiquitin to MDA5, a family protein of RIG-I as well as IPS-1, which is also a downstream protein of RIG-I signaling that results in suppressing the functions of these proteins. Because RNF125 is enhanced by IFN, these functions constitute a negative regulatory loop circuit for IFN production.	SIGNOR-271646
Q9ULT6	O75581	1	ubiquitination	down-regulates quantity	0.656	Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6.	SIGNOR-260112
Q9BX63	P54132	1	binding	up-regulates quantity by stabilization	0.656	In this work, FANCJ and BLM were found to interact physically and functionally in human cells and co-localize to nuclear foci in response to replication stress. The cellular level of BLM is strongly dependent upon FANCJ, and BLM is degraded by a proteasome-mediated pathway when FANCJ is depleted.	SIGNOR-259186
P07949	P29353	1	binding	up-regulates	0.656	We have shown that the sh2 domain of the adaptor protein shc coimmunoprecipitates with all the ret.	SIGNOR-36902
O96014	Q9NPG1	1	binding	up-regulates activity	0.656	Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors.	SIGNOR-141428
P29597	Q14765	1	phosphorylation	up-regulates activity	0.656	IL-12 activates the Janus family tyrosine kinases JAK2 and Tyk2, which in turn phosphorylate STAT4 on tyrosine 693.	SIGNOR-279303
P07948	P19174	1	phosphorylation	up-regulates activity	0.656	The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.	SIGNOR-249381
Q13976	O96001	1	phosphorylation	up-regulates	0.656	Recombinant human G-substrate was phosphorylated efficiently by cGMP-dependent protein kinase exclusively at Thr residues, and it was recognized by antibodies specific for rabbit phospho-G-substrate. The amino acid sequences surrounding the sites of phosphorylation in G-substrate are related to those around Thr-34 and Thr-35 of the dopamine- and cAMP-regulated phosphoprotein DARPP-32 and inhibitor-1, respectively, two potent inhibitors of protein phosphatase 1.	SIGNOR-263148
Q13387	Q9UQF2	1	binding	up-regulates	0.656	Deletion analysis demonstrated that the cooh-terminal regions of jip1 and jip2 were sufficient for the formation of hetero-oligomeric complexes	SIGNOR-70863
P53611	P20336	1	lipidation	up-regulates activity	0.656	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-265575
Q13464	P60484	1	phosphorylation	up-regulates	0.656	In addition, active rhoa is able to stimulate the phospholipid phosphatase activity of pten in human embryonic kidney cells and leukocytes, and this regulation seems to require rhoa's downstream effector, rhoa-associated kinase (rock). together with the observation that individual substitution of ser 229 and thr 223 restored some of the rescuing ability (fig. 4b), we conclude that effective regulation of pten by sdf-1 may require more than one of these residues.	SIGNOR-134855
P63000	Q9Y2X7	1	binding	up-regulates activity	0.656	Activated RAC1 interacts with GIT1, a GAP protein of ARF6, and causes the inactivation of ARF6 [78]. As ARF6 plays a role in the promotion of the recycling of macropinosomes to the plasma membrane [78], the inactivation of ARF6 by RAC1 reduces the recycling of macropinosomes.	SIGNOR-277783
