GleghornLab/Signor_3class · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels int64 0 2	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
O14920	O15111	0	phosphorylation	up-regulates activity	0.67	Our data indicate that IKKα stimulates IKKβ kinase activity for the IκBα substrate. Finally, we demonstrate that IKKα can phosphorylate IKKβ in in vitro kinase assays.	SIGNOR-250772
P12235	Q5TGU0	2	binding	up-regulates activity	0.277	Our results demonstrate the existence of a VDAC-TSPO2-ANT complex that mediates ATP release from RBCs. We previously demonstrated that the translocase protein TSPO2 together with the voltage-dependent anion channel (VDAC) and adenine nucleotide transporter (ANT) were involved in a membrane transport complex in human red blood cells (RBCs). . The present results show that TSPO ligands induce polymerization of VDAC, coupled to activation of ATP release by a supramolecular complex involving VDAC, TSPO2 and ANT.	SIGNOR-261825
Q05586	Q8TBB1	0	ubiquitination	down-regulates quantity by destabilization	0.288	We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.	SIGNOR-272901
O00629	P46531	1	relocalization	up-regulates	0.287	Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7.	SIGNOR-165314
Q09472	Q9UK99	2	binding	down-regulates quantity by destabilization	0.341	O clarify the role of PML in transcription regulation, we purified the PML complex and identified Fbxo3 (Fbx3), Skp1, and Cullin1 as novel components of this complex. Fbx3 formed SCF(Fbx3) ubiquitin ligase and promoted the degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway.	SIGNOR-271742
P42226	O43474	1	transcriptional regulation	up-regulates quantity by expression	0.345	STAT6 coordinates and synergizes with both PPAR? and Krppel-like factor 4 (KLF4), a member of a family of proteins that contribute to macrophage function.	SIGNOR-249568
Q8IYT8	Q9UGI9	1	phosphorylation	down-regulates	0.2	Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity.	SIGNOR-173095
Q6R6M4	Q99538	1	deubiquitination	down-regulates quantity by destabilization	0.309	We demonstrate that TRAF6 ubiquitinates the proform of AEP through K63-linked polyubiquitin, reversible by USP17, and forms a complex with HSP90α to subsequently promote pro-AEP intracellular stability as well as secretion. We now present evidence that AEP is a substrate for TRAF6 ubiquitination, resulting in AEP/TRAF6/HSP90α complex formation.	SIGNOR-272854
P27361	Q14934	1	phosphorylation	up-regulates	0.289	The formation of rsk-nfatc4-dna transcription complex is also apparent upon adipogenesis. Bound rsk phosphorylates ser(676) and potentiates nfatc4 dna binding by escalating nfat-dna association. Ser(676) is also targeted by the erk map kinase, which interacts with nfat at a distinct region than rsk. Thus, integration of the erk/rsk signaling pathway provides a mechanism to modulate nfatc4 transcription activity.	SIGNOR-133276
P00519	P40692	1	phosphorylation	up-regulates quantity by stabilization	0.344	We also observed phosphorylation of MLH1 by ABL1 in an in vitro kinase assay with purified recombinant ABL1 and MLH1, confirming there is a direct phosphorylation between ABL1 and the MLH1 component of the MLH1-PMS2 heterodimer.\|we propose that ABL1 prevents MLH1 from being targeted for degradation by the chaperone Hsp70 and that in the absence of ABL1 activity at least a portion of MLH1 is degraded.	SIGNOR-279581
P60510	P06493	1	dephosphorylation	down-regulates activity	0.397	PP4c efficiently dephosphorylates Cdk1 sites of NDEL1 but does not dephosphorylate the Aurora A site.\|We also found that PP4c negatively regulates Cdk1 activity in interphase.	SIGNOR-277162
Q15118	Q16665	0	transcriptional regulation	up-regulates quantity by expression	0.469	Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA.	SIGNOR-267444
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
Q8WYL5	P53667	1	dephosphorylation	down-regulates activity	0.597	In addition to its cofilin\u2013phosphatase activity, SSH1 can also dephosphorylate LIMK1 and LIMK2, although LIMK1 is a better substrate than LIMK2 [63] .\|SSH1 suppresses the kinase activity of LIMK1 toward cofilin by dephosphorylation at Thr 508 in the kinase catalytic domain and other autophosphorylated residues [63].	SIGNOR-277096
P27708	P27361	0	phosphorylation	up-regulates	0.2	Cad is a multifunctional protein that initiates and regulates mammalian de novo pyrimidine biosynthesis. The activation of the pathway required for cell proliferation is a consequence of the phosphorylation of cad thr-456 by mitogen-activated protein (map) kinase.Activated map kinase (erk1/2), the enzyme responsible for the phosphorylation of thr-456, was also present in larger amounts in the nucleus than the cytosol	SIGNOR-137179
Q02750	P15056	0	phosphorylation	up-regulates activity	0.789	Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf.	SIGNOR-235475
O75925	O75626	1	sumoylation	up-regulates	0.324	Blimp_1 is subjected to pias1_mediated sumoylation at lysine 816 / it appears that sumo_modified blimp_1 is a more potent transcriptional repressor.	SIGNOR-197265
P78536	P01375	1	cleavage	up-regulates quantity	0.704	We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. [...]This enzyme (called the tnf-alpha-converting enzyme, or tace) is a new member of the family of mammalian adamalysins (or adams), for which no physiological catalytic function has previously been identified.	SIGNOR-46754
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
P05113	Q01344	2	binding	up-regulates	0.883	Single chain and wt il5 also had similar binding affinity for soluble il5 receptor alpha chain, the specificity subunit of the il5 receptor, as measured kinetically with an optical biosensor.	SIGNOR-40039
Q13639	P19086	2	binding	up-regulates activity	0.25	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257309
Q99996	Q15642	2	binding	up-regulates activity	0.512	Mechanistically, AKAP-9 interacted with cdc42 interacting protein 4 (CIP4) and regulated its expression. CIP4 levels were interrelated to the AKAP-9 level in CRC cells. Functionally, AKAP-9 was essential for TGF-β1-induced epithelial-mesenchymal transition of CRC cells, and CIP4 played a critical role in mediating the function of AKAP-9. Importantly, CIP4 expression was significantly up-regulated in human CRC tissues.\|Co-immunoprecipitation assay revealed that AKAP-9 and CIP4 physically interacted with each other in Lovo and HT29 cells (Fig. 4B and C).	SIGNOR-260303
Q9Y5F8	Q9Y5I2	2	binding	up-regulates activity	0.2	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265711
Q05655	P40189	1	phosphorylation	up-regulates activity	0.334	Finally, we identified Thr-890, a putative PKC phosphorylation site on gp130, to be critical for the effect of PKCdelta. Our data indicate that PKCdelta plays important regulatory roles in IL-6 signaling.	SIGNOR-249177
Q9Y4G8	P46934	0	ubiquitination	down-regulates quantity	0.401	In line with the previous result (XREF_FIG), overexpression of NEDD4-1 reduced the level of CNrasGEF significantly (XREF_FIG).\|NEDD4-1 ubiquitinates CNrasGEF in glioma cells.	SIGNOR-278705
