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
P41970	Q16539	0	phosphorylation	up-regulates	0.379	Tcf sap-1a is efficiently phosphorylated by p38 map kinase in vitro and in vivo on the homologous residues ser381 and ser387. Mutation of these sites to alanine severely reduces c-fos sre-dependent transcription mediated by sap-1a and p38 map kinase.	SIGNOR-47685
P54756	P52797	2	binding	up-regulates	0.817	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-52381
P54646	Q9UQB8	1	phosphorylation	down-regulates	0.2	Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379 respectively) resulted in almost a complete loss of ampk phosphorylation in these proteins. Termination of irsp53 function is suggested to occur following cdc42 dissociation, kinase phosphorylation of t340 and t360, and subsequent 14-3-3 binding, which competes for sh3 partners, thus allowing filopodial retraction	SIGNOR-195102
P00533	Q9UM47	1	phosphorylation	up-regulates activity	0.593	Here, we report that treatment of EGFR mutated lung cancer cell lines with erlotinib, while showing robust cell death, enriches the ALDH+ stem like cells through EGFR dependent activation of Notch3.\|We also find a kinase-dependent physical association between the Notch3 and EGFR receptors and tyrosine phosphorylation of Notch3.	SIGNOR-280002
P17252	Q6ZN44	1	phosphorylation	down-regulates quantity	0.2	We show that protein interacting with C-kinase 1 (PICK1) recruits activated protein kinase Cα (PKCα) to MycUNC5A at the plasma membrane, stimulating its endocytosis. We identify two PKCα phosphorylation sites at serines 408 and 587, as well as dileucine internalization motifs, which are required for this endocytosis.	SIGNOR-268180
Q8IU57	Q8IZJ0	2	binding	up-regulates	0.71	Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha.	SIGNOR-96206
P10721	Q14451	2	binding	up-regulates activity	0.584	We furthermore demonstrate that the adapter protein Grb2 is a specific binding partner for both phosphorylated Tyr-703 and phosphorylated Tyr-936, whereas the adapter protein Grb7 binds selectively to phosphorylated Tyr-936.	SIGNOR-248291
O15350	P17252	0	phosphorylation	up-regulates activity	0.2	Here, we report that p73 is able to induce cell cycle arrest independently of its amino-terminal transactivation domain, whereas this domain is crucial for p73 proapoptotic functions. its activity is regulated throughout the cell cycle and modified by protein kinase C-dependent phosphorylation at serine residue 388.	SIGNOR-276235
O95999	Q9BXL7	2	binding	up-regulates	0.845	Card11 cooperates with bcl10 in a card domain-dependent manner.;These results implicate card11 in factor- specific activation of nf-kappab	SIGNOR-93869
P35638	Q7Z570	0	transcriptional regulation	up-regulates quantity by expression	0.2	ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3).	SIGNOR-269464
P01106	Q96GD4	0	phosphorylation	up-regulates quantity by stabilization	0.373	AURKB directly phosphorylates MYC at serine 67, counteracting GSK3\u03b2-directed threonine 58 phosphorylation and subsequent FBXW7- mediated proteasomal degradation.	SIGNOR-279439
Q14247	Q05655	0	phosphorylation	up-regulates activity	0.246	Together these findings demonstrate that phosphorylation of cortactin on S405 and S418 residues is required for its interaction with WAVE2 in MCP1-induced cytoskeleton remodeling, facilitating HASMC migration. In addition, the MCP1-induced cortactin phosp	SIGNOR-260890
P78509	Q9Y5W3	0	transcriptional regulation	up-regulates quantity by expression	0.2	KLF2 transactivates the reelin promoter in K562 cells.	SIGNOR-266048
O95817	P11142	2	binding	up-regulates activity	0.788	Heat shock cognate protein 70 (Hsc70) regulates protein homeostasis through its reversible interactions with client proteins. Hsc70 has two major domains: a nucleotide-binding domain (NBD), that hydrolyzes ATP, and a substrate-binding domain (SBD), where clients are bound. Members of the BAG family of co-chaperones, including Bag1 and Bag3, are known to accelerate release of both ADP and client from Hsc70.	SIGNOR-254116
Q9NS23	Q13188	2	binding	up-regulates	0.697	Mst1/2 is also activated by binding to Ras association domain family (RASSF) proteins, possibly owing to alteration of Mst1/2 subcellular localization.	SIGNOR-175790
P60953	Q15811	0	guanine nucleotide exchange factor	up-regulates activity	0.848	Significantly, here we identify the long isoform of ITSN-1, which has Cdc42 GEF activity\| We propose that GCC88 recruits ITSN-1-L to the TGN, which in turn activates Cdc42 at the trans-face of the Golgi (Figure 9A).	SIGNOR-260612
Q12824	P51532	2	binding	up-regulates activity	0.943	The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added.	SIGNOR-65438
P43405	P29353	1	phosphorylation	up-regulates	0.762	The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on sch1 (iso2).	SIGNOR-59635
P49675	P17676	0	transcriptional regulation	up-regulates quantity by expression	0.365	Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells.	SIGNOR-254046
Q15418	P30304	1	phosphorylation	down-regulates	0.366	Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b.	SIGNOR-202117
O43603	O95837	2	binding	up-regulates activity	0.311	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-257136
Q9HCE1	Q92900	2	binding	up-regulates activity	0.521	MOV10 has been shown to promote mRNA degradation by associating with UPF1, this activity requires the helicase activity of MOV10.	SIGNOR-261139
P55211	P12931	0	phosphorylation	up-regulates activity	0.373	As a result, we established that Src was able to directly phosphorylate caspase-9 at tyrosine 251, leading to elevated caspase-9 activity.	SIGNOR-272998
Q99453	Q96F44	0	ubiquitination	down-regulates	0.485	The e3 ubiquitin ligasetrim11mediates the degradation of congenital central hypoventilation syndrome-associated polyalanine-expandedphox2b.	SIGNOR-195878
P67775	P37840	1	dephosphorylation	down-regulates activity	0.332	α-Synuclein (α-Syn) is a key protein that accumulates as hyperphosphorylated aggregates in pathologic hallmark features of Parkinson's disease (PD) and other neurodegenerative disorders. Phosphorylation of this protein at serine 129 is believed to promote its aggregation and neurotoxicity, suggesting that this post-translational modification could be a therapeutic target. Here, we demonstrate that phosphoprotein phosphatase 2A (PP2A) dephosphorylates α-Syn at serine 129	SIGNOR-248635
P28562	P54646	0	phosphorylation	down-regulates quantity by destabilization	0.273	Taken together, these results imply that nicotine acts via AMPKα2 to phosphorylate MKP1 at Ser334, instigating MKP1 ubiquitination and proteasome-mediated degradation.	SIGNOR-276890