Q8IZD9	P63000	1	guanine nucleotide exchange factor	up-regulates activity	0.656	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-260548
P15735	P06737	1	phosphorylation	up-regulates activity	0.656	It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15	SIGNOR-267401
Q9NX24	O14746	1	binding	up-regulates activity	0.656	A complex of four proteins (GAR1, NHP2, NOP10, and the putative pseudouridine synthase dyskerin) associates with snoRNAs to form small nucleolar ribonucleoprotein particles (snoRNPs), and the binding of this complex to the H/ACA domain of TERC may have a role in the biogenesis of the telomerase RNP	SIGNOR-263330
Q00535	P78352	1	phosphorylation	down-regulates activity	0.655	Cdk5 was shown to phosphorylate PSD-95 at three sites, Thr19, Ser25, and Ser35, in PSD fractions, which reduces the ability of PSD-95 to multimerize, resulting in decreased NMDAR clustering (Table 2).	SIGNOR-279152
O15530	P51812	1	phosphorylation	up-regulates	0.655	We characterize two monoclonal antibodies raised against phosphorylated forms of the n- and c-terminal domain of rsk2 (p-s227 and p-t577, respectively). Using these two antibodies, we show that stress signals, such as uv light, induce phosphorylation and activation of the three rsks.	SIGNOR-70612
P21580	Q13546	1	ubiquitination	down-regulates quantity	0.655	The amino-terminal domain of A20, which is a de-ubiquitinating (DUB) enzyme of the OTU (ovarian tumour) family, removes lysine-63 (K63)-linked ubiquitin chains from receptor interacting protein (RIP), an essential mediator of the proximal TNF receptor 1 (TNFR1) signalling complex. The carboxy-terminal domain of A20, composed of seven C2/C2 zinc fingers, then functions as a ubiquitin ligase by polyubiquitinating RIP with K48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation.	SIGNOR-259978
P06493	P46527	2	phosphorylation	down-regulates	0.655	Phosphorylation of kip1 on thr-187, by cdk1 and cdk2 leads to protein ubiquitination and proteasomal degradation.	SIGNOR-80230
O43150	P84077	1	gtpase-activating protein	up-regulates activity	0.655	Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain. In addition, in vitro recombinant Pap exhibits strong GTPase-activating protein (GAP) activity towards the small GTPases Arf1 and Arf5 and weak activity towards Arf6. Pap protein exhibits Arf GAP activity in vitro.	SIGNOR-269705
Q00535	Q16555	1	phosphorylation	down-regulates activity	0.655	Cdk5 and DYRK2 phosphorylate CRMP2 and CRMP4, respectively, priming these proteins at S522 before their subsequent phosphorylation by GSK-3b at T509, T516 and S518\|e CRMP2 phosphorylation by GSK-3b disrupts its interaction with tubulin (Yamashita & Goshima, 2012), leading to growth inhibition	SIGNOR-264838
P46527	P06493	2	binding	down-regulates	0.655	P21 and p27 are key inhibitors of both cdk1 and cdk2.	SIGNOR-128445

