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
P41221	O75581	1	binding	up-regulates activity	0.758	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-131841
P49841	P25054	1	phosphorylation	up-regulates	0.758	Gsk-3beta-dependent phosphorylation of apc.	SIGNOR-75366
P08620	P21802	1	binding	up-regulates	0.758	The nine known fgf ligands and the four signaling fgf receptors (and their alternatively spliced variants) are expressed in specific spatial and temporal patterns. The activity of this signaling pathway is regulated by ligand binding specificity, heparan sulfate proteoglycans, and the differential signaling capacity of individual fgf receptors.	SIGNOR-42377
P05000	P48551	1	binding	up-regulates	0.758	Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2.	SIGNOR-105982
Q96RJ3	Q13114	1	binding	down-regulates quantity by destabilization	0.758	Activation of br3 induces recruitment and degradation of traf3.	SIGNOR-168199
P11802	P84022	1	phosphorylation	down-regulates activity	0.757	We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity	SIGNOR-232142
P06213	Q9Y4H2	1	phosphorylation	down-regulates activity	0.757	Tyr624 and Tyr628 are involved in the interaction between the IR and the KRLB domain of IRS-2, including tyrosine phosphorylation, and Tyr628 seems to be more important than Tyr624 in this process. the binding between the insulin receptor and the KRLB domain of IRS-2 results in tyrosine phosphorylation of the KRLB domain, and this leads to decreased binding of IRS-2 to the insulin receptor.	SIGNOR-251319
Q14596	O95166	1	binding	up-regulates	0.757	We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family	SIGNOR-184261
P28482	Q14790	1	phosphorylation	down-regulates	0.757	We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity	SIGNOR-203473
Q8NES3	P46531	1	binding	up-regulates	0.757	We demonstrate that egf 12, a portion of the ligand-binding site, is modified with o-fucose and that this site is evolutionarily conserved. We also show that endogenous fringe proteins in chinese hamster ovary cells (lunatic fringe and radical fringe) as well as exogenous manic fringe modify o-fucose on many but not all egf repeats of mouse notch1.	SIGNOR-96537
Q14676	O76064	1	relocalization	up-regulates	0.757	Rnf8 relocalizes to dna damage sites via a phospho-dependent interaction with mdc1	SIGNOR-179820
P01031	P21730	1	binding	up-regulates activity	0.757	The chemotactic receptor for human C5a anaphylatoxin\|The human C5a receptor was cloned from U937 and HL-60 cells and identified by high affinity binding when expressed in COS-7 cells.	SIGNOR-263457
Q9Y4P1	Q9BXW4	1	cleavage	up-regulates activity	0.757	Human atg4 homologues cleave the carboxyl termini of the three human atg8 homologues, microtubule-associated protein light chain 3 (lc3), gabarap, and gate-16.	SIGNOR-125489
Q93009	O15151	1	deubiquitination	up-regulates	0.757	Subsequently, hausp was shown to deubiquitinate mdm2 and mdmx, thereby stabilizing these proteins.	SIGNOR-139453
Q9UKT4	Q9UM11	1	ubiquitination	down-regulates	0.756	Emi1 binds cdh1 and inhibits apc-cdh1 activity.	SIGNOR-113385
Q13315	Q00987	1	phosphorylation	down-regulates activity	0.756	Dephosphorylation stabilizes mdm2 and increases its affinity for p53, inducing p53 degredation. ;phosphorylated s260 and s395 ands260d and s395d mutant peptides inhibited binding of binding of a specific monoclonal antibody raised to mdm2. Phosphorylation of mdm2 regulates p53 degradation.	SIGNOR-94268
P24941	Q13416	1	phosphorylation	up-regulates	0.756	We also found that horc2p is phosphorylated in vitro by cyclin a/cdk2, specifically at residues thr116 and thr226. These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability.	SIGNOR-116364
Q9P1A6	Q9Y566	1	relocalization	up-regulates activity	0.756	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-264589
Q9NR31	O95486	1	binding	up-regulates quantity	0.756	Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer.	SIGNOR-265303
Q96JK9	Q04721	1	binding	up-regulates	0.756	We report here the cloning and characterization of two new genes, maml2 and maml3, that also function as transcriptional coactivators for notch receptors.	SIGNOR-94097
Q15759	P15336	1	phosphorylation	up-regulates	0.756	Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target	SIGNOR-65586
Q15831	P04637	1	phosphorylation	up-regulates	0.756	We show that lkb1 physically associates with p53 in the nucleus and directly or indirectly phosphorylates p53 ser15 (previously shown to be phosphorylated by amp-dependent kinase) and p53 ser392	SIGNOR-150830
P00533	P42566	2	phosphorylation	up-regulates	0.755	Earlier studies have shown that eps15 at tyr-849 is phosphorylated in egf-stimulated cells and partly controls the internalization of mono-ubiquitinated egfr via uim domains of eps15 [10]. It has also been shown that active egfr phosphorylates tyr-849 directly;	SIGNOR-203311
Q16620	Q92529-2	1	phosphorylation	up-regulates activity	0.755	We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo.	SIGNOR-273917
Q8TB45	P42345	2	binding	down-regulates activity	0.755	DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival	SIGNOR-251657
P12931	P12830	1	phosphorylation	down-regulates quantity by destabilization	0.755	Activated c-Src phosphorylated E-cadherin at the tyrosine 797 site to initiate RNF43-mediated E-cadherin ubiquitination at lysine 816 and subsequent degradation	SIGNOR-274048
P42345	Q8TB45	2	phosphorylation	down-regulates	0.755	Our data reveal critical roles for mtor itself as well as cki in generating a degron in deptor that is recognized by _-trcp, and promotes deptor turnover by the proteasome.	SIGNOR-176849
Q9NZ94	P78352	1	relocalization	up-regulates activity	0.755	Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions.	SIGNOR-264189
P00734	P00451	1	cleavage	up-regulates activity	0.755	Activation of factor VIII by thrombin occurs via limited proteolysis at R372, R740, and R1689.	SIGNOR-263640
