GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels float64 0 2	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
Q07912	P10275	1	phosphorylation	up-regulates activity	0.545	Ack1 interacted with and phosphorylated AR protein at Tyr 267 and Ack1 was shown to be required for optimal AR target gene expression and AR recruitment.\|Two intracellular tyrosine kinases, Ack1 (activated cdc42 associated kinase) and Src, phosphorylate and enhance AR activity and promote prostate xenograft tumor growth in castrated animals.	SIGNOR-278194
P07948	Q06187	1	phosphorylation	up-regulates	0.545	Phosphorylation at y551 requires lyn kinase activity, indicating that y551 is a transphosphorylation site \ this transphosphorylation at y551 is followed by phosphorylation at a second site, which is dependent on btk catalytic activity.	SIGNOR-41607
P68400	Q6VY07	1	phosphorylation	up-regulates activity	0.545	Phosphorylation of Ser278 by CK2 or a Ser278-->Asp mutation increased the interaction between PACS-1 and cargo, whereas a Ser278-->Ala substitution decreased this interaction. Moreover, the Ser278-->Ala mutation yields a dominant-negative PACS-1 molecule that selectively blocks retrieval of PACS-1-regulated cargo molecules to the TGN.	SIGNOR-250925
Q07812	Q9NR28	1	relocalization	up-regulates	0.545	Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi	SIGNOR-87109
Q96SN8	O43379	1	relocalization	up-regulates activity	0.545	Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome.	SIGNOR-271723
Q6W2J9	Q99496	1	binding	up-regulates activity	0.545	BcoR and Fbxl10/Jhdm1B are among the most abundant Ring1B/Rnf2 interactors identified with the highest confidence, and their association has been validated by coimmunoprecipitation studies; hence we call this the Fbxl10-BcoR complex. In summary, we have widened the set of multiprotein complexes containing the Polycomb group protein Ring1B/Rnf2. The new interactors contain protein motifs whose enzymatic activities and binding properties would expand the regulatory potential and gene target diversity of Ring1B/Rnf2 complexes in terms of recruitment to and modification of chromatin	SIGNOR-252241
O95628	P41229	1	ubiquitination	down-regulates quantity by destabilization	0.545	In our study, we show that the protein level of the yeast histone H3 Lys 4 (H3 K4) demethylase Jhd2/Kdm5 is modulated through polyubiquitination by the E3 ubiquitin ligase Not4 and turnover by the proteasome. Finally, we show that human NOT4 can polyubiquitinate human JARID1C/SMCX, a homolog of Jhd2, suggesting that this is likely a conserved mechanism. We propose that Not4 is an E3 ubiquitin ligase that monitors and controls a precise amount of Jhd2 protein so that the proper balance between histone demethylase and histone methyltransferase activities occur in the cell, ensuring appropriate levels of H3 K4 trimethylation and gene expression.	SIGNOR-271468
P23471	Q9UM73	1	dephosphorylation	down-regulates	0.545	Rptpbeta/zeta dephosphorylates alk at the site(s) in alk that is undergoing autophosphorylation through autoactivation.	SIGNOR-157227
Q96N67	P63000	1	guanine nucleotide exchange factor	up-regulates activity	0.545	As a GEF, Dock7 exchanges GDP for GTP on Cdc42 and Rac1, causing their activation, followed by activation of downstream effectors, including the dephosphorylation (activation) of cofilin, a key regulator of actin turnover.	SIGNOR-261887
Q9Y5Z0	P05067	1	cleavage	up-regulates activity	0.544	BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.\|Figure 6 Preferred BACE1 and BACE2 cleavage sites. (A) Sequence of APP indicating Î±- and Î²-cleavage sites, BACE1- and BACE2-cleavage sites, and the location of mutations analyzed here. APP numbering is that of the 770-aa isoform.	SIGNOR-261773
O15111	Q9NQC7	1	phosphorylation	up-regulates activity	0.544	The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.	SIGNOR-204692
Q86XK2	Q9NZJ0	1	binding	down-regulates	0.544	We determined that the f-box protein fbxo11 interacts with cdt2,a dcaf protein that controls cell-cycle progression, and recruits cdt2 to the scf(fbxo11)complex to promote its proteasomal degradation.	SIGNOR-192325
Q9Y297	P46937	1	ubiquitination	down-regulates	0.544	This cascade of phosphorylation allows the binding of scfbetatrcp that promotes the ubiquitination and degradation of yap.	SIGNOR-201138