P55212

P02545

1

cleavage

down-regulates

0.662

Lamin a breakdown is largely mediated by caspase-6 during the execution phase of apoptosis.

SIGNOR-83611

P01112

O00329

1

binding

up-regulates

0.662

Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k

SIGNOR-175192

P01031

Q9P296

1

binding

up-regulates

0.662

Here we report that the orphan receptor c5l2/gpr77, which shares 35% amino acid identity with cd88, binds c5a with high affinity.

SIGNOR-113558

P42226

P23771

1

null

up-regulates

0.662

GATA-3 plays a central role in regulating Th1 and Th2 cell differentiation. Upon interleukin (IL)-4 binding to its receptor, GATA-3 is induced through the action of Stat6

SIGNOR-254299

Q9Y5K5

O15105

1

binding

up-regulates

0.662

Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases.

SIGNOR-138879

Q9UIC8

P62714

1

methylation

up-regulates activity

0.661

Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits |The PP2A core enzyme was methylated by a PP2A-specific leucine carboxyl methyltransferase (LCMT1)

SIGNOR-265751

Q6ZN44

P43146

1

binding

down-regulates activity

0.661

In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists.

SIGNOR-268164

Q16539

Q02078

1

phosphorylation

up-regulates activity

0.661

We show that mef2a, but not mef2b or mef2d, is a substrate for p38. Threonines 312 and 319 are the key regulatory phosphorylation sites by p38 in mef2a. Phosphorylation at these sites enhances transcriptional activity of mef2a

SIGNOR-62780

P12931

P05106

1

phosphorylation

down-regulates activity

0.661

The phosphorylation level of beta(3) integrin was modulated using a temperature-sensitive v-Src kinase. Increased beta(3) phosphorylation abolished alpha(v)beta(3)- but not alpha(5)beta(1)-mediated adhesion to fibronectin. Thus, phosphorylation of the cytoplasmic domain of beta(3) is a negative regulator of alpha(v)beta(3)-fibronectin binding strength.

SIGNOR-247207

Q99835

P32121

1

binding

up-regulates

0.661

Grk2-mediated phosphorylation of vertebrate smo allows smo to bind to beta-arrestins 1 or 2

SIGNOR-132759

P13385

Q96S42

1

binding

up-regulates activity

0.661

Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors.

SIGNOR-251937

Q8IZQ1

O95166

1

binding

down-regulates quantity by destabilization

0.661

Here, we show that ALFY binds selectively to LC3C and the GABARAPs through a LIR in its WD40 domain. Binding of ALFY to GABARAP is indispensable for its recruitment to LC3B-positive structures and, thus, for the clearance of certain p62 structures by autophagy.

SIGNOR-266796

Q13233

Q02750

1

phosphorylation

up-regulates activity

0.661

Phosphorylation at ser-218 and ser-222 by map kinase kinase kinases (raf or mekk1) positively regulates mek1 kinase activity.

SIGNOR-235587

Q15173

P31749

1

dephosphorylation

down-regulates

0.661

Activation of pp2a is the intermediate step between the abeta-ceramide cascade and the subsequent inactivation of akt.

SIGNOR-252615

P52564

O15264

1

phosphorylation

up-regulates activity

0.661

p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation.

SIGNOR-273952

P42345

Q13542

1

phosphorylation

down-regulates

0.661

Here, we show that cancer cells acquire resistance to astori by downregulating eukaryotic translation initiation factor (eif4e)-binding proteins (4e-bps-eif4ebp1, eif4ebp2).

SIGNOR-122014

P35368

P29992

1

binding

up-regulates activity

0.661

In this report, we demonstrate that in transfected cos-7 cells Gal4 and Ga16, like Gaq and Ga11, can activate PIPLC j3l and that all three al-ARs, alA, alB and alC, can activate endogenous PI-PLC by coupling to Gaq or Ga11.

SIGNOR-278122

Q7Z569

Q8IVT5

1

ubiquitination

down-regulates quantity by destabilization

0.661

Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15.

SIGNOR-272028

O95433

P08238

1

binding

up-regulates activity

0.661

The N-terminal region of Aha1 interacts with the central domain of Hsp90 and stimulates Hsp90 ATPase activity

SIGNOR-252212

O75084

O14640

1

binding

up-regulates

0.661

In non-canonical Wnt signalling, Wnt proteins bind Fzd and glypican-4, to activate Dsh at the cell membrane, leading to activation of Rho and JNK

SIGNOR-255893

P0DP23

P48454

1

binding

up-regulates

0.661

Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.

SIGNOR-114104

Q9HCE7

P36894

1

ubiquitination

down-regulates

0.66

Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps.

SIGNOR-153399

P04049

Q92934

1

phosphorylation

down-regulates

0.66

The activation of several major anti-apoptotic signaling pathways correlates with an increase in the phosphorylation of bad on ser-112, ser-136, and ser-155. These phosphorylation events result in bad inactivation through sequestration by 14-3-3 proteins

SIGNOR-155293

Q13546

Q9Y4K3

1

binding

up-regulates activity

0.66

Collectively, TRIF forms a multiprotein signaling complex along with TRAF6, TRADD, Pellino-1 and RIP1 for the activation of TAK1, which in turn activates the NF-_B and MAPK pathways.