O75419	Q8TEA8	2	binding	up-regulates activity	0.504	The DNA unwinding element (DUE)-binding protein (DUE-B) binds to replication origins coordinately with the minichromosome maintenance (MCM) helicase and the helicase activator Cdc45 in vivo, and loads Cdc45 onto chromatin in Xenopus egg extracts. In egg extracts alanine mutation of the DUE-B C-terminal phosphorylation sites blocks Cdc45 loading and inhibits DNA replication. The effects of DUE-B C-terminal phosphorylation reveal a novel S phase kinase regulatory mechanism for Cdc45 loading and MCM helicase activation.	SIGNOR-273973
Q03167	P61812	2	binding	up-regulates	0.518	Betaglycan binds tgf-b isoforms with high affinity and increases the functional interaction between tgf-b and its type ii and type i signalling receptors.	SIGNOR-76473
Q13214	Q9HCM2	2	binding	up-regulates activity	0.65	We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin.	SIGNOR-261810
O14920	O15530	0	phosphorylation	up-regulates activity	0.474	We found that PDK1 directly phosphorylates IKKbeta at the Ser(181) residue in the activation loop, leading to NF-kappaB nuclear translocation and NF-kappaB-dependent anti-apoptotic gene expression.	SIGNOR-279088
P06241	P78352	1	phosphorylation	up-regulates	0.562	Psd-95 is phosphorylated either by purified src/fyn kinases in vitro or by co-expression of constitutively active src/fyn in cos7 cells. psd-95 tyr(523) phosphorylation contributes to the post-ischaemic over-activation of nmda receptors.	SIGNOR-180449
Q13153	P63167	1	phosphorylation	down-regulates	0.378	Dlc1 phosphorylation on ser(88) by p21-activated kinase 1 (pak1), a signaling nodule, promotes mammalian cell survival by regulating its interaction with bim and the stability of bim. Here we discovered that phosphorylation of ser(88), which juxtapose each other at the interface of the dlc dimer, disrupts dlc1 dimer formation and consequently impairs its interaction with bim	SIGNOR-159995
P84022	Q9UKB1	0	ubiquitination	up-regulates	0.261	Here, we show that smad3 activated by tgf-beta is degraded by the ubiquitin-proteasome pathway. Smad3 interacts with a ring finger protein, roc1, through its c-terminal mh2 domain in a ligand-dependent manner. An e3 ubiquitin ligase complex roc1-scf(fbw1a) consisting of roc1, skp1, cullin1, and fbw1a (also termed betatrcp1) induces ubiquitination of smad3.	SIGNOR-108240
Q9UBR4	O75116	0	phosphorylation	up-regulates activity	0.2	Rok-\u03b1 phosphorylates and activates LIM kinase, which in turn phosphorylates and inactivates cofilin.	SIGNOR-280110
P49593	Q16566	1	dephosphorylation	down-regulates activity	0.348	Calmodulin-dependent protein kinase phosphatase (CaMKP) dephosphorylates and concomitantly deactivates multifunctional Ca(2+)/calmodulin-dependent protein kinases , such as CaMKI, CaMKII, and CaMKIV.	SIGNOR-277157
P48729	Q8TB45	1	phosphorylation	down-regulates	0.2	Phosphorylation of all three serine residues in the deptor degron (ser286, ser287, and ser291) is necessary for - and directly mediates - the interaction with _trcp. ck1 phosphorylated the degron of deptor, as shown by western blotting with the phospho-specific antibody (fig. S3e-f). In contrast, mtor alone was unable to induce phosphorylation of deptor on ser286, ser287, and ser291.	SIGNOR-176871
Q14315	Q4L180	2	binding	down-regulates quantity by destabilization	0.252	We identified the extended basophilic phosphosite motif RxRxxp[S/T]xxp[S/T] in various proteins including filamin-C (FLNc). Importantly, this extended motif, located in a unique insert in Ig-like domain 20 of FLNc, is doubly phosphorylated. The protein kinases responsible for this dual-site phosphorylation are Akt and PKCα. Proximity proteomics and interaction analysis identified filamin A-interacting protein 1 (FILIP1) as direct FLNc binding partner. FILIP1 binding induces filamin degradation, thereby negatively regulating its function. Here, dual-site phosphorylation of FLNc not only reduces FILIP1 binding, providing a mechanism to shield FLNc from FILIP1-mediated degradation, but also enables fast dynamics of FLNc necessary for its function as signaling adaptor in cross-striated muscle cells.	SIGNOR-262618
Q13829	P61586	2	binding	down-regulates quantity	0.35	BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex.	SIGNOR-264235
Q14623	Q13635	2	binding	down-regulates activity	0.838	Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH.	SIGNOR-61311
Q00341	P07333	1	transcriptional regulation	down-regulates quantity by repression	0.342	Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer.	SIGNOR-266696
Q9NR80	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.667	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-260531
O15119	P38936	1	transcriptional regulation	down-regulates quantity by repression	0.304	TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS	SIGNOR-249602
Q8NFZ4	Q9ULB1	2	binding	up-regulates activity	0.825	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.\|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264146
Q13950	Q9UNE7	0	ubiquitination	down-regulates quantity by destabilization	0.407	Here, we show that CHIP promotes Runx2 ubiquitination and degradation and thereby negatively regulates osteoblast differentiation.	SIGNOR-278600
P37198	P61970	2	binding	up-regulates activity	0.845	Our data suggest that NTF2 interacts directly with NPC protein 1362 and exerts its effect at a relatively late step in the nuclear protein import pathway. We obtained a cDNA encoding NTF2 and showed that the recombinant protein restores transport activity to p62-pretreated cytosol.	SIGNOR-261255
Q8N9L9	P31749	0	phosphorylation	up-regulates quantity by stabilization	0.2	HSPA1A was found to associate with ACOT4. Furthermore, we found that phosphorylation of ACOT4 at S392 by AKT decreased the binding of ACOT4 to HSPA1A, resulting in ACOT4 accumulation. \|AKT phosphorylates ACOT4 at S392 and promotes ACOT4 stability	SIGNOR-271820
Q9C0C7	Q99496	0	ubiquitination	down-regulates quantity by destabilization	0.359	RNF2 ubiquitinates AMBRA1 at lysine 45.\|These data indicate that RNF2 directly accelerates the degradation of AMBRA1.	SIGNOR-278596
P40763	P12931	0	phosphorylation	up-regulates activity	0.789	In the present study, we have delineated the mechanism by which Galpha16 stimulates STAT3 in human embryonic kidney 293 cells. A constitutively active Galpha16 mutant, Galpha16QL, stimulated STAT3-dependent luciferase activity as well as the phosphorylation of STAT3 at both Tyr705 and Ser727.The involvement of tyrosine kinases such as c-Src and Janus kinase 2 and 3 (JAK2 and JAK3) in Galpha16QL-induced activation of STAT3 was illustrated by the combined use of selective inhibitors and dominant negative mutants.	SIGNOR-247341
Q14289	P29474	1	phosphorylation	down-regulates	0.309	We found that fluid shear stress induces the association of enos with the proline-rich tyrosine kinase 2 (pyk2) in endothelial cells and that the enos immunoprecipitated from enos- and pyk2-overexpressing hek293 cells was tyrosine-phosphorylated on tyr657.	SIGNOR-161824
Q99835	P32121	2	binding	up-regulates	0.661	Grk2-mediated phosphorylation of vertebrate smo allows smo to bind to beta-arrestins 1 or 2	SIGNOR-132759