Q16620	Q92529	1	binding	up-regulates	0.755	Our present study established that n-shc and sck are expressed in a region-specific manner in the brain and that n-shc is a higher affinity adapter molecule than sck for trka and trkb receptors	SIGNOR-55864
O43318	O14920	1	phosphorylation	up-regulates activity	0.755	Tak1 become activated and then phosphorylates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a our studies suggests that tak1_ acts as an upstream activating kinase for ikkbeta.	SIGNOR-109490
Q8IY92	Q92889	1	binding	up-regulates	0.755	Slx4 is a tumor suppressor that stimulates the activity of the nuclease xpf-ercc1 in dna crosslink repair.	SIGNOR-204890
Q9Y4K3	Q9UDY8	1	ubiquitination	up-regulates	0.755	Traf6 associates with malt1 in response to t-cell activation and can function as an e3 ligase for malt1 in vitro and in vivo, mediating lysine 63-linked ubiquitination of malt1. Multiple lysine residues in the c-terminus of malt1 serve as acceptor sites for the assembly of polyubiquitin chains. (articolo-abstract)	SIGNOR-158554
Q8N1W1	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.755	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-260546
Q9H461	O75581	1	binding	up-regulates activity	0.755	Ligands such as Wnt1, Wnt3a, and Wnt8 couple the seven-transmembrane domain receptor Frizzled (Fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (LRP5/6) to activate WntBeta-catenin signaling.	SIGNOR-169638
P06241	Q13094	1	phosphorylation	down-regulates	0.755	P59fyn_phosphorylated slp-76 at intermediate levels but, significantly, this phosphorylation failed to induce vav?SLP-76 complex formation	SIGNOR-46851
P42574	O00273	1	cleavage	up-regulates activity	0.755	DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. We have identified and purified from HeLa cytosol a protein that induces DNA fragmentation in coincubated nuclei after it is activated by caspase-3.	SIGNOR-47416
Q9HC29	Q676U5	1	binding	up-regulates activity	0.755	By a mechanism independent of the adaptor RIP2 and transcription factor NF-kappaB, Nod1 and Nod2 recruited the autophagy protein ATG16L1 to the plasma membrane at the bacterial entry site. Our results link bacterial sensing by Nod proteins to the induction of autophagy and provide a functional link between Nod2 and ATG16L1, which are encoded by two of the most important genes associated with Crohn's disease.	SIGNOR-252405
P42566	P00533	2	binding	down-regulates activity	0.755	We suggest that the ubiquitinated EGFR or another c-Cbl substrate that is ubiquitinated upon EGFR activation recruits Eps15 to the plasma membrane via its UIM. This event would facilitate EGFR internalization via a clathrin-dependent route in which Eps15 plays a role	SIGNOR-243278
Q96SN8	O94986	1	relocalization	up-regulates activity	0.755	Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome.	SIGNOR-271721
P06239	P10747	1	phosphorylation	up-regulates	0.754	We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor	SIGNOR-45524
P98172	P54760	1	binding	up-regulates	0.754	Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor	SIGNOR-52580
P10911	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.754	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-260556
P03372	P24385	1	transcriptional regulation	up-regulates quantity by expression	0.754	Ikkalpha in conjunction with eralpha and aib1/src-3, is important in activating the transcription of estrogen-responsive genes, including cyclin d1.	SIGNOR-135053
P61812	P37173	1	binding	up-regulates	0.754	We show that tbetarii-b, an alternatively spliced variant of the tgf-beta type ii receptor, is a tgf-beta2 binding receptor, which mediates signalling via the smad pathway in the absence of any tgf-beta type iii receptor	SIGNOR-104795
Q9UMS4	O43395	1	polyubiquitination	up-regulates activity	0.754	Here, we report that the spliceosomal Prp19 complex modifies Prp3, a component of the U4 snRNP, with nonproteolytic K63-linked ubiquitin chains. The K63-linked chains increase the affinity of Prp3 for the U5 snRNP component Prp8, thereby allowing for the stabilization of the U4/U6.U5 snRNP.	SIGNOR-271966
P00519	O15350	1	phosphorylation	up-regulates	0.754	C-abl phosphorylates p73 on a tyrosine residue at position 99 both in vitro and in cells that have been exposed to ionizing radiation. Our results show that c-abl stimulates p73-mediated transactivation and apoptosis.	SIGNOR-68931
Q13546	Q9Y572	2	phosphorylation	up-regulates activity	0.754	In the current scenario, RIPK1 phosphorylates and activates RIPK3, and activated RIPK3 then phosphorylates MLKL.	SIGNOR-278429
Q8N0W4	P78352	1	relocalization	up-regulates activity	0.754	Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions.	SIGNOR-264192
P78527	P31749	1	phosphorylation	up-regulates activity	0.754	DNA-PK phosphorylates HM Ser473 of PKB. However, we also noted similar patterns in T loop Thr308 phosphorylation after _-IR []his function is apparently restricted to the PKBalpha isoform	SIGNOR-252431
Q9UI10	P20042	1	guanine nucleotide exchange factor	up-regulates activity	0.754	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.	SIGNOR-269132
Q9Y572	Q13546	2	phosphorylation	up-regulates activity	0.754	Collectively, TAK1 activates RIPK3, RIPK3 activates TAK1, and RIPK1 activates RIPK3 and facilitates interaction between TAK1 and RIPK3.\|RIPK1 kinase activity is required for RIPK3 phosphorylation, and reciprocally RIPK3 phosphorylates RIPK1.	SIGNOR-280106
P07949	P56159	1	binding	up-regulates	0.754	Gdnfr-alpha-ligand complex, together with the tyrosine kinase receptor (cret) forms a functional receptor that activates downstream signal transduction pathways	SIGNOR-77587
P24941	P30307	1	phosphorylation	up-regulates	0.754	The cyclin e/cdk2 complex phosphorylates cdc25c on ser(214), leading to its premature activation, which coincides with higher cyclin b/cdk1 and polo-like kinase 1 (plk1) activities in an s-phase-enriched population that result in faster mitotic entry.	SIGNOR-165872