SIGNOR-216325

Q9H4B4

O96017

1

phosphorylation

up-regulates activity

0.66

Plk3 phosphorylates Chk2 at two residues, serine 62 (S62) and serine 73 (S73) in vitro, and this phosphorylation facilitates subsequent phosphorylation of Chk2 on T68 by ATM in response to DNA damage. When the Chk2 mutant construct GFP-Chk2 S73A (serine 73 mutated to alanine) is transfected into cells, it no longer associates with a large complex in vivo, and manifests a significant reduction in kinase activity.

SIGNOR-276051

P24666

P29317

1

dephosphorylation

down-regulates activity

0.66

The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates

SIGNOR-246023

Q9Y6H6

P51787

1

binding

up-regulates activity

0.66

Sexual dimorphism and oestrogen regulation of KCNE3 expression modulates the functional properties of KCNQ1 K⁺ channels|The KCNQ1 potassium channel associates with various KCNE ancillary subunits that drastically affect channel gating and pharmacology. Co-assembly with KCNE3 produces a current with nearly instantaneous activation

SIGNOR-275923

P06493

Q9GZM8

1

phosphorylation

up-regulates activity

0.66

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

SIGNOR-274074

P35125

P62330

1

relocalization

up-regulates

0.66

Here we show that tre17 (also called tre-2 and usp6), a founding member of the tbc family, targets the arf family gtpase arf6, which regulates plasma membrane-endosome trafficking. Surprisingly, tre17 does not function as a gap for arf6 but rather promotes its activation in vivo. Forced expression of tre17 promotes the localization of arf6 to the plasma membrane, leading to arf6 activation, presumably due to facilitated access to membrane-associated guanine nucleotide exchange factors (gefs).

SIGNOR-130019

P07550

P63092

1

binding

up-regulates activity

0.66

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-256809

P23443

Q8TB45

1

phosphorylation

down-regulates

0.66

Deptor is phosphorylated by s6k1 and rsk1 on the degron serine residues upon serum stimulation s6k1/rsk1 and _trcp are required for ubiquitination and degradation of endogenous deptor upon mitogen stimulation.

SIGNOR-176866

P18031

P35222

1

dephosphorylation

up-regulates activity

0.66

PTP1B modulates the association of beta-catenin with N-cadherin through binding to an adjacent and partially overlapping target site.|The nonreceptor tyrosine phosphatase PTP1B associates with the cytoplasmic domain of N-cadherin and may regulate cadherin function through dephosphorylation of beta-catenin.|Thus, interaction of PTP1B with N-cadherin is essential for its association with beta-catenin, stable expression at the cell surface, and consequently, cadherin function.

SIGNOR-277121

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

Q06124

P01116

1

dephosphorylation

up-regulates activity

0.66

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

SIGNOR-255982

O75444

P10242

1

binding

down-regulates

0.66

Full-length c-maf binds to the c-myb and ets-1. / c-maf inhibits c-myb and ets-1 transcriptional activity.

SIGNOR-56811

Q00987

P08069

1

ubiquitination

down-regulates quantity by destabilization

0.66

We could prove that Mdm2 physically associates with IGF-1R and that Mdm2 causes IGF-1R ubiquitination in an in vitro assay.

SIGNOR-278571

P23458

P38484

1

phosphorylation

up-regulates activity

0.66

The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process.

SIGNOR-249491

Q13322

P06213

1

binding

down-regulates

0.66

Grb10 negatively regulates growth factor signaling. It binds the insulin and insulin-like growth factor 1 (igf-1) receptors;mice without grb10 are larger and exhibit enhanced insulin sensitivity.

SIGNOR-174065

P31749

P04792

1

phosphorylation

down-regulates

0.66

First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue.

SIGNOR-252526

P00519

O14746

1

phosphorylation

down-regulates activity

0.66

These findings indicate that phosphorylation of hTERT by c-Abl is associated with inhibition of telomerase activity.|We also found that c-Abl phosphorylates hTERT and inhibits hTERT activity.