Q13591	Q9ULL4	2	binding	up-regulates activity	0.623	Plexin-B3 is a functional receptor for semaphorin 5A. Here we show that plexin-B3 is a high-affinity receptor specific for Sema5A. We further demonstrate that plexin-B3 activation by Sema5A mediates functional responses in plexin-B3-expressing cells (either fibroblasts, epithelial and primary endothelial cells).	SIGNOR-268373
P51812	O14649	1	phosphorylation	up-regulates activity	0.2	The chaperone protein, 14-3-3, binds to a critical phosphorylated serine in the channel c termini of k2p3.1 and k2p9.1 (ser(393) and ser(373), respectively) and overcomes retention in the endoplasmic reticulum by ?COP. We sought to identify the kinase responsible for phosphorylation of the terminal serine in human and rat variants of k2p3.1 and k2p9.1. Adopting a bioinformatic approach, three candidate protein kinases were identified: camp-dependent protein kinase, ribosomal s6 kinase, and protein kinase c.	SIGNOR-172470
O43186	P08047	2	binding	up-regulates activity	0.324	Zinc finger DNA-binding domains of both Sp1 and Sp3 interact with Crx. Sp4 and Sp1 produce much higher levels of transcriptional activation when co-transfected with Crx, they may additionally act by directly increasing the rate of transcriptional initiation by the general transcriptional apparatus through their activation domains.	SIGNOR-225336
P12931	P29320	2	binding	up-regulates	0.528	We propose src kinase as a downstream effector that mediates the neuron's response to eph receptor activation.	SIGNOR-58139
P63092	O00222	2	binding	up-regulates activity	0.44	MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits.	SIGNOR-264081
P52952	Q92833	2	binding	down-regulates activity	0.455	JMJ physically associates with Nkx2.5 and GATA4 in vitro and in vivo as determined by glutathione S-transferase pull-down and immunoprecipitation assays. we show that JMJ represses ANF gene expression by inhibiting transcriptional activities of Nkx2.5 and GATA4.	SIGNOR-224787
P24752	P29803	1	acetylation	down-regulates activity	0.2	We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1)	SIGNOR-267634
Q13191	P16333	2	binding	up-regulates activity	0.526	Activated Cbl and Cbl-b interacted with Crk-L, Zap-70, Nck, PLC-gamma	SIGNOR-236054
P21918	P63096	2	binding	up-regulates activity	0.289	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-257043
P14136	P60709	2	binding	up-regulates quantity	0.374	GFAP is the major cytoskeletal element and scaffold of astrocytes In astrocytes, GFAP has close interaction with F-actin molecularly and functionally.	SIGNOR-269271
Q5BJF6	P06493	0	phosphorylation	up-regulates activity	0.543	Phosphorylation of hCenexin1 at S796 is critical for the hCenexin1-Plk1 interaction.Here we show that a splice variant of hODF2 called hCenexin1, but not hODF2 itself, efficiently localizes to somatic centrosomes via a variant-specific C-terminal extension and recruits Plk1 through a Cdc2-dependent phospho-S796 motif within the extension. This interaction and Plk1 activity were important for proper recruitment of pericentrin and gamma-tubulin, and, ultimately, for formation of normal bipolar spindles.	SIGNOR-273584
P12318	P51451	0	phosphorylation	up-regulates activity	0.436	To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point\|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation.	SIGNOR-249312
P10415	P45983	0	phosphorylation	down-regulates	0.582	G(2)/m-phase cells proved more susceptible to death signals, and phosphorylation of bcl-2 appeared to be responsible, as a ser70ala substitution restored resistance to apoptosis. We noted that ask1 and jnk1 were normally activated at g(2)/m phase, and jnk was capable of phosphorylating bcl-2..	SIGNOR-72361
P59594	Q9BYF1	2	binding	down-regulates activity	0.2	Cell entry of severe acute respiratory syndrome coronavirus (SARS-CoV) is mediated by the viral spike (S) protein. Amino acids 319-510 on the S protein have been mapped as the receptor-binding domain (RBD), which mediates binding to the SARS-CoV receptor angiotensin converting enzyme 2 (ACE2) on SARS-CoV susceptible cells. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells.	SIGNOR-260283
Q9NZQ7	P49840	0	phosphorylation	down-regulates quantity by destabilization	0.2	We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal degradation following GSK3α-mediated phosphorylation of Ser279/Ser283. We identify ARIH1 as the E3 ubiquitin ligase responsible for targeting PD-L1 to degradation.	SIGNOR-277552
P43250	P08069	1	phosphorylation	down-regulates quantity by destabilization	0.306	GRK2 and GRK6 coimmunoprecipitate with IGF-1R and increase IGF-1R serine phosphorylation, promoting β-arrestin1 association. Using immunoprecipitation, confocal microscopy, and FRET analysis, we demonstrated β-arrestin/IGF-1R association to be transient for GRK2 and stable for GRK6. Using bioinformatic studies we identified serines 1248 and 1291 as the major serine phosphorylation sites of the IGF-1R. Targeted mutation of S1248 recapitulates GRK2 modulation, whereas S1291 mutation resembles GRK6 effects on IGF-1R signaling/degradation	SIGNOR-276412
P67775	O43815	2	binding	up-regulates activity	0.638	The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms	SIGNOR-261698
P31749	Q9BXL7	1	phosphorylation	up-regulates activity	0.522	Akt phosphorylates S637 and S645 in the linker region of Carma1	SIGNOR-276621
Q8IYT8	P06733	1	phosphorylation	down-regulates activity	0.2	Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).	SIGNOR-274037
P14598	P17252	0	phosphorylation	up-regulates	0.553	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89178
Q8TAP6	P53350	2	binding	down-regulates activity	0.433	Here, we found that centrosomal protein of 76 kDa (Cep76), previously shown to restrain centriole amplification, interacts with cyclin-dependent kinase 2 (CDK2) and is a bona fide substrate of this kinase. Cep76 is preferentially phosphorylated by cyclin A/CDK2 at a single site S83, and this event is crucial to suppress centriole amplification in S phase. Mechanistically, Cep76 phosphorylation inhibits activation of polo-like kinase 1 (Plk1), thereby blocking premature centriole disengagement and subsequent amplification.	SIGNOR-262731
P12931	P63096	2	binding	up-regulates activity	0.486	Here we demonstrate that Galphas and Galphai, but neither Galphaq, Galpha12 nor Gbetay, directly stimulate the kinase activity of downregulated c-Src	SIGNOR-256526
O75581	O94907	2	binding	down-regulates	0.904	We report that dkk-1 is a high-affinity ligand for lrp6 and inhibits wnt signaling by preventing fz-lrp6 complex formation induced by wnt. Dkk1 has been shown to inhibit wnt by binding to and antagonizing lrp5/6.	SIGNOR-109247
Q16539	Q6STE5	1	phosphorylation	up-regulates activity	0.368	P38 phosphorylates the baf60 subunit of the swi-snf chromatin remodelling complex, and p38 recruits this complex to differentiation-specific loci.	SIGNOR-176557
P19174	P63215	2	binding	up-regulates	0.2	Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance.	SIGNOR-199141