P0DP23	Q8N5S9	1	binding	up-regulates	0.754	The binding of Ca2+/CaM to CaM-KK is absolutely required for its activation and efficient phosphorylation of target protein kinases	SIGNOR-232178
P10398	P36507	1	phosphorylation	up-regulates	0.754	Active raf phosphorylates mek.	SIGNOR-175142
P10767	P21802	1	binding	up-regulates	0.753	The nine known fgf ligands and the four signaling fgf receptors (and their alternatively spliced variants) are expressed in specific spatial and temporal patterns. The activity of this signaling pathway is regulated by ligand binding specificity, heparan sulfate proteoglycans, and the differential signaling capacity of individual fgf receptors.	SIGNOR-42380
Q9Y572	Q8NB16	1	phosphorylation	up-regulates activity	0.753	MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays	SIGNOR-266427
Q9UL15	P0DMV8	1	binding	down-regulates activity	0.753	Here, we show that BAG5, a BAG domain-containing family member, interacts with both Hsp70 and parkin with deleterious functional consequences. Through these interactions, BAG5 inhibits Hsp70 chaperone activity and parkin E3 ubiquitin ligase activity; Thus, BAG5 interacts with Hsp70 in vitro and in vivo, and substitution of select residues within the BAG domains is sufficient to abolish this interaction.	SIGNOR-261196
P56704	Q14332	1	binding	up-regulates	0.753	It was also shown that wnt5a inhibits the beta-catenin pathway by competing with wnt3a for binding to fz2, and that the impairment of clathrin-mediated internalization does not affect this wnt5a inhibitory action.	SIGNOR-189117
P04637	Q07812	1	binding	up-regulates	0.753	P53 also accumulates in the cytoplasm where it directly activates bax to promote mitochondrial outer membrane permeabilization.	SIGNOR-140242
Q86YC2	Q06609	1	binding	up-regulates	0.753	We propose that both palb2 chromatin association and its oligomerization serve to secure the brca2 x rad51 repair machinery at the sites of dna damage.	SIGNOR-185656
Q86UT6	Q7Z434	1	binding	down-regulates activity	0.753	Here we describe human NLRX1, a highly conserved nucleotide-binding domain (NBD)- and leucine-rich-repeat (LRR)-containing family member (known as NLR) that localizes to the mitochondrial outer membrane and interacts with MAVS. Expression of NLRX1 results in the potent inhibition of RLH- and MAVS-mediated interferon-beta promoter activity and in the disruption of virus-induced RLH-MAVS interactions. Co-immunoprecipitation studies demonstrate that HA–NLRX1 interacts with MAVS but not with other known mitochondrial outer membrane proteins (BCL2 and BCL2L1), indicating specificity of the NLRX1–MAVS interaction. Finally, endogenous NLRX1 associates strongly with endogenous MAVS after immunoprecipitation with two different MAVS antibodies	SIGNOR-260357
Q9UQK1	P54840	1	binding	up-regulates	0.753	In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2)	SIGNOR-271731
Q9UI47	P35222	1	relocalization	up-regulates quantity	0.753	Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14	SIGNOR-265493
P78344	P20042	1	binding	up-regulates activity	0.753	Unlike eIF4GI/II, DAP5 binds eIF2β, a subunit of the eIF2 complex that delivers methionyl-tRNA to ribosomes.	SIGNOR-266385
O75449	Q9BVA0	2	binding	up-regulates activity	0.753	In its active ATP-bound state, KATNA1 forms hexameric rings capable of binding to and severing microtubule polymers. Typically, KATNA1 binding to KATNB1 enhances severing, likely due to KATNB1 increasing the stability of the KATNA1 hexamer	SIGNOR-267174
Q9BVA0	O75449	2	binding	up-regulates quantity by stabilization	0.753	In its active ATP-bound state, KATNA1 forms hexameric rings capable of binding to and severing microtubule polymers. Typically, KATNA1 binding to KATNB1 enhances severing, likely due to KATNB1 increasing the stability of the KATNA1 hexamer	SIGNOR-267173
P43405	P16885	1	phosphorylation	up-regulates activity	0.753	Syk in turn phosphorylates and activates the B cell linker protein (BLNK), phosphoinositide 3-kinase (PI3K) and phospholipase C\u03b32 (PLC\u03b32).\|Syk in turn phosphorylates and activates the B cell linker protein (BLNK), phosphoinositide 3-kinase (PI3K) and phospholipase Cgamma2 (PLCgamma2).	SIGNOR-278995
P06493	Q9UKT4	1	phosphorylation	down-regulates quantity by destabilization	0.753	We find that both Emi1 phosphorylation by cyclin and Cdc2 and phosphorylation on a consensus site (DSGxxS) direct recruitment of betaTrCP and subsequent Emi1 ubiquitination and destruction.	SIGNOR-279143
Q13214	O14786	1	binding	up-regulates activity	0.753	Further examination of the composition of the functional Sema3B receptor revealed that, unlike Sema3A, which signals exclusively using the NP1 receptor, Sema3B utilizes both NP1 and NP2 for signal transduction.	SIGNOR-261814
P06493	Q99640	2	phosphorylation	down-regulates activity	0.752	Active Cdk1 phosphorylates and inhibits Wee1 and Myt1 kinases and phosphorylates and activates the Cdc25 phosphatases.	SIGNOR-279600
Q9BXH1	Q07820	1	binding	down-regulates	0.752	Only bimbh3 and bbc3 had comparable strong affinities for all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.	SIGNOR-133817
P45985	P45983	1	phosphorylation	up-regulates activity	0.752	Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7. Here we report that MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183) in three SAPK1/JNK1 isoforms tested (JNK1 alpha 1, JNK2 alpha 2 and JNK3 alpha 1).	SIGNOR-251419
Q02750	P27361	1	phosphorylation	up-regulates	0.752	Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis.	SIGNOR-210176
P42830	P25025	1	binding	up-regulates activity	0.752	CXCL5 is another ELR+ CXC chemokine and, thus, also potently attracts neutrophils. Just like CXCL1, CXCL5 also signals through CXCR2, explaining why, often, CXCL5 and CXCL1 are seen to function in parallel in PDAC. CXCL5 was increased in human pancreatic tissue compared to the normal pancreas, and the knockdown of CXCL5 in pancreatic cancer cell lines reduced the proliferation and migration ability of cells	SIGNOR-277730