SIGNOR-279354

Q86WA8

Q2T9J0

1

cleavage

down-regulates quantity by destabilization

0.66

Self-cleavage of Tysnd1 in the active oligomer most likely inactivates its protease activity. Subsequently, the cleaved products are degraded by PsLon and removed from the Tysnd1 oligomer.

SIGNOR-261054

P52564

P53778

1

phosphorylation

up-regulates

0.659

Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily . the p38 mapkinasekinasemkk6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma mapkinaseisoforms . p38mapks are activated by dual phosphorylation on a t-x-y motif in the activation loop through the action of map kinase kinases

SIGNOR-184134

P28482

Q13541

1

phosphorylation

down-regulates activity

0.659

The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding

SIGNOR-249390

Q13467

O14640

1

binding

up-regulates activity

0.659

Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.

SIGNOR-258957

P63000

P45983

1

binding

up-regulates

0.659

The mechanism by which pak1 induced cancer growth might involve activation of jnk 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-152808

Q8IXL6

Q13316

1

phosphorylation

up-regulates quantity

0.659

Fam20c knockdown decreased Dmp1 mRNA and increased Fgf23 mRNA in UMR-106 cells.|Relative migration distances of OPN and DMP1, which were the ratio of the migration distances of OPN or DMP1 co-expressed with mutant FAM20C to that with WT FAM20C, showed that only WT FAM20C could fully phosphorylate OPN and DMP1.

SIGNOR-280011

P07948

P40763

1

phosphorylation

up-regulates activity

0.659

An in vitro phosphorylation assay showed that Lyn directly phosphorylates STAT3.

SIGNOR-279062

Q13309

Q9H211

1

binding

down-regulates quantity by destabilization

0.659

Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCF(Skp2) ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators. Skp2 was associated with Cul1, but not Cul3.

SIGNOR-272565

Q9NPG1

O14640

1

binding

up-regulates activity

0.659

When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp.

SIGNOR-134288

Q06124

Q15116

1

dephosphorylation

down-regulates activity

0.659

Related to the latter notion, we recently showed that SHP2 dephosphorylates PD-1 to disassemble the PD-1:SHP2 complex ( xref ).

SIGNOR-277052

O60907

P35222

1

binding

up-regulates activity

0.659

TBL1 appears to serve two roles in regulating the activity of β-catenin. Besides the initially identified role of TBL1 in recruiting β-catenin to the SCF(TBL1) complex, it has also been shown to function as a transcriptional co-activator of β-catenin in recruiting it to the promoter site of Wnt target genes. Our results indicated that TBL1 can inhibit the polyubiquitination of β-catenin by Siah-1 in vitro (Fig. 3) and stabilize β-catenin in cells by protecting it from Siah-1-mediated ubiquitination and proteasomal degradation (Fig. 4).

SIGNOR-271954

P60604

Q86TM6

1

ubiquitination

up-regulates activity

0.659

We show that human HRD1 is a non-glycosylated, stable ER protein with a cytosolic RING-H2 finger domain. In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation.

SIGNOR-272593

P09619

P29353

1

phosphorylation

up-regulates

0.659

In this study, we have characterized the interaction between the pdgf beta-receptor and shc. multiple autophosphorylation sites in the pdgf beta-receptor are responsible for the binding of shc.

SIGNOR-36906

P18850

P35638

1

transcriptional regulation

up-regulates quantity by expression

0.658

Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network

SIGNOR-260180

P12931

P01116

1

phosphorylation

up-regulates activity

0.658

Src phosphorylation promotes the intrinsic exchange rate of KRAS Q61H.|Wild-type and Q61H-mutant KRAS are both phosphorylated by Src on Tyr32 and Tyr64 and dephosphorylated by SHP2, however, SHP2i does not reduce ERK phosphorylation in KRAS Q61H cells.