P19086	P25105	2	binding	up-regulates activity	0.2	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257329
Q96GD4	Q7Z3K3	2	binding	up-regulates activity	0.323	POGZ is required for the correct activation and dissociation of Aurora B kinase from chromosome arms during M phase. These results reveal POGZ as an essential protein that links HP1alpha dissociation with Aurora B kinase activation during mitosis.	SIGNOR-264497
P12830	P35222	2	binding	up-regulates activity	0.96	At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin	SIGNOR-265863
P04637	O15264	0	phosphorylation	up-regulates	0.462	In mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site.	SIGNOR-72691
Q9HCM2	Q14563	2	binding	up-regulates activity	0.763	We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin.	SIGNOR-261811
P15863	P50222	2	binding	up-regulates activity	0.409	We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family.	SIGNOR-222232
P49841	Q9BZS1	1	phosphorylation	down-regulates quantity by destabilization	0.285	Our previous study showed, by mass spectrometry analysis, that GSK-3β phosphorylates Foxp3 at Ser270 and Ser275	SIGNOR-277245
P53396	P49841	0	phosphorylation	up-regulates activity	0.364	Thr 446 and Ser 450, which are phosphorylated by glycogen synthase kinase-3 (GSK-3). Phosphorylation resulted in a 6-fold increase in V(max) and the conversion of citrate dependence from sigmoidal, displaying negative cooperativity, to hyperbolic.	SIGNOR-251219
Q969P5	P15173	2	binding	down-regulates activity	0.512	Myogenin had a MAFbx-recognition motif and interacted with MAFbx. MAFbx activated polyubiquitination of myogenin. The results of this study suggest that MAFbx functions as an F-box protein for ubiquitination of myogenin.	SIGNOR-237854
P38936	Q15208	0	phosphorylation	down-regulates quantity by destabilization	0.2	More importantly, with the direct regulation of p21 stability by phosphorylation on Ser 146, we define here the first downstream signaling mechanisms by which NDR kinases can control G1/S progression.\|NDR kinases regulate p21 stability by phosphorylation of S146 on p21. \|	SIGNOR-272961
Q86T82	P20248	1	deubiquitination	up-regulates quantity by stabilization	0.581	USP37 Binds, Deubiquitinates, and Stabilizes Cyclin A	SIGNOR-265052
O15379	Q9BXM7	0	phosphorylation	up-regulates activity	0.2	PINK1 positively regulates HDAC3 to suppress dopaminergic neuronal cell death.\|PINK1 prevents H2O2-induced C-terminal cleavage of HDAC3 via phosphorylation of HDAC3 at Ser-424, which is reversed by protein phosphatase 4c.	SIGNOR-279093
P53778	P10636	1	phosphorylation	down-regulates activity	0.525	Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective.	SIGNOR-250087
P20339	Q9UH99	2	binding	up-regulates activity	0.42	Rab5ip represents a novel rab5 interacting protein that may function on endocytic vesicles as a receptor for rab5-GDP and participate in the activation of rab5	SIGNOR-261309
O14672	P22415	0	transcriptional regulation	up-regulates quantity by expression	0.27	The promoter region of ADAM10 contains several transcription factor binding sites that can stimulate its transcription. These include binding sites for transcription factors SP1 and USF, and the spliced form of the X-box binding protein (XBP)-1 as well as a retinoic acid-responsive element	SIGNOR-259837
P01106	P11908	1	transcriptional regulation	up-regulates quantity by expression	0.277	Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation.	SIGNOR-267376
P49841	P14921	1	phosphorylation	up-regulates quantity by stabilization	0.2	Here, we show that ETS1 forms a complex with glycogen synthase kinase-3β (GSK3β). Specifically, GSK3β-mediated phosphorylation of ETS1 at threonine 265 and serine 269 promoted protein stability, induced the transcriptional activation of matrix metalloproteinase (MMP)-9, and increased cell migration.	SIGNOR-277560
Q70E73	Q8N8S7	2	binding	up-regulates activity	0.544	Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins.	SIGNOR-268425
Q05397	P35968	0	null	up-regulates activity	0.496	Here we show that genetic or pharmacological FAK inhibition in ECs prevents VEGF-stimulated permeability downstream of VEGF receptor or Src tyrosine kinase activation in vivo. VEGF promotes tension-independent FAK activation	SIGNOR-261945
Q06124	Q05397	1	dephosphorylation	down-regulates	0.731	Dca concomitantly and significantly increased association of tyrosine phosphatase shp2 with fak. Incubation of immunoprecipitated fak, in vitro, with glutathione-s-transferase-shp2 fusion protein resulted in tyrosine dephosphorylation of fak in a concentration-dependent manner.	SIGNOR-148926
Q92913	P35498	2	binding	down-regulates activity	0.277	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253419
Q16816	P46019	2	binding	down-regulates activity	0.696	Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit.	SIGNOR-267404
P54252	Q9UNE7	0	ubiquitination	down-regulates quantity by destabilization	0.51	Although our data show that CHIP may associate with Atx3 to ubiquitinate Atx3 in vitro, we still wonder whether CHIP is directly involved in the degradation of Atx3.\|As a result, silencing of CHIP significantly increases the amount of Atx3 (XREF_FIG), suggesting that CHIP may down-regulate the Atx3 level.	SIGNOR-278667
P63092	Q96LB1	2	binding	up-regulates activity	0.2	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ‚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-256787
O60481	P10071	2	binding	up-regulates	0.374	Zic3 functions as a transcriptional coactivator of gli3 when it physically associates with gli3	SIGNOR-157637
P30304	P48729	0	phosphorylation	down-regulates	0.333	Here, we report that casein kinase 1 alpha (ck1alpha) phosphorylates cdc25a on both s79 and s82 in a hierarchical manner requiring prior phosphorylation of s76 by chk1 or gsk-3beta. This facilitates beta-trcp binding and ubiquitin-mediated proteolysis of cdc25a	SIGNOR-164734
Q9UJV9	Q06187	0	phosphorylation	up-regulates activity	0.406	The kinase and SH3/SH2 interaction domains of BTK bind, respectively, the DEAD-box domain of DDX41 and transmembrane region of STING. BTK phosphorylates DDX41, and its kinase activities are critical for STING-mediated IFN-β production. We show that Tyr364 and Tyr414 of DDX41 are critical for its recognition of AT-rich DNA and binding to STING, and tandem mass spectrometry identifies Tyr414 as the BTK phosphorylation site.	SIGNOR-266404
P10586	P07949	1	dephosphorylation	down-regulates	0.426	Lar expression significantly reduced tyrosine-1062 phosphorylation in ret-men2a but not in ret-men2b	SIGNOR-85170
P00797	O75787	2	binding	up-regulates	0.787	We report the expression cloning of the human renin receptor complementary dna encoding a 350-amino acid protein with a single transmembrane domain and no homology with any known membrane protein. Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. The binding of renin induced a fourfold increase of the catalytic efficiency of angiotensinogen conversion to angiotensin i and induced an intracellular signal with phosphorylation of serine and tyrosine residues associated to an activation of map kinases erk1 and erk2	SIGNOR-88416