Q99640	P06493	2	phosphorylation	down-regulates	0.752	Myt1hu preferentially phosphorylates cdc2 on threonine 14 in a cyclin-dependent manner;phosphorylation of threonine 14 and tyrosine 15 is inhibitory.	SIGNOR-45729
P45983	Q13469	1	phosphorylation	down-regulates	0.752	Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin jnk directly regulated nuclear factor of activated t-cell (nfat) activation in culture and in transgenic mice containing an nfat-dependent luciferase reporter.	SIGNOR-118217
O43561	P15498	1	binding	up-regulates activity	0.752	By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively.	SIGNOR-246045
Q9ULV1	O14641	1	binding	up-regulates activity	0.751	Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin.	SIGNOR-258958
P15248	Q01113	1	binding	up-regulates	0.751	Interleukin 9 (il-9) exerts its pleiotropic effects through the il-9 receptor (il-9r) complex, which consists of the il-9r alpha-chain, which determines the cytokine specificity, and the il-2 receptor gamma-chain	SIGNOR-73601
P0DP23	Q08209	1	binding	up-regulates	0.751	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-114098
Q9H082	Q676U5	1	binding	up-regulates	0.751	Olgi-resident small gtpase rab33b interacts with atg16l and modulates autophagosome formation.	SIGNOR-178542
P26678	P16615	1	binding	down-regulates activity	0.751	Heart failure can be traced, in part, to alterations in the activity of the sarcoplasmic reticulum Ca2+ pump that are induced by its interactions with phospholamban, a reversible inhibitor.	SIGNOR-252031
P08887	P40189	1	binding	up-regulates	0.751	Part of the receptor for interleukin 6. Binds to il6 with low affinity, but does not transduce a signal. Signal activation necessitate an association with il6st. Activation may lead to the regulation of the immune response, acute-phase reactions and hematopoiesis.	SIGNOR-105504
Q92838	Q9UNE0	1	binding	up-regulates	0.751	Ultimately, in mammals, eda-a1 and eda-a2 trimers each bind a different receptor, edar and xedar, respectively, through their trimerized tnf domain.	SIGNOR-161109
Q86UR1	Q9Y5S8	1	binding	up-regulates activity	0.751	Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner\|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein\|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation	SIGNOR-264710
P31751	O43524	1	phosphorylation	down-regulates activity	0.751	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites.	SIGNOR-236671
O14965	Q15398	1	phosphorylation	up-regulates quantity by stabilization	0.751	Phosphorylation and stabilization of HURP by Aurora-A. Four phosphorylated residues were identified, namely, HURP-S627, -S725, -S757, and -S830, with 65% amino acid sequence coverage. we propose here that Aurora-A may phosphorylate HURP and this probably attenuates the negative impact of cdk1 phosphorylation and by inhibiting subsequent proteasome activity and this will generate a longer HURP half-life.	SIGNOR-262651
Q12983	Q15382	1	binding	down-regulates	0.751	Bnip3, a hypoxia-inducible bcl-2 homology 3 domain-containing protein, directly binds rheb and inhibits the mtor pathway. Bnip3 decreases rheb gtp levels in a manner depending on the binding to rheb.	SIGNOR-158274
O15068	P60953	1	guanine nucleotide exchange factor	up-regulates activity	0.751	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-260560
P11226	P48740	1	binding	up-regulates activity	0.751	The results (Fig. 3A) show that the anti-MBL antibody, in addition to binding MBL captures both MASP-1 and MASP-2\|Our results emphasize the similarity between complement activation through the MBL, or 'MBLectin' pathway of the innate immune system and the classical pathway of complement activation (Fig. 5).	SIGNOR-263414
Q96A54	Q9UKG1	1	binding	up-regulates	0.751	Appl1 interacts with adiponectin receptors in mammalian cells and the interaction is stimulated by adiponectin.	SIGNOR-146212
P13725	P40189	1	binding	up-regulates	0.751	Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. The dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-2.	SIGNOR-48114
O60716	P22223	1	binding	up-regulates quantity by stabilization	0.751	To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member.	SIGNOR-252124
P00519	Q13671	1	phosphorylation	up-regulates	0.751	We also report that the amino-terminal domain of rin1 contains sequences that can mediate interactions with the abl tyrosine kinase and that rin1 is itself tyrosine phosphorylated by c-abl.	SIGNOR-48142
P49770	P20042	1	guanine nucleotide exchange factor	up-regulates activity	0.751	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.	SIGNOR-269130
Q9Y2R2	P06239	1	dephosphorylation	down-regulates activity	0.751	In vitro experiments with purified recombinant proteins demonstrated that PTPN22-D195A/C227S interacted directly with activated Lck, Zap70, and TCRzeta, confirming the initial substrate trap results. Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively, but not at the regulatory tyrosines Tyr-505 (Lck) or Tyr-319 (Zap70). Native PTPN22 also dephosphorylated TCRzeta in vitro and in cells, and its substrate trap variant co-immunoprecipitated with TCRzeta when both were coexpressed in 293T cells, establishing TCRzeta as a direct substrate of PTPN22.	SIGNOR-248836
P28482	P40763	1	phosphorylation	down-regulates activity	0.75	ERK2 phosphorylates Stat3 on three serine-containing peptides and decreases its tyrosine phosphorylation induced by EGF treatment.\|Here, we report that ERK2 activated by its upstream kinase, MEK1, represses Stat3 transcriptional activity induced by Src or Jak-2.	SIGNOR-279635
P52735	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.75	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-260582