Q15417	P06241	0	phosphorylation	down-regulates activity	0.333	We identify, for the first time, tyrosine-phosphorylated calponin h3 within COS 7 cells, before and after their transfection with the pSV vector containing cDNA encoding the cytoplasmic, Src-related, tyrosine kinase, Fyn. we have localized the tyrosines phosphorylated without actin to Tyr261 in calponin h3 and to Tyr261 and Tyr182 in calponin h1. Tyrosine phosphorylation of calponins inhibits their binding to F-actin	SIGNOR-251159
P14921	Q9Y458	1	transcriptional regulation	up-regulates quantity by expression	0.2	TBX22 is an X-linked gene, which encodes a T-box-containing transcription factor. Loss-of-function mutation in the X-linked TBX22 promoter disrupts an ETS-1 binding site and leads to cleft palate. We first link the transcription factor ETS-1 to TBX22 pathway during embryonic palatogenesis.	SIGNOR-265565
Q92917	P22694	0	phosphorylation	up-regulates activity	0.307	Using yeast two-hybrid screening with the PKA Cβ2 subunit as bait we identified GPKOW, also known as MOS2 homolog or T54 protein, as an interaction partner for Cβ2.PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites.	SIGNOR-266298
P12931	P37173	1	phosphorylation	up-regulates	0.281	Tbetarii can also be phosphorylated by src, a non-rtk, on y284, which can serve as a docking site for the recruitment of grb2 and shc, thereby bridging tbetarii to mapk activation.	SIGNOR-182963
P17693	Q8NHL6	2	binding	up-regulates	0.77	Hla-g binds a limited repertoire of peptides and interacts with the inhibitory leukocyte ig-like receptors lir-1 and lir-2	SIGNOR-134180
Q14676	P16104	2	binding	up-regulates	0.2	Here, we demonstrate that mammalian mdc1/nfbd1 directly binds to phospho-h2ax (gammah2ax) by specifically interacting with the phosphoepitope at the gammah2ax carboxyl terminus.	SIGNOR-143377
Q8ND25	Q03135	1	polyubiquitination	down-regulates quantity by destabilization	0.364	The ubiquitin ligase ZNRF1 promotes caveolin-1 ubiquitination and degradation to modulate inflammation. ZNRF1 mediates CAV1 polyubiquitination at lysine 39 and promote CAV1 degradation to modulate TLR4-mediated immune response.	SIGNOR-272327
Q9UQL6	Q06413	2	binding	down-regulates	0.696	The histone deacetylase hdac-5, upon dephosphorylation and translocation to the nucleus, directly inactivates mef2, preventing myogenesis.	SIGNOR-84026
Q12770	Q12772	1	relocalization	up-regulates activity	0.901	SCAP contains two domains: an NH2-terminal membrane attachment domain with eight membrane-spanning helices (Nohturfft et al., 1998b) and a long COOH-terminal extension that contains multiple copies of a WD40 repeat sequence, which forms a propeller-like structure that binds to the COOH-terminal domains of the SREBPs, thereby permitting the escort function	SIGNOR-267502
Q13705	O95390	2	binding	up-regulates	0.625	Here we demonstrate using genetic and biochemical studies that actriib and its subfamily receptor, actriia, cooperatively mediate the gdf11 signal in patterning the axial vertebrae, and that gdf11 binds to both actriia and actriib, and induces phosphorylation of smad2	SIGNOR-95309
P00519	P37840	1	phosphorylation	up-regulates quantity	0.424	C-Abl interacts with alpha-synuclein and phosphorylates alpha-synuclein at Y39 (XREF_FIG) .	SIGNOR-279582
P06493	P05787	1	phosphorylation	up-regulates	0.248	With regard to k8 phosphorylation at ser-431, it increases dramatically upon stimulation of cells with epidermal growth factor (egf) or after mitotic arrest and is the major k8 phosphorylated residue after incubating k8 immunoprecipitates with mitogen-activated protein or cdc2 kinases.	SIGNOR-56054
P12931	P22681	0	ubiquitination	down-regulates quantity by destabilization	0.738	Cbl-b also targets active Src for degradation in cells, and Nedd4 similarly reverses Cbl mediated Src degradation.\|Cbl-b also targets active Src for degradation in cells, and Nedd4 similarly reverses Cbl-mediated Src degradation	SIGNOR-278539
P07384	P49841	1	cleavage	up-regulates activity	0.297	Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase	SIGNOR-251586
Q27J81	O43791	2	binding	down-regulates activity	0.2	SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. It revealed that INF2 was ubiquitinated at least at 7 lysine residues (Fig 2I). Interestingly, 5 of 7 ubiquitin attachment sites are localized in a short stretch of sequence (amino acids 612–682) within the FH2 domain of INF2 (Fig 2J).	SIGNOR-272798
Q9H2G9	Q9H2K2	0	ADP-ribosylation	down-regulates quantity by destabilization	0.2	Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation.	SIGNOR-263384
P28482	P28482	2	phosphorylation	up-regulates activity	0.2	Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation.\|	SIGNOR-249415
P31749	P08670	1	phosphorylation	up-regulates quantity by stabilization	0.647	The binding of akt (tail region) to vim (head region) results in vim ser39 phosphorylation enhancing the ability of vim to induce motility and invasion while protecting vim from caspase-induced proteolysis.	SIGNOR-252511
P00519	O00401	1	phosphorylation	up-regulates activity	0.55	Abl phosphorylates N-WASP on tyrosines 175 and 256. Phosphorylation at this site stabilizes the active conformation of N-WASP, resulting in comet tail elongation.	SIGNOR-251437
Q71U36	Q92949	0	transcriptional regulation	up-regulates quantity by expression	0.298	FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).	SIGNOR-266938
O43474	P40424	2	binding	up-regulates activity	0.479	We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4.	SIGNOR-267237
Q2M1P5	P10070	2	binding	up-regulates quantity by stabilization	0.586	Kif7 physically interacted with Gli transcription factors and controlled their proteolysis and stability, and acted both positively and negatively in Hh signaling.	SIGNOR-209611
Q9P212	P01112	1	guanine nucleotide exchange factor	up-regulates	0.578	The presence of a rasgef motif in the n terminus of plcepsilon suggests that plcepsilon can activate ras by acting as an exchange factor by promoting the exchange of gtp for bound gdp.	SIGNOR-82859
P01344	Q9H9Z2	0	translation regulation	up-regulates quantity by expression	0.397	Lin-28 binds IGF-2 mRNA and participates in skeletal myogenesis by increasing translation efficiency	SIGNOR-277339
Q9HCK8	Q92886	1	transcriptional regulation	down-regulates quantity	0.2	Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells	SIGNOR-268919
P10636-2	P05129	0	phosphorylation	down-regulates activity	0.27	We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs.	SIGNOR-275445
P12931	P52565	1	phosphorylation	down-regulates	0.399	We show here that src kinase binds and phosphorylates rhogdi both in vitro and in vivo at tyr156. analysis of rho gtpase-rhogdi complexes using in vitro assays of complexation and in vivo by coimmunoprecipitation analysis indicates that src-mediated phosphorylation of tyr156 causes a dramatic decrease in the ability of rhogdi to form a complex with rhoa, rac1, or cdc42.	SIGNOR-149282