O60566	Q12834	1	phosphorylation	up-regulates activity	0.993	Furthermore, BUBR1 phosphorylates p55CDC in vitro, and the phosphorylation of p55CDC by BUBR1 appears to be correlated with spindle checkpoint activation.	SIGNOR-279507
Q13315	P78527	2	phosphorylation	up-regulates	0.702	Atm mediates dna-pkcs phosphorylation at thr-2609 as well as at the adjacent (s/t)q motifs within the thr-2609 cluster. In addition, our data suggest that dna-pkcs- and atm-mediated dna-pkcs phosphorylations are cooperative and required for the full activation of dna-pkcs and the subsequent dsb repair.	SIGNOR-151441
Q03113	Q9NZN5	2	binding	up-regulates activity	0.765	P115 RhoGEF stimulates the intrinsic GTP hydrolysis activity of G alpha 12/13 subunits and acts as an effector for G13-coupled receptors by linking receptor activation to RhoA activation.	SIGNOR-256522
P01275	P47871	2	binding	up-regulates	0.777	In contrast, stimulation of gs-coupled receptors by glucagon or epinephrine activates lats1/2 kinase activity, thereby inhibiting yap function.	SIGNOR-198504
Q9C0C7	Q14457	2	binding	up-regulates activity	0.786	we show that the BECLIN 1-VPS34 complex is tethered to the cytoskeleton through an interaction between the BECLIN 1-interacting protein AMBRA1 and dynein light chains 1/2.	SIGNOR-168252
P61764	Q02156	0	phosphorylation	down-regulates quantity	0.273	These results show that nPKC\u03b5 induces Munc18-1 phosphorylation during synaptic activity and reinforce the idea that nPKC\u03b5 downregulates Munc18-1 levels, induced by the nerve stimulation.\|These results show that nPKCepsilon induces Munc18-1 phosphorylation during synaptic activity and reinforce the idea that nPKCepsilon downregulates Munc18-1 levels, induced by the nerve stimulation.	SIGNOR-279479
P31645	Q13976	0	phosphorylation	up-regulates	0.382	These results are consistent with the hypothesis that pkg phosphorylates hsert at thr-276 and increases its activity by modifying the substrate permeation pathway formed, in part, by tm5.	SIGNOR-158186
O00198	P10415	2	binding	down-regulates	0.472	Hrk, physically interacts with the death-repressor proteins bcl2 and bcl2l1. Hrk activates cell death at least in part by interacting with and inhibiting the protection afforded by bcl2 and bcl2l1.	SIGNOR-47794
Q92562	Q08AM6	2	binding	up-regulates quantity by stabilization	0.921	Our data indentify a novel regulatory mechanism whereby ArPIKfyve enhances Sac3 abundance by attenuating Sac3 proteasome-dependent degradation and suggest that a failure of this mechanism could be the primary molecular defect in the pathogenesis of CMT4J. our data are consistent with the notion that when associated with ArPIKfyve, Sac3 is stabilized and protected from degradation, whereas in the absence of associated ArPIKfyve, Sac3 remains unfolded and, hence, prone to rapid destruction.	SIGNOR-253534
P09619	P17706	0	dephosphorylation	down-regulates activity	0.564	The PDGF beta receptor is negatively regulated by protein tyrosine phosphatases (PTPs).\|In summary, our findings identify TC-PTP as a previously unrecognized negative regulator of PDGF beta receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors.The fact that two of the investigated PDGF β receptor sites, Y1021 and Y771, displayed a larger increase in phosphorylation than Y579 and Y751 in TC-PTP ko MEFs indicated that these two sites are preferred substrates for TC-PTP.	SIGNOR-248389
P05771	P17302	1	phosphorylation	down-regulates activity	0.388	Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.\|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication.	SIGNOR-249049
P04150	Q00535	0	phosphorylation	down-regulates activity	0.481	Cdk5 phosphorylated gr at multiple serines, including ser203 and ser211 of its n-terminal domain, and suppressed the transcriptional activity of this receptor on glucocorticoid-responsive promoters by attenuating attraction of transcriptional cofactors to dna.\| the effect of CDK5 on GR-induced transcriptional activity is specific to gene promoter, and possibly, to tissue	SIGNOR-154405
Q03431	P63092	2	binding	up-regulates activity	0.506	This calciotropic hormone exerts its actions via binding to the PTH/PTH-related peptide receptor (PTH1R), which couples to multiple heterotrimeric G proteins, including Gs and Gq/11.	SIGNOR-270551
P00533	P23470	0	dephosphorylation	down-regulates activity	0.481	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254699
P01106	O60674	2	binding	up-regulates quantity by stabilization	0.451	In this study, we show that Jak2 is involved in c-Myc induction by inducing c-MYC mRNA and protecting c-Myc protein from 26S proteasome-dependent degradation. These results indicate that c-Myc is a downstream target of activated Jak2 in Bcr-Abl positive cells.	SIGNOR-255810
P35568	P42336	2	binding	up-regulates activity	0.722	Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin.	SIGNOR-168985
Q9NQT8	Q00535	0	phosphorylation	down-regulates activity	0.365	Overexpression of Cdk5 or its activator p35 promoted and inhibition of Cdk5 activity prevented the KIF13B-TRPV1 association, indicating that Cdk5 promotes TRPV1 anterograde transport by mediating the motor-cargo association. Cdk5 phosphorylates KIF13B at Thr-506, a residue located in the FHA domain. T506A mutation reduced the motor-cargo interaction and the cell-permeable TAT-T506 peptide, targeting to the Thr-506, decreased TRPV1 surface localization, demonstrating the essential role of Thr-506 phosphorylation in TRPV1 transport.	SIGNOR-262737
P34947	P09619	0	phosphorylation	up-regulates activity	0.2	Purified GRK5 was tyrosine-phosphorylated by the wild-type PDGFRbeta to a stoichiometry of 0.8 mol phosphate/mol GRK5, an extent approximately 5 times greater than observed with a Y857F PDGFRbeta mutant that fails to phosphorylate exogenous substrates but autophosphorylates and activates Src normally.\|We conclude that GRK5 tyrosyl phosphorylation is required for the activation of GRK5 by the PDGFRbeta, but not by the beta(2)-adrenergic receptor, and that by activating GRK5, the PDGFRbeta triggers its own desensitization.	SIGNOR-279642
Q15691	O75122	2	binding	up-regulates activity	0.632	GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules.\| CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells	SIGNOR-264829
P00797	P01019	2	cleavage	up-regulates activity	0.928	Angiotensinogen, an _-glycoprotein, is released from the liver (152, 250, 444) and is cleaved in the circulation by the enzyme renin that is secreted from the juxtaglomerular apparatus of the kidney (245, 250, 540, 631) to form the decapeptide angiotensin (ANG) I	SIGNOR-252297
Q13564	Q14669	0	ubiquitination	down-regulates quantity by destabilization	0.432	Our data suggest that that TRIP12 promotes degradation of APP-BP1 by catalyzing its ubiquitination, which in turn modulates the neddylation pathway.	SIGNOR-266780
Q92630	P43686	1	phosphorylation	down-regulates quantity by destabilization	0.284	Through a kinome-wide screen, we have identified dual-specificity tyrosine-regulated kinase 2 (DYRK2) as the primary kinase that phosphorylates Rpt3-Thr25, leading to enhanced substrate translocation and degradation.	SIGNOR-275845