P41221

O75581

1

binding

up-regulates activity

0.758

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-131841

P49841

P25054

1

phosphorylation

up-regulates

0.758

Gsk-3beta-dependent phosphorylation of apc.

SIGNOR-75366

P08620

P21802

1

binding

up-regulates

0.758

The nine known fgf ligands and the four signaling fgf receptors (and their alternatively spliced variants) are expressed in specific spatial and temporal patterns. The activity of this signaling pathway is regulated by ligand binding specificity, heparan sulfate proteoglycans, and the differential signaling capacity of individual fgf receptors.

SIGNOR-42377

P05000

P48551

1

binding

up-regulates

0.758

Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2.

SIGNOR-105982

Q96RJ3

Q13114

1

binding

down-regulates quantity by destabilization

0.758

Activation of br3 induces recruitment and degradation of traf3.

SIGNOR-168199

P11802

P84022

1

phosphorylation

down-regulates activity

0.757

We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity

SIGNOR-232142

P06213

Q9Y4H2

1

phosphorylation

down-regulates activity

0.757

Tyr624 and Tyr628 are involved in the interaction between the IR and the KRLB domain of IRS-2, including tyrosine phosphorylation, and Tyr628 seems to be more important than Tyr624 in this process. the binding between the insulin receptor and the KRLB domain of IRS-2 results in tyrosine phosphorylation of the KRLB domain, and this leads to decreased binding of IRS-2 to the insulin receptor.

SIGNOR-251319

Q14596

O95166

1

binding

up-regulates

0.757

We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family

SIGNOR-184261

P28482

Q14790

1

phosphorylation

down-regulates

0.757

We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity

SIGNOR-203473

Q8NES3

P46531

1

binding

up-regulates

0.757

We demonstrate that egf 12, a portion of the ligand-binding site, is modified with o-fucose and that this site is evolutionarily conserved. We also show that endogenous fringe proteins in chinese hamster ovary cells (lunatic fringe and radical fringe) as well as exogenous manic fringe modify o-fucose on many but not all egf repeats of mouse notch1.

SIGNOR-96537

Q14676

O76064

1

relocalization

up-regulates

0.757

Rnf8 relocalizes to dna damage sites via a phospho-dependent interaction with mdc1

SIGNOR-179820

P01031

P21730

1

binding

up-regulates activity

0.757

The chemotactic receptor for human C5a anaphylatoxin|The human C5a receptor was cloned from U937 and HL-60 cells and identified by high affinity binding when expressed in COS-7 cells.

SIGNOR-263457

Q9Y4P1

Q9BXW4

1

cleavage

up-regulates activity

0.757

Human atg4 homologues cleave the carboxyl termini of the three human atg8 homologues, microtubule-associated protein light chain 3 (lc3), gabarap, and gate-16.

SIGNOR-125489

Q93009

O15151

1

deubiquitination

up-regulates

0.757

Subsequently, hausp was shown to deubiquitinate mdm2 and mdmx, thereby stabilizing these proteins.

SIGNOR-139453

Q9UKT4

Q9UM11

1

ubiquitination

down-regulates

0.756

Emi1 binds cdh1 and inhibits apc-cdh1 activity.

SIGNOR-113385

Q13315

Q00987

1

phosphorylation

down-regulates activity

0.756

Dephosphorylation stabilizes mdm2 and increases its affinity for p53, inducing p53 degredation. ;phosphorylated s260 and s395 ands260d and s395d mutant peptides inhibited binding of binding of a specific monoclonal antibody raised to mdm2. Phosphorylation of mdm2 regulates p53 degradation.

SIGNOR-94268

P24941

Q13416

1

phosphorylation

up-regulates

0.756

We also found that horc2p is phosphorylated in vitro by cyclin a/cdk2, specifically at residues thr116 and thr226. These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability.

SIGNOR-116364

Q9P1A6

Q9Y566

1

relocalization

up-regulates activity

0.756

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-264589

Q9NR31

O95486

1

binding

up-regulates quantity

0.756

Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer.

SIGNOR-265303

Q96JK9

Q04721

1

binding

up-regulates

0.756

We report here the cloning and characterization of two new genes, maml2 and maml3, that also function as transcriptional coactivators for notch receptors.

SIGNOR-94097

Q15759

P15336

1

phosphorylation

up-regulates

0.756

Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target

SIGNOR-65586

Q15831

P04637

1

phosphorylation

up-regulates

0.756

We show that lkb1 physically associates with p53 in the nucleus and directly or indirectly phosphorylates p53 ser15 (previously shown to be phosphorylated by amp-dependent kinase) and p53 ser392

SIGNOR-150830

P00533

P42566

2

phosphorylation

up-regulates

0.755

Earlier studies have shown that eps15 at tyr-849 is phosphorylated in egf-stimulated cells and partly controls the internalization of mono-ubiquitinated egfr via uim domains of eps15 [10]. It has also been shown that active egfr phosphorylates tyr-849 directly;

SIGNOR-203311

Q16620

Q92529-2

1

phosphorylation

up-regulates activity

0.755

We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo.

SIGNOR-273917

Q8TB45

P42345

2

binding

down-regulates activity

0.755

DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival

SIGNOR-251657

P12931

P12830

1

phosphorylation

down-regulates quantity by destabilization

0.755

Activated c-Src phosphorylated E-cadherin at the tyrosine 797 site to initiate RNF43-mediated E-cadherin ubiquitination at lysine 816 and subsequent degradation

SIGNOR-274048

P42345

Q8TB45

2

phosphorylation

down-regulates

0.755

Our data reveal critical roles for mtor itself as well as cki in generating a degron in deptor that is recognized by _-trcp, and promotes deptor turnover by the proteasome.

SIGNOR-176849

Q9NZ94

P78352

1

relocalization

up-regulates activity

0.755

Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions.