O60500	P19544	0	transcriptional regulation	up-regulates quantity by expression	0.487	The Wilms tumor suppressor gene (WT1) is a zinc-finger-containing transcription factor that is coexpressed with NPHS1 in differentiated podocytes; gel shift binding assays demonstrate that a recombinant WT1 protein can bind and activate the 186-bp NPHS1 fragment in a sequence-specific manner	SIGNOR-252299
P61088	Q12933	2	ubiquitination	up-regulates activity	0.428	Intact ring and zinc finger domains are required for tnfalfa-induced traf2 ubiquitination, which is also dependent on ubc13. Traf2 ubiquitination coincides with its translocation to the insoluble cellular fraction, resulting in selective activation of jnk. Ubc13 expression by rnai resulted in tnfalfa-induced traf2 translocation and impaired activation of jnk but not of ikk or p38.	SIGNOR-121274
O75874	A8MYZ6	0	transcriptional regulation	up-regulates quantity by expression	0.2	We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH.	SIGNOR-260092
Q9NZQ7	Q99720	0	stabilization	up-regulates quantity by stabilization	0.2	We propose that Sigma1 is a ligand-operated scaffolding protein that promotes the stability, processing, assembly, and trafficking of specific proteins in the secretory pathway of cancer cells. In support of this hypothesis, we found that siRNA-mediated knockdown of Sigma1 resulted in a significant decrease in PD-L1 protein levels in triple-negative MDA-MB-231 breast cancer and androgen-independent PC3 prostate cancer cells	SIGNOR-274974
Q92995	Q9H1Y0	1	deubiquitination	up-regulates quantity by stabilization	0.274	Here, we identified USP13 as an essential deubiquitinase that stabilizes ATG5 in a process that depends on the PAK1 serine/threonine-protein kinase and which enhances autophagy and promotes IM resistance in GIST cells.	SIGNOR-275838
O95166	Q9NQX3	2	binding	up-regulates activity	0.561	The GABA(A)R-associated protein GABARAP was found to bind to the gamma2 subunit of GABA(A)Rs. Here we show that GABARAP interacts with gephyrin in both biochemical assays and transfected cells. Our data indicate that GABARAP-gephyrin interactions are not important for postsynaptic GABA(A)R anchoring but may be implicated in receptor sorting and/or targeting mechanisms.	SIGNOR-264971
O95988	P31751	2	binding	up-regulates	0.56	In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation.	SIGNOR-81716
P38405	P37288	2	binding	up-regulates activity	0.271	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-256948
P11309	P17612	0	phosphorylation	up-regulates activity	0.266	In this study, we found that PKCα stabilized and activated PIM-1L by phosphorylation at Ser65. The PIM-1L phosphorylation suppressed sotrastaurin-induced apoptosis. These findings suggest that PKCα promotes cell survival and proliferation by upregulating PIM-1L in acute myeloid leukemia.	SIGNOR-256153
O00571	P06730	2	binding	down-regulates activity	0.628	DDX3 is a human RNA helicase with plethoric functions. we identified translation initiation factor eukaryotic initiation factor 4E (eIF4E) as a DDX3-binding partner. Interestingly, DDX3 utilizes a consensus eIF4E-binding sequence YIPPHLR to interact with the functionally important dorsal surface of eIF4E in a similar manner to other eIF4E-binding proteins. Furthermore, cap affinity chromatography analysis suggests that DDX3 traps eIF4E in a translationally inactive complex by blocking interaction with eIF4G.	SIGNOR-269193
Q14814	P17661	1	transcriptional regulation	up-regulates quantity by expression	0.2	Ectopic expression of myogenin and a specific Mef2 isoform induced myogenic differentiation without activating endogenous MyoD expression. Under these conditions, the regulatory sequences of late gene loci were not in close proximity, and these genes were prematurely activated.	SIGNOR-241504
Q05639	P05771	0	phosphorylation	up-regulates activity	0.2	PKCβI phosphorylates eEF1A at Ser53.our proteomics exploration of cPKC signaling in the nuclei of C2C12 cells demonstrated that the up-regulation of eEF1A intranuclear content, evoked by insulin, is associated with an increase in the phosphorylation of the Ser53 residue of the protein.	SIGNOR-263166
Q7LBC6	P68431	1	demethylation	down-regulates activity	0.2	We have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. JHDM2A exhibits hormone-dependent recruitment to androgen-receptor target genes, resulting in H3K9 demethylation and transcriptional activation. Thus, our work identifies a histone demethylase and links its function to hormone-dependent transcriptional activation.	SIGNOR-266634
P43405	P06239	1	phosphorylation	down-regulates activity	0.592	Our experiments indicate that the TCR-induced activation of Erk2 depends on the function of SH2 domain of Lck and is reduced by phosphorylation of wild type Lck at Tyr192 or by mutation of this site to a negatively charged amino acid. Such dependence on the SH2 domain has also been reported for the bulk of TCR-induced tyrosine phosphorylation and activation of the interleukin 2 gene (26). Thus, phosphorylation of Lck at Tyr192 may represent a negative feedback mechanism in the interplay between Src and Syk family PTKs in TCR signaling	SIGNOR-246562
P78406	P52948	2	binding	up-regulates activity	0.882	Nup98 is a major interacting partner of Rae1 and known to beinvolved in mRNA export.	SIGNOR-260868
P78317	P08047	1	polyubiquitination	down-regulates quantity by destabilization	0.39	Here, we identified RNF4 as the ubiquitin E3 ligase of Sp1. From in vitro and in vivo experiments, we found that sumoylated Sp1 can recruit RNF4 as a ubiquitin E3 ligase that subjects sumoylated Sp1 to proteasomal degradation.	SIGNOR-272720
Q04206	P47710	0	phosphorylation	up-regulates	0.2	Phosphorylation of serine 529 of p65 is mediated by casein kinase ii, but is prevented in nonstimulated cells by the interaction with ikba	SIGNOR-171222
O14904	O15146	2	binding	up-regulates	0.399	we provide evidence that wnt9a and wnt11 bind directly to the extracellular domain of musk, to induce musk dimerization and subsequent tyrosine phosphorylation of the kinase	SIGNOR-195975
Q9Y5H9	Q9Y5H1	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-265691
P07949	P07949	2	phosphorylation	up-regulates	0.2	Mass spectrometric analysis revealed that ret tyr(900) was autophosphorylation site. Tyr900 can partially replace the function of tyr905 as a local switch for kinase activation	SIGNOR-148992
Q92974	P28482	0	phosphorylation	up-regulates	0.358	Importantly tnf-alpha enhanced the erk pathway-dependent phosphorylation of thr-678 of gef-h1 that was key for activation.	SIGNOR-184469
P35498	Q96PU5	0	ubiquitination	down-regulates quantity by destabilization	0.292	The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2).	SIGNOR-253457