O14920

O15111

0

phosphorylation

up-regulates activity

0.67

Our data indicate that IKKα stimulates IKKβ kinase activity for the IκBα substrate. Finally, we demonstrate that IKKα can phosphorylate IKKβ in in vitro kinase assays.

SIGNOR-250772

P12235

Q5TGU0

2

binding

up-regulates activity

0.277

Our results demonstrate the existence of a VDAC-TSPO2-ANT complex that mediates ATP release from RBCs. We previously demonstrated that the translocase protein TSPO2 together with the voltage-dependent anion channel (VDAC) and adenine nucleotide transporter (ANT) were involved in a membrane transport complex in human red blood cells (RBCs). . The present results show that TSPO ligands induce polymerization of VDAC, coupled to activation of ATP release by a supramolecular complex involving VDAC, TSPO2 and ANT.

SIGNOR-261825

Q05586

Q8TBB1

0

ubiquitination

down-regulates quantity by destabilization

0.288

We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.

SIGNOR-272901

O00629

P46531

1

relocalization

up-regulates

0.287

Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7.

SIGNOR-165314

Q09472

Q9UK99

2

binding

down-regulates quantity by destabilization

0.341

O clarify the role of PML in transcription regulation, we purified the PML complex and identified Fbxo3 (Fbx3), Skp1, and Cullin1 as novel components of this complex. Fbx3 formed SCF(Fbx3) ubiquitin ligase and promoted the degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway.

SIGNOR-271742

P42226

O43474

1

transcriptional regulation

up-regulates quantity by expression

0.345

STAT6 coordinates and synergizes with both PPAR? and Krppel-like factor 4 (KLF4), a member of a family of proteins that contribute to macrophage function.

SIGNOR-249568

Q8IYT8

Q9UGI9

1

phosphorylation

down-regulates

0.2

Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity.

SIGNOR-173095

Q6R6M4

Q99538

1

deubiquitination

down-regulates quantity by destabilization

0.309

We demonstrate that TRAF6 ubiquitinates the proform of AEP through K63-linked polyubiquitin, reversible by USP17, and forms a complex with HSP90α to subsequently promote pro-AEP intracellular stability as well as secretion. We now present evidence that AEP is a substrate for TRAF6 ubiquitination, resulting in AEP/TRAF6/HSP90α complex formation.

SIGNOR-272854

P27361

Q14934

1

phosphorylation

up-regulates

0.289

The formation of rsk-nfatc4-dna transcription complex is also apparent upon adipogenesis. Bound rsk phosphorylates ser(676) and potentiates nfatc4 dna binding by escalating nfat-dna association. Ser(676) is also targeted by the erk map kinase, which interacts with nfat at a distinct region than rsk. Thus, integration of the erk/rsk signaling pathway provides a mechanism to modulate nfatc4 transcription activity.

SIGNOR-133276

P00519

P40692

1

phosphorylation

up-regulates quantity by stabilization

0.344

We also observed phosphorylation of MLH1 by ABL1 in an in vitro kinase assay with purified recombinant ABL1 and MLH1, confirming there is a direct phosphorylation between ABL1 and the MLH1 component of the MLH1-PMS2 heterodimer.|we propose that ABL1 prevents MLH1 from being targeted for degradation by the chaperone Hsp70 and that in the absence of ABL1 activity at least a portion of MLH1 is degraded.

SIGNOR-279581

P60510

P06493

1

dephosphorylation

down-regulates activity

0.397

PP4c efficiently dephosphorylates Cdk1 sites of NDEL1 but does not dephosphorylate the Aurora A site.|We also found that PP4c negatively regulates Cdk1 activity in interphase.

SIGNOR-277162

Q15118

Q16665

0

transcriptional regulation

up-regulates quantity by expression

0.469

Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA.

SIGNOR-267444

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

Q8WYL5

P53667

1

dephosphorylation

down-regulates activity

0.597

In addition to its cofilin\u2013phosphatase activity, SSH1 can also dephosphorylate LIMK1 and LIMK2, although LIMK1 is a better substrate than LIMK2 [63] .|SSH1 suppresses the kinase activity of LIMK1 toward cofilin by dephosphorylation at Thr 508 in the kinase catalytic domain and other autophosphorylated residues [63].

SIGNOR-277096

P27708

P27361

0

phosphorylation

up-regulates

0.2

Cad is a multifunctional protein that initiates and regulates mammalian de novo pyrimidine biosynthesis. The activation of the pathway required for cell proliferation is a consequence of the phosphorylation of cad thr-456 by mitogen-activated protein (map) kinase.Activated map kinase (erk1/2), the enzyme responsible for the phosphorylation of thr-456, was also present in larger amounts in the nucleus than the cytosol

SIGNOR-137179

Q02750

P15056

0

phosphorylation

up-regulates activity

0.789

Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf.

SIGNOR-235475

O75925

O75626

1

sumoylation

up-regulates

0.324

Blimp_1 is subjected to pias1_mediated sumoylation at lysine 816 / it appears that sumo_modified blimp_1 is a more potent transcriptional repressor.

SIGNOR-197265

P78536

P01375

1

cleavage

up-regulates quantity

0.704

We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. [...]This enzyme (called the tnf-alpha-converting enzyme, or tace) is a new member of the family of mammalian adamalysins (or adams), for which no physiological catalytic function has previously been identified.

SIGNOR-46754

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

P05113

Q01344

2

binding

up-regulates

0.883

Single chain and wt il5 also had similar binding affinity for soluble il5 receptor alpha chain, the specificity subunit of the il5 receptor, as measured kinetically with an optical biosensor.

SIGNOR-40039

Q13639

P19086

2

binding

up-regulates activity

0.25

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

SIGNOR-257309

Q99996

Q15642

2

binding

up-regulates activity

0.512

Mechanistically, AKAP-9 interacted with cdc42 interacting protein 4 (CIP4) and regulated its expression. CIP4 levels were interrelated to the AKAP-9 level in CRC cells. Functionally, AKAP-9 was essential for TGF-β1-induced epithelial-mesenchymal transition of CRC cells, and CIP4 played a critical role in mediating the function of AKAP-9. Importantly, CIP4 expression was significantly up-regulated in human CRC tissues.|Co-immunoprecipitation assay revealed that AKAP-9 and CIP4 physically interacted with each other in Lovo and HT29 cells (Fig. 4B and C).

SIGNOR-260303

Q9Y5F8

Q9Y5I2

2

binding

up-regulates activity

0.2

The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.

SIGNOR-265711

Q05655

P40189

1

phosphorylation

up-regulates activity

0.334

Finally, we identified Thr-890, a putative PKC phosphorylation site on gp130, to be critical for the effect of PKCdelta. Our data indicate that PKCdelta plays important regulatory roles in IL-6 signaling.

SIGNOR-249177

Q9Y4G8

P46934

0

ubiquitination

down-regulates quantity

0.401

In line with the previous result (XREF_FIG), overexpression of NEDD4-1 reduced the level of CNrasGEF significantly (XREF_FIG).|NEDD4-1 ubiquitinates CNrasGEF in glioma cells.