P01106	P25490	2	binding	down-regulates activity	0.544	Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc.Yin-Yang-1 (YY1) regulates the transcription of many genes, including the oncogenes c-fos and c-myc. Depending on the context, YY1 acts as a transcriptional repressor, a transcriptional activator, or a transcriptional initiator. In cotransfections, c-Myc inhibits both the repressor and the activator functions of YY1, which suggests that one way c-Myc acts is by modulating the activity of YY1.	SIGNOR-268795
Q05209	Q14289	1	dephosphorylation	down-regulates activity	0.544	Inhibition of the catalytic activity of cell adhesion kinase beta by protein-tyrosine phosphatase-pest-mediated dephosphorylation. / dephosphorylation of tyr402 and tyr579/580 by ptp-pest	SIGNOR-107502
Q13131	Q53ET0	1	phosphorylation	down-regulates	0.544	Collectively, these findings suggest ampk suppresses glucose production through two transcriptional effects:reduced expression of creb targets via crtc inactivation and reduced expression of foxo target genes via class iia hdac inactivation	SIGNOR-176426
Q9UI95	Q9UM11	1	binding	down-regulates activity	0.544	The APC is activated in mitosis and G1 by CDC20 and CDH1, and inhibited by the checkpoint protein MAD2, a specific inhibitor of CDC20. We show here that a MAD2 homolog MAD2B also inhibits APC. MAD2B directly inhibits activation of APC by CDC20 and CDH1	SIGNOR-264902
Q96QT4	P04083	1	phosphorylation	up-regulates	0.544	Trpm7 was responsible for phosphorylation of the serine 5 (ser5) residue [29]. In 2009, the study focused on an association between anxa1 and trpm7 confirmed the presence of a trpm7/annexin a1/mg2_+ complex, suggesting a novel pathway in bradykinin signaling, dependent on pkc and c-src [30]. Even though that pathway is not fully characterized, the same team that discovered the ser5 phosphorylation of anxa1 also reported crucial relevance of this modification for anxa1 membrane binding and especially for the interaction between annexin a1 and its known partner, the calcium binding protein s100a11	SIGNOR-202804
Q92633	P50148	1	binding	up-regulates activity	0.544	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-257091
P68036	P46934	1	ubiquitination	up-regulates activity	0.544	Only UbcH5 and Related Class I E2s Support Ubiquitination of S5a—UbcH5 belongs to the Class I family of E2s which contains a catalytic core (UBC domain) without a distinct Ub binding domain (38). To test whether other Class I E2s can also support ubiquitination of S5a, we assayed the ubiquitination of S5a with UbcH7 and the E3s, Nedd4, or Parkin. With either of these E3s, UbcH7 supported ubiquitination of S5a (Fig. 8, A and B). In addition, another Class I E2, Ubc4, a close homolog of UbcH5, supported ubiquitination of S5a by the APC, a multimeric Ring finger E3 responsible for cell cycle progression through mitosis (39) (Fig. 8C). Thus, multiple Class I E2s can support ubiquitination of S5a by various types of E3s (Table 1).	SIGNOR-272735
Q9ULX6	Q08211	1	binding	up-regulates activity	0.544	We report evidence for a novel nuclear export signal in HAP95 and showed that the domains involved in RHA binding and nuclear localization are required for CTE activation. Finally, we showed that HAP95 synergizes significantly with RHA on CTE-mediated reporter gene expression and promotes nuclear export of unspliced mRNA in transfected cells. Taken together, these data support the proposal that HAP95 specifically facilitates CTE-mediated gene expression by directly binding to RHA.	SIGNOR-260950
Q92823	P16157	1	relocalization	up-regulates quantity	0.544	Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.	SIGNOR-266721
P06241	Q07666	1	phosphorylation	up-regulates activity	0.544	The tyrosine kinase Fyn modulates Sam68 mediated alternative splicing of Bcl-x mRNA.\|Tyrosine phosphorylation of Sam68 by Fyn inverted this effect and favored the Bcl-x(L) splice site selection.	SIGNOR-279462
P25490	P01106	2	transcriptional regulation	down-regulates quantity by repression	0.544	Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc.Yin-Yang-1 (YY1) regulates the transcription of many genes, including the oncogenes c-fos and c-myc. Depending on the context, YY1 acts as a transcriptional repressor, a transcriptional activator, or a transcriptional initiator. In cotransfections, c-Myc inhibits both the repressor and the activator functions of YY1, which suggests that one way c-Myc acts is by modulating the activity of YY1.	SIGNOR-268794