P41970

Q16539

0

phosphorylation

up-regulates

0.379

Tcf sap-1a is efficiently phosphorylated by p38 map kinase in vitro and in vivo on the homologous residues ser381 and ser387. Mutation of these sites to alanine severely reduces c-fos sre-dependent transcription mediated by sap-1a and p38 map kinase.

SIGNOR-47685

P54756

P52797

2

binding

up-regulates

0.817

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-52381

P54646

Q9UQB8

1

phosphorylation

down-regulates

0.2

Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379 respectively) resulted in almost a complete loss of ampk phosphorylation in these proteins. Termination of irsp53 function is suggested to occur following cdc42 dissociation, kinase phosphorylation of t340 and t360, and subsequent 14-3-3 binding, which competes for sh3 partners, thus allowing filopodial retraction

SIGNOR-195102

P00533

Q9UM47

1

phosphorylation

up-regulates activity

0.593

Here, we report that treatment of EGFR mutated lung cancer cell lines with erlotinib, while showing robust cell death, enriches the ALDH+ stem like cells through EGFR dependent activation of Notch3.|We also find a kinase-dependent physical association between the Notch3 and EGFR receptors and tyrosine phosphorylation of Notch3.

SIGNOR-280002

P17252

Q6ZN44

1

phosphorylation

down-regulates quantity

0.2

We show that protein interacting with C-kinase 1 (PICK1) recruits activated protein kinase Cα (PKCα) to MycUNC5A at the plasma membrane, stimulating its endocytosis. We identify two PKCα phosphorylation sites at serines 408 and 587, as well as dileucine internalization motifs, which are required for this endocytosis.

SIGNOR-268180

Q8IU57

Q8IZJ0

2

binding

up-regulates

0.71

Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha.

SIGNOR-96206

P10721

Q14451

2

binding

up-regulates activity

0.584

We furthermore demonstrate that the adapter protein Grb2 is a specific binding partner for both phosphorylated Tyr-703 and phosphorylated Tyr-936, whereas the adapter protein Grb7 binds selectively to phosphorylated Tyr-936.

SIGNOR-248291

O15350

P17252

0

phosphorylation

up-regulates activity

0.2

Here, we report that p73 is able to induce cell cycle arrest independently of its amino-terminal transactivation domain, whereas this domain is crucial for p73 proapoptotic functions. its activity is regulated throughout the cell cycle and modified by protein kinase C-dependent phosphorylation at serine residue 388.

SIGNOR-276235

O95999

Q9BXL7

2

binding

up-regulates

0.845

Card11 cooperates with bcl10 in a card domain-dependent manner.;These results implicate card11 in factor- specific activation of nf-kappab

SIGNOR-93869

P35638

Q7Z570

0

transcriptional regulation

up-regulates quantity by expression

0.2

ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3).

SIGNOR-269464

P01106

Q96GD4

0

phosphorylation

up-regulates quantity by stabilization

0.373

AURKB directly phosphorylates MYC at serine 67, counteracting GSK3\u03b2-directed threonine 58 phosphorylation and subsequent FBXW7- mediated proteasomal degradation.

SIGNOR-279439

Q14247

Q05655

0

phosphorylation

up-regulates activity

0.246

Together these findings demonstrate that phosphorylation of cortactin on S405 and S418 residues is required for its interaction with WAVE2 in MCP1-induced cytoskeleton remodeling, facilitating HASMC migration. In addition, the MCP1-induced cortactin phosp

SIGNOR-260890

P78509

Q9Y5W3

0

transcriptional regulation

up-regulates quantity by expression

0.2

KLF2 transactivates the reelin promoter in K562 cells.

SIGNOR-266048

O95817

P11142

2

binding

up-regulates activity

0.788

Heat shock cognate protein 70 (Hsc70) regulates protein homeostasis through its reversible interactions with client proteins. Hsc70 has two major domains: a nucleotide-binding domain (NBD), that hydrolyzes ATP, and a substrate-binding domain (SBD), where clients are bound. Members of the BAG family of co-chaperones, including Bag1 and Bag3, are known to accelerate release of both ADP and client from Hsc70.

SIGNOR-254116

Q9NS23

Q13188

2

binding

up-regulates

0.697

Mst1/2 is also activated by binding to Ras association domain family (RASSF) proteins, possibly owing to alteration of Mst1/2 subcellular localization.

SIGNOR-175790

P60953

Q15811

0

guanine nucleotide exchange factor

up-regulates activity

0.848

Significantly, here we identify the long isoform of ITSN-1, which has Cdc42 GEF activity| We propose that GCC88 recruits ITSN-1-L to the TGN, which in turn activates Cdc42 at the trans-face of the Golgi (Figure 9A).

SIGNOR-260612

Q12824

P51532

2

binding

up-regulates activity

0.943

The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added.

SIGNOR-65438

P43405

P29353

1

phosphorylation

up-regulates

0.762

The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on sch1 (iso2).

SIGNOR-59635

P49675

P17676

0

transcriptional regulation

up-regulates quantity by expression

0.365

Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells.

SIGNOR-254046

Q15418

P30304

1

phosphorylation

down-regulates

0.366

Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b.

SIGNOR-202117

O43603

O95837

2

binding

up-regulates activity

0.311

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-257136

Q9HCE1

Q92900

2

binding

up-regulates activity

0.521

MOV10 has been shown to promote mRNA degradation by associating with UPF1, this activity requires the helicase activity of MOV10.

SIGNOR-261139

P55211

P12931

0

phosphorylation

up-regulates activity

0.373

As a result, we established that Src was able to directly phosphorylate caspase-9 at tyrosine 251, leading to elevated caspase-9 activity.

SIGNOR-272998

Q99453

Q96F44

0

ubiquitination

down-regulates

0.485

The e3 ubiquitin ligasetrim11mediates the degradation of congenital central hypoventilation syndrome-associated polyalanine-expandedphox2b.

SIGNOR-195878

P67775

P37840

1

dephosphorylation

down-regulates activity

0.332

α-Synuclein (α-Syn) is a key protein that accumulates as hyperphosphorylated aggregates in pathologic hallmark features of Parkinson's disease (PD) and other neurodegenerative disorders. Phosphorylation of this protein at serine 129 is believed to promote its aggregation and neurotoxicity, suggesting that this post-translational modification could be a therapeutic target. Here, we demonstrate that phosphoprotein phosphatase 2A (PP2A) dephosphorylates α-Syn at serine 129

SIGNOR-248635

P28562

P54646

0

phosphorylation

down-regulates quantity by destabilization

0.273

Taken together, these results imply that nicotine acts via AMPKα2 to phosphorylate MKP1 at Ser334, instigating MKP1 ubiquitination and proteasome-mediated degradation.