SIGNOR-264189

P00734

P00451

1

cleavage

up-regulates activity

0.755

Activation of factor VIII by thrombin occurs via limited proteolysis at R372, R740, and R1689.

SIGNOR-263640

Q16620

Q92529

1

binding

up-regulates

0.755

Our present study established that n-shc and sck are expressed in a region-specific manner in the brain and that n-shc is a higher affinity adapter molecule than sck for trka and trkb receptors

SIGNOR-55864

O43318

O14920

1

phosphorylation

up-regulates activity

0.755

Tak1 become activated and then phosphorylates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a our studies suggests that tak1_ acts as an upstream activating kinase for ikkbeta.

SIGNOR-109490

Q8IY92

Q92889

1

binding

up-regulates

0.755

Slx4 is a tumor suppressor that stimulates the activity of the nuclease xpf-ercc1 in dna crosslink repair.

SIGNOR-204890

Q9Y4K3

Q9UDY8

1

ubiquitination

up-regulates

0.755

Traf6 associates with malt1 in response to t-cell activation and can function as an e3 ligase for malt1 in vitro and in vivo, mediating lysine 63-linked ubiquitination of malt1. Multiple lysine residues in the c-terminus of malt1 serve as acceptor sites for the assembly of polyubiquitin chains. (articolo-abstract)

SIGNOR-158554

Q8N1W1

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.755

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-260546

Q9H461

O75581

1

binding

up-regulates activity

0.755

Ligands such as Wnt1, Wnt3a, and Wnt8 couple the seven-transmembrane domain receptor Frizzled (Fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (LRP5/6) to activate WntBeta-catenin signaling.

SIGNOR-169638

P06241

Q13094

1

phosphorylation

down-regulates

0.755

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

SIGNOR-46851

P42574

O00273

1

cleavage

up-regulates activity

0.755

DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. We have identified and purified from HeLa cytosol a protein that induces DNA fragmentation in coincubated nuclei after it is activated by caspase-3.

SIGNOR-47416

Q9HC29

Q676U5

1

binding

up-regulates activity

0.755

By a mechanism independent of the adaptor RIP2 and transcription factor NF-kappaB, Nod1 and Nod2 recruited the autophagy protein ATG16L1 to the plasma membrane at the bacterial entry site. Our results link bacterial sensing by Nod proteins to the induction of autophagy and provide a functional link between Nod2 and ATG16L1, which are encoded by two of the most important genes associated with Crohn's disease.

SIGNOR-252405

P42566

P00533

2

binding

down-regulates activity

0.755

We suggest that the ubiquitinated EGFR or another c-Cbl substrate that is ubiquitinated upon EGFR activation recruits Eps15 to the plasma membrane via its UIM. This event would facilitate EGFR internalization via a clathrin-dependent route in which Eps15 plays a role

SIGNOR-243278

Q96SN8

O94986

1

relocalization

up-regulates activity

0.755

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

SIGNOR-271721

P06239

P10747

1

phosphorylation

up-regulates

0.754

We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor

SIGNOR-45524

P98172

P54760

1

binding

up-regulates

0.754

Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor

SIGNOR-52580

P10911

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.754

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-260556

P03372

P24385

1

transcriptional regulation

up-regulates quantity by expression

0.754

Ikkalpha in conjunction with eralpha and aib1/src-3, is important in activating the transcription of estrogen-responsive genes, including cyclin d1.

SIGNOR-135053

P61812

P37173

1

binding

up-regulates

0.754

We show that tbetarii-b, an alternatively spliced variant of the tgf-beta type ii receptor, is a tgf-beta2 binding receptor, which mediates signalling via the smad pathway in the absence of any tgf-beta type iii receptor

SIGNOR-104795

Q9UMS4

O43395

1

polyubiquitination

up-regulates activity

0.754

Here, we report that the spliceosomal Prp19 complex modifies Prp3, a component of the U4 snRNP, with nonproteolytic K63-linked ubiquitin chains. The K63-linked chains increase the affinity of Prp3 for the U5 snRNP component Prp8, thereby allowing for the stabilization of the U4/U6.U5 snRNP.

SIGNOR-271966

P00519

O15350

1

phosphorylation

up-regulates

0.754

C-abl phosphorylates p73 on a tyrosine residue at position 99 both in vitro and in cells that have been exposed to ionizing radiation. Our results show that c-abl stimulates p73-mediated transactivation and apoptosis.

SIGNOR-68931

Q13546

Q9Y572

2

phosphorylation

up-regulates activity

0.754

In the current scenario, RIPK1 phosphorylates and activates RIPK3, and activated RIPK3 then phosphorylates MLKL.

SIGNOR-278429

Q8N0W4

P78352

1

relocalization

up-regulates activity

0.754

Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions.

SIGNOR-264192

P78527

P31749

1

phosphorylation

up-regulates activity

0.754

DNA-PK phosphorylates HM Ser473 of PKB. However, we also noted similar patterns in T loop Thr308 phosphorylation after _-IR []his function is apparently restricted to the PKBalpha isoform

SIGNOR-252431

Q9UI10

P20042

1

guanine nucleotide exchange factor

up-regulates activity

0.754

EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.

SIGNOR-269132

Q9Y572

Q13546

2

phosphorylation

up-regulates activity

0.754

Collectively, TAK1 activates RIPK3, RIPK3 activates TAK1, and RIPK1 activates RIPK3 and facilitates interaction between TAK1 and RIPK3.|RIPK1 kinase activity is required for RIPK3 phosphorylation, and reciprocally RIPK3 phosphorylates RIPK1.

SIGNOR-280106

P07949

P56159

1

binding

up-regulates

0.754

Gdnfr-alpha-ligand complex, together with the tyrosine kinase receptor (cret) forms a functional receptor that activates downstream signal transduction pathways

SIGNOR-77587

P24941

P30307

1

phosphorylation

up-regulates

0.754

The cyclin e/cdk2 complex phosphorylates cdc25c on ser(214), leading to its premature activation, which coincides with higher cyclin b/cdk1 and polo-like kinase 1 (plk1) activities in an s-phase-enriched population that result in faster mitotic entry.