P18075	Q13705	1	binding	up-regulates	0.544	We show that bmp7 and activin bind to the same type ii receptors, actrii and iib, but recruit distinct type i receptors into heteromeric receptor complexes.	SIGNOR-60240
Q70E73	Q8N8S7	1	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
P45452	P02458	1	cleavage	down-regulates quantity by destabilization	0.544	Although it appears that MMP-1 and MMP-13 both cleave type II collagen initially at the same site, MMP-13 affects a secondary cleavage to produce a 1/4-size collagen fragment with an NH2 terminus three amino acids removed from the primary cleavage site.The present work has demonstrated expression of MMP-13 in human osteoarthritic cartilage and shown that MMP-13 has significant type II collagen degrading activity.	SIGNOR-256340
Q8WWW0	Q9NS23	1	binding	up-regulates activity	0.543	NORE1A can heterodimerize with RASSF1A and, thus, mediate K-Ras regulation of RASSF1A	SIGNOR-249587
Q9Y371	Q14457	1	binding	up-regulates	0.543	Bif-1 forms a complex with beclin1 through uvrag and promotes the activation of the class iii pi3 kinase, vps34, in mammalian cells.	SIGNOR-171899
Q7Z5H3	P60953	1	gtpase-activating protein	down-regulates activity	0.543	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-260478
P84022	P46531	1	binding	up-regulates	0.543	Nicd and smad3 were shown to interact directly, both in vitro and in cells, in a ligand-dependent manner, and smad3 could be recruited to csl-binding sites on dna in the presence of csl and nicd	SIGNOR-119374
O00444	Q969U6	1	phosphorylation	down-regulates activity	0.543	The activity of SCF-FBXW5 is in turn negatively regulated by Polo-like kinase 4 (PLK4), which phosphorylates FBXW5 at Ser 151 to suppress its ability to ubiquitylate HsSAS-6.	SIGNOR-275476
Q9UPQ7	O15146	1	ubiquitination	down-regulates quantity	0.543	We have identified a PDZ domain containing RING finger 3 (PDZRN3) as a synapse-associated E3 ubiquitin ligase and have demonstrated that it regulates the surface expression of muscle-specific receptor tyrosine kinase (MuSK), the key organizer of postsynaptic development at the mammalian neuromuscular junction. PDZRN3 binds to MuSK and promotes its ubiquitination. Together, these data demonstrate that PDZRN3 is a catalytically active RING-type E3 ubiquitin ligase	SIGNOR-271664
O43312	P08151	1	binding	up-regulates	0.543	Mim is a shh-responsive gene that can potentiate gli transcriptional activity.MIM Appears to regulate target gene expression through its association with the gli complex	SIGNOR-157650
P15531	Q8IVT5	1	phosphorylation	down-regulates	0.543	Autophosphorylated recombinant nm23-h1 phosphorylated ksr in vitro. Using site-directed mutagenesis, we found that nm23-h1 phosphorylated ksr serine 392, a 14-3-3-binding site, consistent with the recent identification of c-tak1 as a kinase for this site.	SIGNOR-90390
P00519	Q9H3D4	1	phosphorylation	up-regulates quantity by stabilization	0.543	In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters.	SIGNOR-260934
P06493	Q5BJF6	1	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
P07949	Q13322	1	binding	up-regulates	0.543	Grb7 and grb10, likely relay signals emanating from ret to other, as yet, unidentified targets within the cell	SIGNOR-41699
Q15418	P67809	1	phosphorylation	up-regulates	0.543	We therefore conclude that rsk1/rsk2 are novel activators of yb-1, able to phosphorylate the serine 102 residue.	SIGNOR-182497
P41143	P63096	1	binding	up-regulates activity	0.543	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-256683
P46695	Q13362	1	binding	down-regulates	0.542	Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit.	SIGNOR-144309
P25101	P50148	1	binding	up-regulates	0.542	The response to endothelin-1 (et-1) consisted of two phases in both cell types. The initial, transient phase of contraction and phosphorylation of 20-kda myosin light chain (mlc20) was mediated additively by eta and etb receptors and initiated by galphaq-, ca2+/calmodulin-dependent activation of mlc kinase.	SIGNOR-129817
Q06187	O43516	1	phosphorylation	up-regulates activity	0.542	Based on previous reports and the present data we suggest that Btk can induce WASP activation and also facilitates its subsequent inactivation through WIP phosphorylation.\|We confirmed that Btk can indeed phosphorylate Y468 of baculovirus-generated human His-tagged WIP ( xref ), but that this is more difficult to show in cell extracts where WIP would be purified along with cellular WASP ().	SIGNOR-279801