SIGNOR-276890

Q13591

Q9ULL4

2

binding

up-regulates activity

0.623

Plexin-B3 is a functional receptor for semaphorin 5A. Here we show that plexin-B3 is a high-affinity receptor specific for Sema5A. We further demonstrate that plexin-B3 activation by Sema5A mediates functional responses in plexin-B3-expressing cells (either fibroblasts, epithelial and primary endothelial cells).

SIGNOR-268373

P51812

O14649

1

phosphorylation

up-regulates activity

0.2

The chaperone protein, 14-3-3, binds to a critical phosphorylated serine in the channel c termini of k2p3.1 and k2p9.1 (ser(393) and ser(373), respectively) and overcomes retention in the endoplasmic reticulum by ?COP. We sought to identify the kinase responsible for phosphorylation of the terminal serine in human and rat variants of k2p3.1 and k2p9.1. Adopting a bioinformatic approach, three candidate protein kinases were identified: camp-dependent protein kinase, ribosomal s6 kinase, and protein kinase c.

SIGNOR-172470

O43186

P08047

2

binding

up-regulates activity

0.324

Zinc finger DNA-binding domains of both Sp1 and Sp3 interact with Crx. Sp4 and Sp1 produce much higher levels of transcriptional activation when co-transfected with Crx, they may additionally act by directly increasing the rate of transcriptional initiation by the general transcriptional apparatus through their activation domains.

SIGNOR-225336

P12931

P29320

2

binding

up-regulates

0.528

We propose src kinase as a downstream effector that mediates the neuron's response to eph receptor activation.

SIGNOR-58139

P63092

O00222

2

binding

up-regulates activity

0.44

MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits.

SIGNOR-264081

P52952

Q92833

2

binding

down-regulates activity

0.455

JMJ physically associates with Nkx2.5 and GATA4 in vitro and in vivo as determined by glutathione S-transferase pull-down and immunoprecipitation assays. we show that JMJ represses ANF gene expression by inhibiting transcriptional activities of Nkx2.5 and GATA4.

SIGNOR-224787

P24752

P29803

1

acetylation

down-regulates activity

0.2

We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1)

SIGNOR-267634

Q13191

P16333

2

binding

up-regulates activity

0.526

Activated Cbl and Cbl-b interacted with Crk-L, Zap-70, Nck, PLC-gamma

SIGNOR-236054

P21918

P63096

2

binding

up-regulates activity

0.289

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-257043

P14136

P60709

2

binding

up-regulates quantity

0.374

GFAP is the major cytoskeletal element and scaffold of astrocytes In astrocytes, GFAP has close interaction with F-actin molecularly and functionally.

SIGNOR-269271

Q5BJF6

P06493

0

phosphorylation

up-regulates activity

0.543

Phosphorylation of hCenexin1 at S796 is critical for the hCenexin1-Plk1 interaction.Here we show that a splice variant of hODF2 called hCenexin1, but not hODF2 itself, efficiently localizes to somatic centrosomes via a variant-specific C-terminal extension and recruits Plk1 through a Cdc2-dependent phospho-S796 motif within the extension. This interaction and Plk1 activity were important for proper recruitment of pericentrin and gamma-tubulin, and, ultimately, for formation of normal bipolar spindles.

SIGNOR-273584

P12318

P51451

0

phosphorylation

up-regulates activity

0.436

To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation.

SIGNOR-249312

P10415

P45983

0

phosphorylation

down-regulates

0.582

G(2)/m-phase cells proved more susceptible to death signals, and phosphorylation of bcl-2 appeared to be responsible, as a ser70ala substitution restored resistance to apoptosis. We noted that ask1 and jnk1 were normally activated at g(2)/m phase, and jnk was capable of phosphorylating bcl-2..

SIGNOR-72361

P59594

Q9BYF1

2

binding

down-regulates activity

0.2

Cell entry of severe acute respiratory syndrome coronavirus (SARS-CoV) is mediated by the viral spike (S) protein. Amino acids 319-510 on the S protein have been mapped as the receptor-binding domain (RBD), which mediates binding to the SARS-CoV receptor angiotensin converting enzyme 2 (ACE2) on SARS-CoV susceptible cells. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells.

SIGNOR-260283

Q9NZQ7

P49840

0

phosphorylation

down-regulates quantity by destabilization

0.2

We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal degradation following GSK3α-mediated phosphorylation of Ser279/Ser283. We identify ARIH1 as the E3 ubiquitin ligase responsible for targeting PD-L1 to degradation.

SIGNOR-277552

P43250

P08069

1

phosphorylation

down-regulates quantity by destabilization

0.306

GRK2 and GRK6 coimmunoprecipitate with IGF-1R and increase IGF-1R serine phosphorylation, promoting β-arrestin1 association. Using immunoprecipitation, confocal microscopy, and FRET analysis, we demonstrated β-arrestin/IGF-1R association to be transient for GRK2 and stable for GRK6. Using bioinformatic studies we identified serines 1248 and 1291 as the major serine phosphorylation sites of the IGF-1R. Targeted mutation of S1248 recapitulates GRK2 modulation, whereas S1291 mutation resembles GRK6 effects on IGF-1R signaling/degradation

SIGNOR-276412

P67775

O43815

2

binding

up-regulates activity

0.638

The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms

SIGNOR-261698

P31749

Q9BXL7

1

phosphorylation

up-regulates activity

0.522

Akt phosphorylates S637 and S645 in the linker region of Carma1

SIGNOR-276621

Q8IYT8

P06733

1

phosphorylation

down-regulates activity

0.2

Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).

SIGNOR-274037

P14598

P17252

0

phosphorylation

up-regulates

0.553

Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.

SIGNOR-89178

Q8TAP6

P53350

2

binding

down-regulates activity

0.433

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

SIGNOR-262731

P12931

P63096

2

binding

up-regulates activity

0.486

Here we demonstrate that Galphas and Galphai, but neither Galphaq, Galpha12 nor Gbetay, directly stimulate the kinase activity of downregulated c-Src

SIGNOR-256526

O75581

O94907

2

binding

down-regulates

0.904

We report that dkk-1 is a high-affinity ligand for lrp6 and inhibits wnt signaling by preventing fz-lrp6 complex formation induced by wnt. Dkk1 has been shown to inhibit wnt by binding to and antagonizing lrp5/6.

SIGNOR-109247

Q16539

Q6STE5

1

phosphorylation

up-regulates activity

0.368

P38 phosphorylates the baf60 subunit of the swi-snf chromatin remodelling complex, and p38 recruits this complex to differentiation-specific loci.

SIGNOR-176557

P19174

P63215

2

binding

up-regulates

0.2

Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance.