SIGNOR-278705

O75419

Q8TEA8

2

binding

up-regulates activity

0.504

The DNA unwinding element (DUE)-binding protein (DUE-B) binds to replication origins coordinately with the minichromosome maintenance (MCM) helicase and the helicase activator Cdc45 in vivo, and loads Cdc45 onto chromatin in Xenopus egg extracts. In egg extracts alanine mutation of the DUE-B C-terminal phosphorylation sites blocks Cdc45 loading and inhibits DNA replication. The effects of DUE-B C-terminal phosphorylation reveal a novel S phase kinase regulatory mechanism for Cdc45 loading and MCM helicase activation.

SIGNOR-273973

Q03167

P61812

2

binding

up-regulates

0.518

Betaglycan binds tgf-b isoforms with high affinity and increases the functional interaction between tgf-b and its type ii and type i signalling receptors.

SIGNOR-76473

Q13214

Q9HCM2

2

binding

up-regulates activity

0.65

We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin.

SIGNOR-261810

O14920

O15530

0

phosphorylation

up-regulates activity

0.474

We found that PDK1 directly phosphorylates IKKbeta at the Ser(181) residue in the activation loop, leading to NF-kappaB nuclear translocation and NF-kappaB-dependent anti-apoptotic gene expression.

SIGNOR-279088

P06241

P78352

1

phosphorylation

up-regulates

0.562

Psd-95 is phosphorylated either by purified src/fyn kinases in vitro or by co-expression of constitutively active src/fyn in cos7 cells. psd-95 tyr(523) phosphorylation contributes to the post-ischaemic over-activation of nmda receptors.

SIGNOR-180449

Q13153

P63167

1

phosphorylation

down-regulates

0.378

Dlc1 phosphorylation on ser(88) by p21-activated kinase 1 (pak1), a signaling nodule, promotes mammalian cell survival by regulating its interaction with bim and the stability of bim. Here we discovered that phosphorylation of ser(88), which juxtapose each other at the interface of the dlc dimer, disrupts dlc1 dimer formation and consequently impairs its interaction with bim

SIGNOR-159995

P84022

Q9UKB1

0

ubiquitination

up-regulates

0.261

Here, we show that smad3 activated by tgf-beta is degraded by the ubiquitin-proteasome pathway. Smad3 interacts with a ring finger protein, roc1, through its c-terminal mh2 domain in a ligand-dependent manner. An e3 ubiquitin ligase complex roc1-scf(fbw1a) consisting of roc1, skp1, cullin1, and fbw1a (also termed betatrcp1) induces ubiquitination of smad3.

SIGNOR-108240

Q9UBR4

O75116

0

phosphorylation

up-regulates activity

0.2

Rok-\u03b1 phosphorylates and activates LIM kinase, which in turn phosphorylates and inactivates cofilin.

SIGNOR-280110

P49593

Q16566

1

dephosphorylation

down-regulates activity

0.348

Calmodulin-dependent protein kinase phosphatase (CaMKP) dephosphorylates and concomitantly deactivates multifunctional Ca(2+)/calmodulin-dependent protein kinases , such as CaMKI, CaMKII, and CaMKIV.

SIGNOR-277157

P48729

Q8TB45

1

phosphorylation

down-regulates

0.2

Phosphorylation of all three serine residues in the deptor degron (ser286, ser287, and ser291) is necessary for - and directly mediates - the interaction with _trcp. ck1 phosphorylated the degron of deptor, as shown by western blotting with the phospho-specific antibody (fig. S3e-f). In contrast, mtor alone was unable to induce phosphorylation of deptor on ser286, ser287, and ser291.

SIGNOR-176871

Q14315

Q4L180

2

binding

down-regulates quantity by destabilization

0.252

We identified the extended basophilic phosphosite motif RxRxxp[S/T]xxp[S/T] in various proteins including filamin-C (FLNc). Importantly, this extended motif, located in a unique insert in Ig-like domain 20 of FLNc, is doubly phosphorylated. The protein kinases responsible for this dual-site phosphorylation are Akt and PKCα. Proximity proteomics and interaction analysis identified filamin A-interacting protein 1 (FILIP1) as direct FLNc binding partner. FILIP1 binding induces filamin degradation, thereby negatively regulating its function. Here, dual-site phosphorylation of FLNc not only reduces FILIP1 binding, providing a mechanism to shield FLNc from FILIP1-mediated degradation, but also enables fast dynamics of FLNc necessary for its function as signaling adaptor in cross-striated muscle cells.

SIGNOR-262618

Q13829

P61586

2

binding

down-regulates quantity

0.35

BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex.

SIGNOR-264235

Q14623

Q13635

2

binding

down-regulates activity

0.838

Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH.

SIGNOR-61311

Q00341

P07333

1

transcriptional regulation

down-regulates quantity by repression

0.342

Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer.

SIGNOR-266696

Q9NR80

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.667

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-260531

O15119

P38936

1

transcriptional regulation

down-regulates quantity by repression

0.304

TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS

SIGNOR-249602

Q8NFZ4

Q9ULB1

2

binding

up-regulates activity

0.825

Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)

SIGNOR-264146

Q13950

Q9UNE7

0

ubiquitination

down-regulates quantity by destabilization

0.407

Here, we show that CHIP promotes Runx2 ubiquitination and degradation and thereby negatively regulates osteoblast differentiation.

SIGNOR-278600

P37198

P61970

2

binding

up-regulates activity

0.845

Our data suggest that NTF2 interacts directly with NPC protein 1362 and exerts its effect at a relatively late step in the nuclear protein import pathway. We obtained a cDNA encoding NTF2 and showed that the recombinant protein restores transport activity to p62-pretreated cytosol.

SIGNOR-261255

Q8N9L9

P31749

0

phosphorylation

up-regulates quantity by stabilization

0.2

HSPA1A was found to associate with ACOT4. Furthermore, we found that phosphorylation of ACOT4 at S392 by AKT decreased the binding of ACOT4 to HSPA1A, resulting in ACOT4 accumulation. |AKT phosphorylates ACOT4 at S392 and promotes ACOT4 stability

SIGNOR-271820

Q9C0C7

Q99496

0

ubiquitination

down-regulates quantity by destabilization

0.359

RNF2 ubiquitinates AMBRA1 at lysine 45.|These data indicate that RNF2 directly accelerates the degradation of AMBRA1.

SIGNOR-278596

P40763

P12931

0

phosphorylation

up-regulates activity

0.789

In the present study, we have delineated the mechanism by which Galpha16 stimulates STAT3 in human embryonic kidney 293 cells. A constitutively active Galpha16 mutant, Galpha16QL, stimulated STAT3-dependent luciferase activity as well as the phosphorylation of STAT3 at both Tyr705 and Ser727.The involvement of tyrosine kinases such as c-Src and Janus kinase 2 and 3 (JAK2 and JAK3) in Galpha16QL-induced activation of STAT3 was illustrated by the combined use of selective inhibitors and dominant negative mutants.

SIGNOR-247341

Q14289

P29474

1

phosphorylation

down-regulates

0.309

We found that fluid shear stress induces the association of enos with the proline-rich tyrosine kinase 2 (pyk2) in endothelial cells and that the enos immunoprecipitated from enos- and pyk2-overexpressing hek293 cells was tyrosine-phosphorylated on tyr657.