SIGNOR-278990

Q9NWZ3

Q96FA3

1

phosphorylation

up-regulates activity

0.658

The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites.

SIGNOR-276128

P18433

P06241

1

dephosphorylation

up-regulates

0.658

Ptpalpha is a more widely expressed transmembrane ptp that has been shown to regulate the src family kinases, src and fyn, and is also present in t cells.

SIGNOR-154796

Q6ZTQ3

Q13188

1

binding

down-regulates

0.658

When rassf 6 is bound to mst2, rassf 6 inhibits mst2 activity, thus, inhibiting its role in the hippo pathway.

SIGNOR-198463

Q9P2J9

P08559

1

dephosphorylation

up-regulates activity

0.658

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

SIGNOR-251665

P31751

Q12778

1

phosphorylation

down-regulates activity

0.658

Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus.

SIGNOR-68652

P06241

Q13291

1

phosphorylation

up-regulates activity

0.658

All 3 tyrosines of CD150 (Tyr281, Tyr307, Tyr327) are phosphorylated by the src kinase Fyn. CD150 is unique among its homologues in the immunoglobulin superfamily in that it is able to bind SAP, a floating SH2 domain, in the absence of tyrosine phosphorylation. In this study, using a detailed mutagenesis mapping approach we have shown that SAP binding to CD150 is in fact bimodal. Prior to tyrosine phosphorylation, SAP binds the membrane-proximal motif surrounding Tyr281. Following tyrosine phosphorylation by tyrosine kinases such as Fyn, SAP binds additionally to the distal motif surrounding Tyr327.

SIGNOR-251182

Q8IZJ1

P43146

1

binding

down-regulates activity

0.658

In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists.

SIGNOR-268166

P27361

P47712

1

phosphorylation

up-regulates

0.658

Activated map kinase phosphorylates cpla2 at ser-505, causing increased enzymatic activity of cpla2, which is only realized upon translocation of cpla2 to the membrane.

SIGNOR-38434

O14904

O75197

1

binding

up-regulates

0.658

Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.

SIGNOR-132073

Q9BXY4

O75473

1

binding

up-regulates

0.657

Here we demonstrate that lgr4 and lgr5 bind the r-spondins with high affinity and mediate the potentiation of wnt/betBeta-catenin signaling by enhancing wnt-induced lrp6 phosphorylation

SIGNOR-174535

P49674

P35222

1

phosphorylation

down-regulates activity

0.657

Using mass spectrometry and phosphopeptide-specific antibodies, we show that a complex of axin and casein kinase I (CKI) induces Beta-catenin phosphorylation at a single site: serine 45 (S45).

SIGNOR-244102

Q9Y6R4

P52564

1

phosphorylation

up-regulates activity

0.657

When truncated mapkkk4 (deltamapkkk4) was overexpressed in hek293 cells, it was constitutively activeco-expressed map kinase kinase (mkk)-1, mkk-4, mkk-3 and mkk-6 were activated in vivo by deltamapkkk4. All of the above mkks purified from escherichia coli were phosphorylated and activated by deltamapkkk4 immunoprecipitates in vitro.

SIGNOR-62372

P08069

O14654

1

phosphorylation

up-regulates

0.657

Insulin-like growth factor i acting through its receptor was as effective as insulin in eliciting tyrosine phosphorylation of irs-4.

SIGNOR-56604

Q13535

Q9UBU7

1

phosphorylation

down-regulates

0.657

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

SIGNOR-177809

Q9Y5J3

Q06330

1

binding

down-regulates

0.657

These findings suggest a novel mechanism for negative feedback on notch signaling that requires rbp-jkappa to interact physically with hrt and hes.

SIGNOR-146687

P12931

Q13009

1

phosphorylation

up-regulates

0.657

Tiam1 cooperated with src to induce activation of rac1 in vivo and the formation of membrane ruffles.