Q9UKB1	P25963	1	ubiquitination	down-regulates	0.542	We report here the identification of an ikappab-ubiquitin (ub) ligase complex containing the f-box/wd40-repeat protein, beta-trcp, a vertebrate homolog of drosophila slimb. beta-trcp binds to ikappabalpha only when the latter is specifically phosphorylated by an ikappab kinase complex. here we provide evidence that lysine residues 21 and 22 serve as the primary sites for signal-induced ubiquitination of i kappa b alpha.	SIGNOR-64317
P17612	Q92934	1	phosphorylation	down-regulates	0.542	Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo.	SIGNOR-67387
P27361	O75030	1	phosphorylation	down-regulates quantity by destabilization	0.542	More interestingly, ERK-dependent phosphorylation of MITF at Ser 73 is essential for MITF ubiquitinilation and degradation (87). Putting together all these findings, it can be proposed that MAPK activation inhibits melanogenesis due to an increased MITF degradation which is dependent on the MAPK-induced MITF phosphorylation and ubiquitinilation. In summary, although the phosphorylation of MITF at Ser73 increases its intrinsic transcriptional activity, this phosphorylation also targets MITF to the proteasome for its degradation. Consequently, the decrease in MITF levels leads to a down-regulation of melanogenic enzymes expression and to an inhibition of melanogenesis.	SIGNOR-249620
Q05209	P12931	1	dephosphorylation	up-regulates activity	0.542	PTP-PEST increases dephosphorylation of Src at Y527 and activates it.\|The data presented here supports our hypothesis that PTP-PEST activates Src via dephosphorylating it at Y527 (Tyr530 in human c-Src equivalent to Tyr527 in chicken Src).	SIGNOR-277086
P62136	Q9GZV5	1	dephosphorylation	up-regulates activity	0.542	PP1A dephosphorylates TAZ at Ser-89 and Ser-311, promotes TAZ nuclear translocation, and stabilizes TAZ by disrupting the binding to the SCF E3 ubiquitin ligase.	SIGNOR-277116
P53778	P15336	1	phosphorylation	up-regulates	0.542	Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target	SIGNOR-65589
Q9Y243	Q92934	1	phosphorylation	down-regulates	0.542	Ser-136 is the major phosphoacceptor site for akt;akt can weakly phosphorilate ser-155.	SIGNOR-81122
P12931	Q9Y2X7	1	phosphorylation	up-regulates activity	0.542	Tyrosines 246 and 293 are required to hold GIT1 in a closed conformation.Hyperphosphorylation of GIT1-N by Src and pervanadate does not affect its binding in vitro to full length GIT1 proteins. Mutations Y246E and Y293E of GIT1 enhance binding to paxillin.	SIGNOR-276627
P27361	P04150	1	phosphorylation	down-regulates	0.542	Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.\|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action.	SIGNOR-154409
Q9UPT6	Q13233	1	binding	up-regulates	0.542	Overexpression of full-length jsap1 in cos-7 cells led to a considerable enhancement of jnk3 activation, and modest enhancement of jnk1 and jnk2 activation, by the mekk1-sek1 pathwaythe regions of jsap1 that bound jnk, sek1, and mekk1 were distinct from one another. Jnk and mekk1 also bound jsap1 in vitro, suggesting that these interactions are direct.	SIGNOR-71471
Q8N6P7	P29597	1	binding	up-regulates	0.542	Il-22 activates jak1 and tyk2	SIGNOR-90165
Q99708	Q96T58	1	binding	down-regulates	0.542	We identify the ctip and ctbp corepressors as novel components of the human rbp-jk/sharp-corepressor complex and show that ctip binds directly to the sharp repression domain.	SIGNOR-141616
Q13315	Q9NUW8	1	phosphorylation	up-regulates	0.542	Optimal function of the dna repair enzyme tdp1 requires its phosphorylation by atm and/or dna-pk. Here we show that top1-associated dna double-stranded breaks (dsbs) induce the phosphorylation of tdp1 at s81. This phosphorylation is mediated by the protein kinases: ataxia-telangiectasia-mutated (atm) and dna-dependent protein kinase (dna-pk)	SIGNOR-188772
Q9UBV4	O75581	1	binding	up-regulates	0.542	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131677
Q9UBS3	P11021	1	binding	up-regulates activity	0.542	When BAP was added to BiP (2:1 molar ratio of BAP:BiP), it increased the ATPase activity of BiP by about 2-fold, which was similar to the increase observed when the J domain of ERdj4 was added to BiP (Fig.5). When both BAP and the J domain were added to BiP, the rate of ATP hydrolysis by BiP was stimulated by about 4-fold over basal levels, indicating that both BAP and ERdj4 positively regulate the ATPase activity of BiP	SIGNOR-261044