SIGNOR-161824

Q99835

P32121

2

binding

up-regulates

0.661

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

SIGNOR-132759

P19086

P25105

2

binding

up-regulates activity

0.2

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

SIGNOR-257329

Q96GD4

Q7Z3K3

2

binding

up-regulates activity

0.323

POGZ is required for the correct activation and dissociation of Aurora B kinase from chromosome arms during M phase. These results reveal POGZ as an essential protein that links HP1alpha dissociation with Aurora B kinase activation during mitosis.

SIGNOR-264497

P12830

P35222

2

binding

up-regulates activity

0.96

At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin

SIGNOR-265863

P04637

O15264

0

phosphorylation

up-regulates

0.462

In mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site.

SIGNOR-72691

Q9HCM2

Q14563

2

binding

up-regulates activity

0.763

We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin.

SIGNOR-261811

P15863

P50222

2

binding

up-regulates activity

0.409

We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family.

SIGNOR-222232

P49841

Q9BZS1

1

phosphorylation

down-regulates quantity by destabilization

0.285

Our previous study showed, by mass spectrometry analysis, that GSK-3β phosphorylates Foxp3 at Ser270 and Ser275

SIGNOR-277245

P53396

P49841

0

phosphorylation

up-regulates activity

0.364

Thr 446 and Ser 450, which are phosphorylated by glycogen synthase kinase-3 (GSK-3). Phosphorylation resulted in a 6-fold increase in V(max) and the conversion of citrate dependence from sigmoidal, displaying negative cooperativity, to hyperbolic.

SIGNOR-251219

Q969P5

P15173

2

binding

down-regulates activity

0.512

Myogenin had a MAFbx-recognition motif and interacted with MAFbx. MAFbx activated polyubiquitination of myogenin. The results of this study suggest that MAFbx functions as an F-box protein for ubiquitination of myogenin.

SIGNOR-237854

P38936

Q15208

0

phosphorylation

down-regulates quantity by destabilization

0.2

More importantly, with the direct regulation of p21 stability by phosphorylation on Ser 146, we define here the first downstream signaling mechanisms by which NDR kinases can control G1/S progression.|NDR kinases regulate p21 stability by phosphorylation of S146 on p21. |

SIGNOR-272961

Q86T82

P20248

1

deubiquitination

up-regulates quantity by stabilization

0.581

USP37 Binds, Deubiquitinates, and Stabilizes Cyclin A

SIGNOR-265052

O15379

Q9BXM7

0

phosphorylation

up-regulates activity

0.2

PINK1 positively regulates HDAC3 to suppress dopaminergic neuronal cell death.|PINK1 prevents H2O2-induced C-terminal cleavage of HDAC3 via phosphorylation of HDAC3 at Ser-424, which is reversed by protein phosphatase 4c.

SIGNOR-279093

P53778

P10636

1

phosphorylation

down-regulates activity

0.525

Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective.

SIGNOR-250087

P20339

Q9UH99

2

binding

up-regulates activity

0.42

Rab5ip represents a novel rab5 interacting protein that may function on endocytic vesicles as a receptor for rab5-GDP and participate in the activation of rab5

SIGNOR-261309

O14672

P22415

0

transcriptional regulation

up-regulates quantity by expression

0.27

The promoter region of ADAM10 contains several transcription factor binding sites that can stimulate its transcription. These include binding sites for transcription factors SP1 and USF, and the spliced form of the X-box binding protein (XBP)-1 as well as a retinoic acid-responsive element

SIGNOR-259837

P01106

P11908

1

transcriptional regulation

up-regulates quantity by expression

0.277

Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation.

SIGNOR-267376

P49841

P14921

1

phosphorylation

up-regulates quantity by stabilization

0.2

Here, we show that ETS1 forms a complex with glycogen synthase kinase-3β (GSK3β). Specifically, GSK3β-mediated phosphorylation of ETS1 at threonine 265 and serine 269 promoted protein stability, induced the transcriptional activation of matrix metalloproteinase (MMP)-9, and increased cell migration.

SIGNOR-277560

Q70E73

Q8N8S7

2

binding

up-regulates activity

0.544

Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins.

SIGNOR-268425

Q05397

P35968

0

null

up-regulates activity

0.496

Here we show that genetic or pharmacological FAK inhibition in ECs prevents VEGF-stimulated permeability downstream of VEGF receptor or Src tyrosine kinase activation in vivo. VEGF promotes tension-independent FAK activation

SIGNOR-261945

Q06124

Q05397

1

dephosphorylation

down-regulates

0.731

Dca concomitantly and significantly increased association of tyrosine phosphatase shp2 with fak. Incubation of immunoprecipitated fak, in vitro, with glutathione-s-transferase-shp2 fusion protein resulted in tyrosine dephosphorylation of fak in a concentration-dependent manner.

SIGNOR-148926

Q92913

P35498

2

binding

down-regulates activity

0.277

Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.

SIGNOR-253419

Q16816

P46019

2

binding

down-regulates activity

0.696

Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit.

SIGNOR-267404

P54252

Q9UNE7

0

ubiquitination

down-regulates quantity by destabilization

0.51

Although our data show that CHIP may associate with Atx3 to ubiquitinate Atx3 in vitro, we still wonder whether CHIP is directly involved in the degradation of Atx3.|As a result, silencing of CHIP significantly increases the amount of Atx3 (XREF_FIG), suggesting that CHIP may down-regulate the Atx3 level.

SIGNOR-278667

P63092

Q96LB1

2

binding

up-regulates activity

0.2

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚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-256787

O60481

P10071

2

binding

up-regulates

0.374

Zic3 functions as a transcriptional coactivator of gli3 when it physically associates with gli3

SIGNOR-157637

P30304

P48729

0

phosphorylation

down-regulates

0.333

Here, we report that casein kinase 1 alpha (ck1alpha) phosphorylates cdc25a on both s79 and s82 in a hierarchical manner requiring prior phosphorylation of s76 by chk1 or gsk-3beta. This facilitates beta-trcp binding and ubiquitin-mediated proteolysis of cdc25a

SIGNOR-164734

Q9UJV9

Q06187

0

phosphorylation

up-regulates activity

0.406

The kinase and SH3/SH2 interaction domains of BTK bind, respectively, the DEAD-box domain of DDX41 and transmembrane region of STING. BTK phosphorylates DDX41, and its kinase activities are critical for STING-mediated IFN-β production. We show that Tyr364 and Tyr414 of DDX41 are critical for its recognition of AT-rich DNA and binding to STING, and tandem mass spectrometry identifies Tyr414 as the BTK phosphorylation site.

SIGNOR-266404

P10586

P07949

1

dephosphorylation

down-regulates

0.426

Lar expression significantly reduced tyrosine-1062 phosphorylation in ret-men2a but not in ret-men2b

SIGNOR-85170

P00797

O75787

2

binding

up-regulates

0.787

We report the expression cloning of the human renin receptor complementary dna encoding a 350-amino acid protein with a single transmembrane domain and no homology with any known membrane protein. Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. The binding of renin induced a fourfold increase of the catalytic efficiency of angiotensinogen conversion to angiotensin i and induced an intracellular signal with phosphorylation of serine and tyrosine residues associated to an activation of map kinases erk1 and erk2

SIGNOR-88416

O60566

Q12834

1

phosphorylation

up-regulates activity

0.993

Furthermore, BUBR1 phosphorylates p55CDC in vitro, and the phosphorylation of p55CDC by BUBR1 appears to be correlated with spindle checkpoint activation.