SIGNOR-165872

P0DP23

Q8N5S9

1

binding

up-regulates

0.754

The binding of Ca2+/CaM to CaM-KK is absolutely required for its activation and efficient phosphorylation of target protein kinases

SIGNOR-232178

P10398

P36507

1

phosphorylation

up-regulates

0.754

Active raf phosphorylates mek.

SIGNOR-175142

P10767

P21802

1

binding

up-regulates

0.753

The nine known fgf ligands and the four signaling fgf receptors (and their alternatively spliced variants) are expressed in specific spatial and temporal patterns. The activity of this signaling pathway is regulated by ligand binding specificity, heparan sulfate proteoglycans, and the differential signaling capacity of individual fgf receptors.

SIGNOR-42380

Q9Y572

Q8NB16

1

phosphorylation

up-regulates activity

0.753

MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays

SIGNOR-266427

Q9UL15

P0DMV8

1

binding

down-regulates activity

0.753

Here, we show that BAG5, a BAG domain-containing family member, interacts with both Hsp70 and parkin with deleterious functional consequences. Through these interactions, BAG5 inhibits Hsp70 chaperone activity and parkin E3 ubiquitin ligase activity; Thus, BAG5 interacts with Hsp70 in vitro and in vivo, and substitution of select residues within the BAG domains is sufficient to abolish this interaction.

SIGNOR-261196

P56704

Q14332

1

binding

up-regulates

0.753

It was also shown that wnt5a inhibits the beta-catenin pathway by competing with wnt3a for binding to fz2, and that the impairment of clathrin-mediated internalization does not affect this wnt5a inhibitory action.

SIGNOR-189117

P04637

Q07812

1

binding

up-regulates

0.753

P53 also accumulates in the cytoplasm where it directly activates bax to promote mitochondrial outer membrane permeabilization.

SIGNOR-140242

Q86YC2

Q06609

1

binding

up-regulates

0.753

We propose that both palb2 chromatin association and its oligomerization serve to secure the brca2 x rad51 repair machinery at the sites of dna damage.

SIGNOR-185656

Q86UT6

Q7Z434

1

binding

down-regulates activity

0.753

Here we describe human NLRX1, a highly conserved nucleotide-binding domain (NBD)- and leucine-rich-repeat (LRR)-containing family member (known as NLR) that localizes to the mitochondrial outer membrane and interacts with MAVS. Expression of NLRX1 results in the potent inhibition of RLH- and MAVS-mediated interferon-beta promoter activity and in the disruption of virus-induced RLH-MAVS interactions. Co-immunoprecipitation studies demonstrate that HA–NLRX1 interacts with MAVS but not with other known mitochondrial outer membrane proteins (BCL2 and BCL2L1), indicating specificity of the NLRX1–MAVS interaction. Finally, endogenous NLRX1 associates strongly with endogenous MAVS after immunoprecipitation with two different MAVS antibodies

SIGNOR-260357

Q9UQK1

P54840

1

binding

up-regulates

0.753

In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2)

SIGNOR-271731

Q9UI47

P35222

1

relocalization

up-regulates quantity

0.753

Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14

SIGNOR-265493

P78344

P20042

1

binding

up-regulates activity

0.753

Unlike eIF4GI/II, DAP5 binds eIF2β, a subunit of the eIF2 complex that delivers methionyl-tRNA to ribosomes.

SIGNOR-266385

O75449

Q9BVA0

2

binding

up-regulates activity

0.753

In its active ATP-bound state, KATNA1 forms hexameric rings capable of binding to and severing microtubule polymers. Typically, KATNA1 binding to KATNB1 enhances severing, likely due to KATNB1 increasing the stability of the KATNA1 hexamer

SIGNOR-267174

Q9BVA0

O75449

2

binding

up-regulates quantity by stabilization

0.753

In its active ATP-bound state, KATNA1 forms hexameric rings capable of binding to and severing microtubule polymers. Typically, KATNA1 binding to KATNB1 enhances severing, likely due to KATNB1 increasing the stability of the KATNA1 hexamer

SIGNOR-267173

P43405

P16885

1

phosphorylation

up-regulates activity

0.753

Syk in turn phosphorylates and activates the B cell linker protein (BLNK), phosphoinositide 3-kinase (PI3K) and phospholipase C\u03b32 (PLC\u03b32).|Syk in turn phosphorylates and activates the B cell linker protein (BLNK), phosphoinositide 3-kinase (PI3K) and phospholipase Cgamma2 (PLCgamma2).

SIGNOR-278995

P06493

Q9UKT4

1

phosphorylation

down-regulates quantity by destabilization

0.753

We find that both Emi1 phosphorylation by cyclin and Cdc2 and phosphorylation on a consensus site (DSGxxS) direct recruitment of betaTrCP and subsequent Emi1 ubiquitination and destruction.

SIGNOR-279143

Q13214

O14786

1

binding

up-regulates activity

0.753

Further examination of the composition of the functional Sema3B receptor revealed that, unlike Sema3A, which signals exclusively using the NP1 receptor, Sema3B utilizes both NP1 and NP2 for signal transduction.

SIGNOR-261814

P06493

Q99640

2

phosphorylation

down-regulates activity

0.752

Active Cdk1 phosphorylates and inhibits Wee1 and Myt1 kinases and phosphorylates and activates the Cdc25 phosphatases.

SIGNOR-279600

Q9BXH1

Q07820

1

binding

down-regulates

0.752

Only bimbh3 and bbc3 had comparable strong affinities for all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.

SIGNOR-133817

P45985

P45983

1

phosphorylation

up-regulates activity

0.752

Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7. Here we report that MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183) in three SAPK1/JNK1 isoforms tested (JNK1 alpha 1, JNK2 alpha 2 and JNK3 alpha 1).

SIGNOR-251419

Q02750

P27361

1

phosphorylation

up-regulates

0.752

Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis.