SIGNOR-199141

Q15417

P06241

0

phosphorylation

down-regulates activity

0.333

We identify, for the first time, tyrosine-phosphorylated calponin h3 within COS 7 cells, before and after their transfection with the pSV vector containing cDNA encoding the cytoplasmic, Src-related, tyrosine kinase, Fyn. we have localized the tyrosines phosphorylated without actin to Tyr261 in calponin h3 and to Tyr261 and Tyr182 in calponin h1. Tyrosine phosphorylation of calponins inhibits their binding to F-actin

SIGNOR-251159

P14921

Q9Y458

1

transcriptional regulation

up-regulates quantity by expression

0.2

TBX22 is an X-linked gene, which encodes a T-box-containing transcription factor. Loss-of-function mutation in the X-linked TBX22 promoter disrupts an ETS-1 binding site and leads to cleft palate. We first link the transcription factor ETS-1 to TBX22 pathway during embryonic palatogenesis.

SIGNOR-265565

Q92917

P22694

0

phosphorylation

up-regulates activity

0.307

Using yeast two-hybrid screening with the PKA Cβ2 subunit as bait we identified GPKOW, also known as MOS2 homolog or T54 protein, as an interaction partner for Cβ2.PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites.

SIGNOR-266298

P12931

P37173

1

phosphorylation

up-regulates

0.281

Tbetarii can also be phosphorylated by src, a non-rtk, on y284, which can serve as a docking site for the recruitment of grb2 and shc, thereby bridging tbetarii to mapk activation.

SIGNOR-182963

P17693

Q8NHL6

2

binding

up-regulates

0.77

Hla-g binds a limited repertoire of peptides and interacts with the inhibitory leukocyte ig-like receptors lir-1 and lir-2

SIGNOR-134180

Q14676

P16104

2

binding

up-regulates

0.2

Here, we demonstrate that mammalian mdc1/nfbd1 directly binds to phospho-h2ax (gammah2ax) by specifically interacting with the phosphoepitope at the gammah2ax carboxyl terminus.

SIGNOR-143377

Q8ND25

Q03135

1

polyubiquitination

down-regulates quantity by destabilization

0.364

The ubiquitin ligase ZNRF1 promotes caveolin-1 ubiquitination and degradation to modulate inflammation. ZNRF1 mediates CAV1 polyubiquitination at lysine 39 and promote CAV1 degradation to modulate TLR4-mediated immune response.

SIGNOR-272327

Q9UQL6

Q06413

2

binding

down-regulates

0.696

The histone deacetylase hdac-5, upon dephosphorylation and translocation to the nucleus, directly inactivates mef2, preventing myogenesis.

SIGNOR-84026

Q12770

Q12772

1

relocalization

up-regulates activity

0.901

SCAP contains two domains: an NH2-terminal membrane attachment domain with eight membrane-spanning helices (Nohturfft et al., 1998b) and a long COOH-terminal extension that contains multiple copies of a WD40 repeat sequence, which forms a propeller-like structure that binds to the COOH-terminal domains of the SREBPs, thereby permitting the escort function

SIGNOR-267502

Q13705

O95390

2

binding

up-regulates

0.625

Here we demonstrate using genetic and biochemical studies that actriib and its subfamily receptor, actriia, cooperatively mediate the gdf11 signal in patterning the axial vertebrae, and that gdf11 binds to both actriia and actriib, and induces phosphorylation of smad2

SIGNOR-95309

P00519

P37840

1

phosphorylation

up-regulates quantity

0.424

C-Abl interacts with alpha-synuclein and phosphorylates alpha-synuclein at Y39 (XREF_FIG) .

SIGNOR-279582

P06493

P05787

1

phosphorylation

up-regulates

0.248

With regard to k8 phosphorylation at ser-431, it increases dramatically upon stimulation of cells with epidermal growth factor (egf) or after mitotic arrest and is the major k8 phosphorylated residue after incubating k8 immunoprecipitates with mitogen-activated protein or cdc2 kinases.

SIGNOR-56054

P12931

P22681

0

ubiquitination

down-regulates quantity by destabilization

0.738

Cbl-b also targets active Src for degradation in cells, and Nedd4 similarly reverses Cbl mediated Src degradation.|Cbl-b also targets active Src for degradation in cells, and Nedd4 similarly reverses Cbl-mediated Src degradation

SIGNOR-278539

P07384

P49841

1

cleavage

up-regulates activity

0.297

Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase

SIGNOR-251586

Q27J81

O43791

2

binding

down-regulates activity

0.2

SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. It revealed that INF2 was ubiquitinated at least at 7 lysine residues (Fig 2I). Interestingly, 5 of 7 ubiquitin attachment sites are localized in a short stretch of sequence (amino acids 612–682) within the FH2 domain of INF2 (Fig 2J).

SIGNOR-272798

Q9H2G9

Q9H2K2

0

ADP-ribosylation

down-regulates quantity by destabilization

0.2

Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation.

SIGNOR-263384

P28482

2

phosphorylation

up-regulates activity

0.2

Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation.|

SIGNOR-249415

P31749

P08670

1

phosphorylation

up-regulates quantity by stabilization

0.647

The binding of akt (tail region) to vim (head region) results in vim ser39 phosphorylation enhancing the ability of vim to induce motility and invasion while protecting vim from caspase-induced proteolysis.

SIGNOR-252511

P00519

O00401

1

phosphorylation

up-regulates activity

0.55

Abl phosphorylates N-WASP on tyrosines 175 and 256. Phosphorylation at this site stabilizes the active conformation of N-WASP, resulting in comet tail elongation.

SIGNOR-251437

Q71U36

Q92949

0

transcriptional regulation

up-regulates quantity by expression

0.298

FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).

SIGNOR-266938

O43474

P40424

2

binding

up-regulates activity

0.479

We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4.

SIGNOR-267237

Q2M1P5

P10070

2

binding

up-regulates quantity by stabilization

0.586

Kif7 physically interacted with Gli transcription factors and controlled their proteolysis and stability, and acted both positively and negatively in Hh signaling.

SIGNOR-209611

Q9P212

P01112

1

guanine nucleotide exchange factor

up-regulates

0.578

The presence of a rasgef motif in the n terminus of plcepsilon suggests that plcepsilon can activate ras by acting as an exchange factor by promoting the exchange of gtp for bound gdp.

SIGNOR-82859

P01344

Q9H9Z2

0

translation regulation

up-regulates quantity by expression

0.397

Lin-28 binds IGF-2 mRNA and participates in skeletal myogenesis by increasing translation efficiency

SIGNOR-277339

Q9HCK8

Q92886

1

transcriptional regulation

down-regulates quantity

0.2

Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells

SIGNOR-268919

P10636-2

P05129

0

phosphorylation

down-regulates activity

0.27

We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs.

SIGNOR-275445

P12931

P52565

1

phosphorylation

down-regulates

0.399

We show here that src kinase binds and phosphorylates rhogdi both in vitro and in vivo at tyr156. analysis of rho gtpase-rhogdi complexes using in vitro assays of complexation and in vivo by coimmunoprecipitation analysis indicates that src-mediated phosphorylation of tyr156 causes a dramatic decrease in the ability of rhogdi to form a complex with rhoa, rac1, or cdc42.