SIGNOR-279507

Q13315

P78527

2

phosphorylation

up-regulates

0.702

Atm mediates dna-pkcs phosphorylation at thr-2609 as well as at the adjacent (s/t)q motifs within the thr-2609 cluster. In addition, our data suggest that dna-pkcs- and atm-mediated dna-pkcs phosphorylations are cooperative and required for the full activation of dna-pkcs and the subsequent dsb repair.

SIGNOR-151441

Q03113

Q9NZN5

2

binding

up-regulates activity

0.765

P115 RhoGEF stimulates the intrinsic GTP hydrolysis activity of G alpha 12/13 subunits and acts as an effector for G13-coupled receptors by linking receptor activation to RhoA activation.

SIGNOR-256522

P01275

P47871

2

binding

up-regulates

0.777

In contrast, stimulation of gs-coupled receptors by glucagon or epinephrine activates lats1/2 kinase activity, thereby inhibiting yap function.

SIGNOR-198504

Q9C0C7

Q14457

2

binding

up-regulates activity

0.786

we show that the BECLIN 1-VPS34 complex is tethered to the cytoskeleton through an interaction between the BECLIN 1-interacting protein AMBRA1 and dynein light chains 1/2.

SIGNOR-168252

P61764

Q02156

0

phosphorylation

down-regulates quantity

0.273

These results show that nPKC\u03b5 induces Munc18-1 phosphorylation during synaptic activity and reinforce the idea that nPKC\u03b5 downregulates Munc18-1 levels, induced by the nerve stimulation.|These results show that nPKCepsilon induces Munc18-1 phosphorylation during synaptic activity and reinforce the idea that nPKCepsilon downregulates Munc18-1 levels, induced by the nerve stimulation.

SIGNOR-279479

P31645

Q13976

0

phosphorylation

up-regulates

0.382

These results are consistent with the hypothesis that pkg phosphorylates hsert at thr-276 and increases its activity by modifying the substrate permeation pathway formed, in part, by tm5.

SIGNOR-158186

O00198

P10415

2

binding

down-regulates

0.472

Hrk, physically interacts with the death-repressor proteins bcl2 and bcl2l1. Hrk activates cell death at least in part by interacting with and inhibiting the protection afforded by bcl2 and bcl2l1.

SIGNOR-47794

Q92562

Q08AM6

2

binding

up-regulates quantity by stabilization

0.921

Our data indentify a novel regulatory mechanism whereby ArPIKfyve enhances Sac3 abundance by attenuating Sac3 proteasome-dependent degradation and suggest that a failure of this mechanism could be the primary molecular defect in the pathogenesis of CMT4J. our data are consistent with the notion that when associated with ArPIKfyve, Sac3 is stabilized and protected from degradation, whereas in the absence of associated ArPIKfyve, Sac3 remains unfolded and, hence, prone to rapid destruction.

SIGNOR-253534

P09619

P17706

0

dephosphorylation

down-regulates activity

0.564

The PDGF beta receptor is negatively regulated by protein tyrosine phosphatases (PTPs).|In summary, our findings identify TC-PTP as a previously unrecognized negative regulator of PDGF beta receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors.The fact that two of the investigated PDGF β receptor sites, Y1021 and Y771, displayed a larger increase in phosphorylation than Y579 and Y751 in TC-PTP ko MEFs indicated that these two sites are preferred substrates for TC-PTP.

SIGNOR-248389

P05771

P17302

1

phosphorylation

down-regulates activity

0.388

Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication.

SIGNOR-249049

P04150

Q00535

0

phosphorylation

down-regulates activity

0.481

Cdk5 phosphorylated gr at multiple serines, including ser203 and ser211 of its n-terminal domain, and suppressed the transcriptional activity of this receptor on glucocorticoid-responsive promoters by attenuating attraction of transcriptional cofactors to dna.| the effect of CDK5 on GR-induced transcriptional activity is specific to gene promoter, and possibly, to tissue

SIGNOR-154405

Q03431

P63092

2

binding

up-regulates activity

0.506

This calciotropic hormone exerts its actions via binding to the PTH/PTH-related peptide receptor (PTH1R), which couples to multiple heterotrimeric G proteins, including Gs and Gq/11.

SIGNOR-270551

P00533

P23470

0

dephosphorylation

down-regulates activity

0.481

PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.

SIGNOR-254699

P01106

O60674

2

binding

up-regulates quantity by stabilization

0.451

In this study, we show that Jak2 is involved in c-Myc induction by inducing c-MYC mRNA and protecting c-Myc protein from 26S proteasome-dependent degradation. These results indicate that c-Myc is a downstream target of activated Jak2 in Bcr-Abl positive cells.

SIGNOR-255810

P35568

P42336

2

binding

up-regulates activity

0.722

Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin.

SIGNOR-168985

Q9NQT8

Q00535

0

phosphorylation

down-regulates activity

0.365

Overexpression of Cdk5 or its activator p35 promoted and inhibition of Cdk5 activity prevented the KIF13B-TRPV1 association, indicating that Cdk5 promotes TRPV1 anterograde transport by mediating the motor-cargo association. Cdk5 phosphorylates KIF13B at Thr-506, a residue located in the FHA domain. T506A mutation reduced the motor-cargo interaction and the cell-permeable TAT-T506 peptide, targeting to the Thr-506, decreased TRPV1 surface localization, demonstrating the essential role of Thr-506 phosphorylation in TRPV1 transport.

SIGNOR-262737

P34947

P09619

0

phosphorylation

up-regulates activity

0.2

Purified GRK5 was tyrosine-phosphorylated by the wild-type PDGFRbeta to a stoichiometry of 0.8 mol phosphate/mol GRK5, an extent approximately 5 times greater than observed with a Y857F PDGFRbeta mutant that fails to phosphorylate exogenous substrates but autophosphorylates and activates Src normally.|We conclude that GRK5 tyrosyl phosphorylation is required for the activation of GRK5 by the PDGFRbeta, but not by the beta(2)-adrenergic receptor, and that by activating GRK5, the PDGFRbeta triggers its own desensitization.

SIGNOR-279642

Q15691

O75122

2

binding

up-regulates activity

0.632

GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules.| CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells

SIGNOR-264829

P00797

P01019

2

cleavage

up-regulates activity

0.928

Angiotensinogen, an _-glycoprotein, is released from the liver (152, 250, 444) and is cleaved in the circulation by the enzyme renin that is secreted from the juxtaglomerular apparatus of the kidney (245, 250, 540, 631) to form the decapeptide angiotensin (ANG) I

SIGNOR-252297

Q13564

Q14669

0

ubiquitination

down-regulates quantity by destabilization

0.432

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

SIGNOR-266780

Q92630

P43686

1

phosphorylation

down-regulates quantity by destabilization

0.284

Through a kinome-wide screen, we have identified dual-specificity tyrosine-regulated kinase 2 (DYRK2) as the primary kinase that phosphorylates Rpt3-Thr25, leading to enhanced substrate translocation and degradation.

SIGNOR-275845