SIGNOR-102354

Q16829

Q16539

1

dephosphorylation

down-regulates

0.657

The activity of mapks can be also regulated by a family of dusps, which dephosphorylates bot phosphotyrosine and phopsphothreonine residues

SIGNOR-166577

Q9NTG7

P48735

1

deacetylation

up-regulates

0.657

Site-specific, genetic incorporation of n(_)-acetyllysine into position 413 of idh2 revealed that acetylated idh2 displays a dramatic 44-fold loss in activity. Deacetylation by sirt3 fully restored maximum idh2 activity.

SIGNOR-196617

Q9UP38

Q92997

1

binding

up-regulates activity

0.657

Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.

SIGNOR-258953

P04626

Q05397

1

phosphorylation

up-regulates activity

0.657

HER2, EGFR, and additional RTKs directly phosphorylate FAK FERM at Y397.|To further confirm the mechanism of direct FAK activation by HER2, we performed a series of GST pull-down assays with purified recombinant proteins.

SIGNOR-278475

P18848

O75807

1

transcriptional regulation

up-regulates quantity by expression

0.657

ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress.

SIGNOR-260172

P01008

P03951

1

cleavage

down-regulates activity

0.657

Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1

SIGNOR-264137

P31749

Q07352

1

phosphorylation

down-regulates

0.657

Here we report that protein kinase b (pkb/akt) stabilizes are transcripts by phosphorylating brf1 at serine 92 (s92). Recombinant brf1 promoted in vitro decay of are-containing mrna (are-mrna), yet phosphorylation by pkb impaired this activity.

SIGNOR-130376

Q96EQ8

Q9BYX4

1

polyubiquitination

down-regulates quantity by destabilization

0.657

Here, we found that RIG-I undergoes proteasomal degradation after conjugation to ubiquitin by RNF125. Further, RNF125 conjugates ubiquitin to MDA5, a family protein of RIG-I as well as IPS-1, which is also a downstream protein of RIG-I signaling that results in suppressing the functions of these proteins. Because RNF125 is enhanced by IFN, these functions constitute a negative regulatory loop circuit for IFN production.

SIGNOR-271646

Q9ULT6

O75581

1

ubiquitination

down-regulates quantity

0.656

Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6.

SIGNOR-260112

Q9BX63

P54132

1

binding

up-regulates quantity by stabilization

0.656

In this work, FANCJ and BLM were found to interact physically and functionally in human cells and co-localize to nuclear foci in response to replication stress. The cellular level of BLM is strongly dependent upon FANCJ, and BLM is degraded by a proteasome-mediated pathway when FANCJ is depleted.

SIGNOR-259186

P07949

P29353

1

binding

up-regulates

0.656

We have shown that the sh2 domain of the adaptor protein shc coimmunoprecipitates with all the ret.

SIGNOR-36902

O96014

Q9NPG1

1

binding

up-regulates activity

0.656

Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors.

SIGNOR-141428

P29597

Q14765

1

phosphorylation

up-regulates activity

0.656

IL-12 activates the Janus family tyrosine kinases JAK2 and Tyk2, which in turn phosphorylate STAT4 on tyrosine 693.

SIGNOR-279303

P07948

P19174

1

phosphorylation

up-regulates activity

0.656

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

SIGNOR-249381

Q13976

O96001

1

phosphorylation

up-regulates

0.656

Recombinant human G-substrate was phosphorylated efficiently by cGMP-dependent protein kinase exclusively at Thr residues, and it was recognized by antibodies specific for rabbit phospho-G-substrate. The amino acid sequences surrounding the sites of phosphorylation in G-substrate are related to those around Thr-34 and Thr-35 of the dopamine- and cAMP-regulated phosphoprotein DARPP-32 and inhibitor-1, respectively, two potent inhibitors of protein phosphatase 1.