SIGNOR-210176

P42830

P25025

1

binding

up-regulates activity

0.752

CXCL5 is another ELR+ CXC chemokine and, thus, also potently attracts neutrophils. Just like CXCL1, CXCL5 also signals through CXCR2, explaining why, often, CXCL5 and CXCL1 are seen to function in parallel in PDAC. CXCL5 was increased in human pancreatic tissue compared to the normal pancreas, and the knockdown of CXCL5 in pancreatic cancer cell lines reduced the proliferation and migration ability of cells

SIGNOR-277730

Q99640

P06493

2

phosphorylation

down-regulates

0.752

Myt1hu preferentially phosphorylates cdc2 on threonine 14 in a cyclin-dependent manner;phosphorylation of threonine 14 and tyrosine 15 is inhibitory.

SIGNOR-45729

P45983

Q13469

1

phosphorylation

down-regulates

0.752

Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin jnk directly regulated nuclear factor of activated t-cell (nfat) activation in culture and in transgenic mice containing an nfat-dependent luciferase reporter.

SIGNOR-118217

O43561

P15498

1

binding

up-regulates activity

0.752

By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively.

SIGNOR-246045

Q9ULV1

O14641

1

binding

up-regulates activity

0.751

Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin.

SIGNOR-258958

P15248

Q01113

1

binding

up-regulates

0.751

Interleukin 9 (il-9) exerts its pleiotropic effects through the il-9 receptor (il-9r) complex, which consists of the il-9r alpha-chain, which determines the cytokine specificity, and the il-2 receptor gamma-chain

SIGNOR-73601

P0DP23

Q08209

1

binding

up-regulates

0.751

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

SIGNOR-114098

Q9H082

Q676U5

1

binding

up-regulates

0.751

Olgi-resident small gtpase rab33b interacts with atg16l and modulates autophagosome formation.

SIGNOR-178542

P26678

P16615

1

binding

down-regulates activity

0.751

Heart failure can be traced, in part, to alterations in the activity of the sarcoplasmic reticulum Ca2+ pump that are induced by its interactions with phospholamban, a reversible inhibitor.

SIGNOR-252031

P08887

P40189

1

binding

up-regulates

0.751

Part of the receptor for interleukin 6. Binds to il6 with low affinity, but does not transduce a signal. Signal activation necessitate an association with il6st. Activation may lead to the regulation of the immune response, acute-phase reactions and hematopoiesis.

SIGNOR-105504

Q92838

Q9UNE0

1

binding

up-regulates

0.751

Ultimately, in mammals, eda-a1 and eda-a2 trimers each bind a different receptor, edar and xedar, respectively, through their trimerized tnf domain.

SIGNOR-161109

Q86UR1

Q9Y5S8

1

binding

up-regulates activity

0.751

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

SIGNOR-264710

P31751

O43524

1

phosphorylation

down-regulates activity

0.751

Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites.

SIGNOR-236671

O14965

Q15398

1

phosphorylation

up-regulates quantity by stabilization

0.751

Phosphorylation and stabilization of HURP by Aurora-A. Four phosphorylated residues were identified, namely, HURP-S627, -S725, -S757, and -S830, with 65% amino acid sequence coverage. we propose here that Aurora-A may phosphorylate HURP and this probably attenuates the negative impact of cdk1 phosphorylation and by inhibiting subsequent proteasome activity and this will generate a longer HURP half-life.

SIGNOR-262651

Q12983

Q15382

1

binding

down-regulates

0.751

Bnip3, a hypoxia-inducible bcl-2 homology 3 domain-containing protein, directly binds rheb and inhibits the mtor pathway. Bnip3 decreases rheb gtp levels in a manner depending on the binding to rheb.

SIGNOR-158274

O15068

P60953

1

guanine nucleotide exchange factor

up-regulates activity

0.751

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-260560

P11226

P48740

1

binding

up-regulates activity

0.751

The results (Fig. 3A) show that the anti-MBL antibody, in addition to binding MBL captures both MASP-1 and MASP-2|Our results emphasize the similarity between complement activation through the MBL, or 'MBLectin' pathway of the innate immune system and the classical pathway of complement activation (Fig. 5).

SIGNOR-263414

Q96A54

Q9UKG1

1

binding

up-regulates

0.751

Appl1 interacts with adiponectin receptors in mammalian cells and the interaction is stimulated by adiponectin.

SIGNOR-146212

P13725

P40189

1

binding

up-regulates

0.751

Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. The dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-2.

SIGNOR-48114

O60716

P22223

1

binding

up-regulates quantity by stabilization

0.751

To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member.

SIGNOR-252124

P00519

Q13671

1

phosphorylation

up-regulates

0.751

We also report that the amino-terminal domain of rin1 contains sequences that can mediate interactions with the abl tyrosine kinase and that rin1 is itself tyrosine phosphorylated by c-abl.

SIGNOR-48142

P49770

P20042

1

guanine nucleotide exchange factor

up-regulates activity

0.751

EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.

SIGNOR-269130

Q9Y2R2

P06239

1

dephosphorylation

down-regulates activity

0.751

In vitro experiments with purified recombinant proteins demonstrated that PTPN22-D195A/C227S interacted directly with activated Lck, Zap70, and TCRzeta, confirming the initial substrate trap results. Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively, but not at the regulatory tyrosines Tyr-505 (Lck) or Tyr-319 (Zap70). Native PTPN22 also dephosphorylated TCRzeta in vitro and in cells, and its substrate trap variant co-immunoprecipitated with TCRzeta when both were coexpressed in 293T cells, establishing TCRzeta as a direct substrate of PTPN22.

SIGNOR-248836

P28482

P40763

1

phosphorylation

down-regulates activity

0.75

ERK2 phosphorylates Stat3 on three serine-containing peptides and decreases its tyrosine phosphorylation induced by EGF treatment.|Here, we report that ERK2 activated by its upstream kinase, MEK1, represses Stat3 transcriptional activity induced by Src or Jak-2.

SIGNOR-279635

P52735

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.75

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-260582