SIGNOR-149282

O60500

P19544

0

transcriptional regulation

up-regulates quantity by expression

0.487

The Wilms tumor suppressor gene (WT1) is a zinc-finger-containing transcription factor that is coexpressed with NPHS1 in differentiated podocytes; gel shift binding assays demonstrate that a recombinant WT1 protein can bind and activate the 186-bp NPHS1 fragment in a sequence-specific manner

SIGNOR-252299

P61088

Q12933

2

ubiquitination

up-regulates activity

0.428

Intact ring and zinc finger domains are required for tnfalfa-induced traf2 ubiquitination, which is also dependent on ubc13. Traf2 ubiquitination coincides with its translocation to the insoluble cellular fraction, resulting in selective activation of jnk. Ubc13 expression by rnai resulted in tnfalfa-induced traf2 translocation and impaired activation of jnk but not of ikk or p38.

SIGNOR-121274

O75874

A8MYZ6

0

transcriptional regulation

up-regulates quantity by expression

0.2

We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH.

SIGNOR-260092

Q9NZQ7

Q99720

0

stabilization

up-regulates quantity by stabilization

0.2

We propose that Sigma1 is a ligand-operated scaffolding protein that promotes the stability, processing, assembly, and trafficking of specific proteins in the secretory pathway of cancer cells. In support of this hypothesis, we found that siRNA-mediated knockdown of Sigma1 resulted in a significant decrease in PD-L1 protein levels in triple-negative MDA-MB-231 breast cancer and androgen-independent PC3 prostate cancer cells

SIGNOR-274974

Q92995

Q9H1Y0

1

deubiquitination

up-regulates quantity by stabilization

0.274

Here, we identified USP13 as an essential deubiquitinase that stabilizes ATG5 in a process that depends on the PAK1 serine/threonine-protein kinase and which enhances autophagy and promotes IM resistance in GIST cells.

SIGNOR-275838

O95166

Q9NQX3

2

binding

up-regulates activity

0.561

The GABA(A)R-associated protein GABARAP was found to bind to the gamma2 subunit of GABA(A)Rs. Here we show that GABARAP interacts with gephyrin in both biochemical assays and transfected cells. Our data indicate that GABARAP-gephyrin interactions are not important for postsynaptic GABA(A)R anchoring but may be implicated in receptor sorting and/or targeting mechanisms.

SIGNOR-264971

O95988

P31751

2

binding

up-regulates

0.56

In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation.

SIGNOR-81716

P38405

P37288

2

binding

up-regulates activity

0.271

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-256948

P11309

P17612

0

phosphorylation

up-regulates activity

0.266

In this study, we found that PKCα stabilized and activated PIM-1L by phosphorylation at Ser65. The PIM-1L phosphorylation suppressed sotrastaurin-induced apoptosis. These findings suggest that PKCα promotes cell survival and proliferation by upregulating PIM-1L in acute myeloid leukemia.

SIGNOR-256153

O00571

P06730

2

binding

down-regulates activity

0.628

DDX3 is a human RNA helicase with plethoric functions. we identified translation initiation factor eukaryotic initiation factor 4E (eIF4E) as a DDX3-binding partner. Interestingly, DDX3 utilizes a consensus eIF4E-binding sequence YIPPHLR to interact with the functionally important dorsal surface of eIF4E in a similar manner to other eIF4E-binding proteins. Furthermore, cap affinity chromatography analysis suggests that DDX3 traps eIF4E in a translationally inactive complex by blocking interaction with eIF4G.

SIGNOR-269193

Q14814

P17661

1

transcriptional regulation

up-regulates quantity by expression

0.2

Ectopic expression of myogenin and a specific Mef2 isoform induced myogenic differentiation without activating endogenous MyoD expression. Under these conditions, the regulatory sequences of late gene loci were not in close proximity, and these genes were prematurely activated.

SIGNOR-241504

Q05639

P05771

0

phosphorylation

up-regulates activity

0.2

PKCβI phosphorylates eEF1A at Ser53.our proteomics exploration of cPKC signaling in the nuclei of C2C12 cells demonstrated that the up-regulation of eEF1A intranuclear content, evoked by insulin, is associated with an increase in the phosphorylation of the Ser53 residue of the protein.

SIGNOR-263166

Q7LBC6

P68431

1

demethylation

down-regulates activity

0.2

We have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. JHDM2A exhibits hormone-dependent recruitment to androgen-receptor target genes, resulting in H3K9 demethylation and transcriptional activation. Thus, our work identifies a histone demethylase and links its function to hormone-dependent transcriptional activation.

SIGNOR-266634

P43405

P06239

1

phosphorylation

down-regulates activity

0.592

Our experiments indicate that the TCR-induced activation of Erk2 depends on the function of SH2 domain of Lck and is reduced by phosphorylation of wild type Lck at Tyr192 or by mutation of this site to a negatively charged amino acid. Such dependence on the SH2 domain has also been reported for the bulk of TCR-induced tyrosine phosphorylation and activation of the interleukin 2 gene (26). Thus, phosphorylation of Lck at Tyr192 may represent a negative feedback mechanism in the interplay between Src and Syk family PTKs in TCR signaling

SIGNOR-246562

P78406

P52948

2

binding

up-regulates activity

0.882

Nup98 is a major interacting partner of Rae1 and known to beinvolved in mRNA export.

SIGNOR-260868

P78317

P08047

1

polyubiquitination

down-regulates quantity by destabilization

0.39

Here, we identified RNF4 as the ubiquitin E3 ligase of Sp1. From in vitro and in vivo experiments, we found that sumoylated Sp1 can recruit RNF4 as a ubiquitin E3 ligase that subjects sumoylated Sp1 to proteasomal degradation.

SIGNOR-272720

Q04206

P47710

0

phosphorylation

up-regulates

0.2

Phosphorylation of serine 529 of p65 is mediated by casein kinase ii, but is prevented in nonstimulated cells by the interaction with ikba

SIGNOR-171222

O14904

O15146

2

binding

up-regulates

0.399

we provide evidence that wnt9a and wnt11 bind directly to the extracellular domain of musk, to induce musk dimerization and subsequent tyrosine phosphorylation of the kinase

SIGNOR-195975

Q9Y5H9

Q9Y5H1

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-265691

P07949

2

phosphorylation

up-regulates

0.2

Mass spectrometric analysis revealed that ret tyr(900) was autophosphorylation site. Tyr900 can partially replace the function of tyr905 as a local switch for kinase activation

SIGNOR-148992

Q92974

P28482

0

phosphorylation

up-regulates

0.358

Importantly tnf-alpha enhanced the erk pathway-dependent phosphorylation of thr-678 of gef-h1 that was key for activation.

SIGNOR-184469

P35498

Q96PU5

0

ubiquitination

down-regulates quantity by destabilization

0.292

The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2).

SIGNOR-253457