SIGNOR-263148

Q13387

Q9UQF2

1

binding

up-regulates

0.656

Deletion analysis demonstrated that the cooh-terminal regions of jip1 and jip2 were sufficient for the formation of hetero-oligomeric complexes

SIGNOR-70863

P53611

P20336

1

lipidation

up-regulates activity

0.656

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-265575

Q13464

P60484

1

phosphorylation

up-regulates

0.656

In addition, active rhoa is able to stimulate the phospholipid phosphatase activity of pten in human embryonic kidney cells and leukocytes, and this regulation seems to require rhoa's downstream effector, rhoa-associated kinase (rock). together with the observation that individual substitution of ser 229 and thr 223 restored some of the rescuing ability (fig. 4b), we conclude that effective regulation of pten by sdf-1 may require more than one of these residues.

SIGNOR-134855

P63000

Q9Y2X7

1

binding

up-regulates activity

0.656

Activated RAC1 interacts with GIT1, a GAP protein of ARF6, and causes the inactivation of ARF6 [78]. As ARF6 plays a role in the promotion of the recycling of macropinosomes to the plasma membrane [78], the inactivation of ARF6 by RAC1 reduces the recycling of macropinosomes.

SIGNOR-277783

Q8IZD9

P63000

1

guanine nucleotide exchange factor

up-regulates activity

0.656

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-260548

P15735

P06737

1

phosphorylation

up-regulates activity

0.656

It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15

SIGNOR-267401

Q9NX24

O14746

1

binding

up-regulates activity

0.656

A complex of four proteins (GAR1, NHP2, NOP10, and the putative pseudouridine synthase dyskerin) associates with snoRNAs to form small nucleolar ribonucleoprotein particles (snoRNPs), and the binding of this complex to the H/ACA domain of TERC may have a role in the biogenesis of the telomerase RNP

SIGNOR-263330

Q00535

P78352

1

phosphorylation

down-regulates activity

0.655

Cdk5 was shown to phosphorylate PSD-95 at three sites, Thr19, Ser25, and Ser35, in PSD fractions, which reduces the ability of PSD-95 to multimerize, resulting in decreased NMDAR clustering (Table 2).

SIGNOR-279152

O15530

P51812

1

phosphorylation

up-regulates

0.655

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

SIGNOR-70612

P21580

Q13546

1

ubiquitination

down-regulates quantity

0.655

The amino-terminal domain of A20, which is a de-ubiquitinating (DUB) enzyme of the OTU (ovarian tumour) family, removes lysine-63 (K63)-linked ubiquitin chains from receptor interacting protein (RIP), an essential mediator of the proximal TNF receptor 1 (TNFR1) signalling complex. The carboxy-terminal domain of A20, composed of seven C2/C2 zinc fingers, then functions as a ubiquitin ligase by polyubiquitinating RIP with K48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation.

SIGNOR-259978

P06493

P46527

2

phosphorylation

down-regulates

0.655

Phosphorylation of kip1 on thr-187, by cdk1 and cdk2 leads to protein ubiquitination and proteasomal degradation.

SIGNOR-80230

O43150

P84077

1

gtpase-activating protein

up-regulates activity

0.655

Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain. In addition, in vitro recombinant Pap exhibits strong GTPase-activating protein (GAP) activity towards the small GTPases Arf1 and Arf5 and weak activity towards Arf6. Pap protein exhibits Arf GAP activity in vitro.

SIGNOR-269705

Q00535

Q16555

1

phosphorylation

down-regulates activity

0.655

Cdk5 and DYRK2 phosphorylate CRMP2 and CRMP4, respectively, priming these proteins at S522 before their subsequent phosphorylation by GSK-3b at T509, T516 and S518|e CRMP2 phosphorylation by GSK-3b disrupts its interaction with tubulin (Yamashita & Goshima, 2012), leading to growth inhibition

SIGNOR-264838

P46527

P06493

2

binding

down-regulates

0.655

P21 and p27 are key inhibitors of both cdk1 and cdk2.

SIGNOR-128445