P05412	P01137	1	transcriptional regulation	up-regulates quantity by expression	0.542	MAPKs have cis-acting regulatory elements in the mouse-TGF promoter region, which respond to various transcription factors, including specificity protein-1 and activating protein 1. Thus, it is possible that apoptotic cell-induced TGF-beta mRNA expression is mediated through activation of these transcription factors via MAPK signaling. Xiao et al. reported that all of the MAPK members, including p38/ERK/JNK, are required for apoptotic Jurkat cells up-regulation of TGF-beta production	SIGNOR-251713
Q14004	P24928	1	phosphorylation	up-regulates activity	0.541	Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.\|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence	SIGNOR-273054
P06239	P06127	1	phosphorylation	up-regulates activity	0.541	Tyrosine phosphorylation of cd5 requires lck activity. We propose that t cell activation mediates cd5 tyrosine phosphorylation at residues y429 and y463 mainly through the activation of lck	SIGNOR-106799
P21554	P08754	1	binding	up-regulates activity	0.541	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-256867
P63096	O43306	1	binding	down-regulates activity	0.541	Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3	SIGNOR-278077
P08709	P00742	2	binding	up-regulates activity	0.541	TF has a high affinity for FVII and enables the trace levels (∼1% of the total FVII) of activated FVII (FVIIa) in the blood to cleave specific sites in the serine proteases FIX and FX, activating them into FIXa and FXa, respectively.	SIGNOR-263545
O14965	P25963	1	phosphorylation	down-regulates activity	0.541	The results of the in vitro kinase assay, using purified human recombinant AURKA and IkappaBalpha proteins, confirmed that AURKA can directly phosphorylate IkappaBalpha (Ser32) at a concentration as low as 2.5 ng/mul (XREF_FIG).\|While an earlier study suggested that AURKA down-regulates IkappaBalpha indirectly through activation of the PI3K and AKT pathway 35, our data demonstrate, for the first time, that AURKA directly binds and phosphorylates the IkappaBalpha subunit, leading to activation of NF-kappaB.	SIGNOR-278912
P21554	P63096	1	binding	up-regulates activity	0.541	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-256724
Q13459	P63000	1	gtpase-activating protein	down-regulates activity	0.541	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-260510
Q9UHD2	Q13568	1	phosphorylation	up-regulates	0.541	Activation of interferon regulatory factor 5 by site specific phosphorylation. Although the gene induction by irf5 in the presence of tbk-1 was modest, phosphorylation by tbk-1 produced a significant shift in the mobility of irf5 in sds-page. For this reason we identified the residues that are phosphorylated on irf5 by tbk-1 with mass spectrometry. Ser-158 and ser-309 were found to be phosphorylated	SIGNOR-196528
P45984	Q13469	1	phosphorylation	down-regulates	0.541	Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin	SIGNOR-118223
P0DP24	Q96RR4	1	binding	up-regulates	0.541	The ca2+-calmodulin-dependent protein kinase (cam kinase) cascade includes three kinases: cam-kinase kinase (camkk);and the cam kinases camki and camkiv, which are phosphorylated and activated by camkk.	SIGNOR-266329
P28827	O60716	1	dephosphorylation	down-regulates quantity	0.541	Specifically, RPTP\u03bc dephosphorylated p120 catenin, subsequently leading to a lower level of cytoplasmic protein compared with that observed with the vector control and RPTP\u03bc-CS.	SIGNOR-277042
P00742	P08709	2	cleavage	up-regulates activity	0.541	The factor VII zymogen is cleaved at arginine 152 by a variety of proteases, including thrombin, factor IXa, factor Xa, and factor VIIa–tissue factor to produce the serine protease factor VIIa.	SIGNOR-263523
Q96HW7	P24928	1	binding	up-regulates activity	0.541	The Integrator Complex Can Directly Associate with the C-Terminal Domain of RNA Polymerase II Largest Subunit	SIGNOR-261185
O00221	P19838	1	binding	down-regulates	0.541	Nf-kb is normally sequestered in the cell cytoplasm by binding to ikbx, ikbb, ikbe	SIGNOR-102774
P53041	P04150	1	dephosphorylation	down-regulates activity	0.541	Estrogen inhibits glucocorticoid action via protein phosphatase 5 (PP5)-mediated glucocorticoid receptor dephosphorylation.\|Inhibition of GR phosphorylation at Ser-211 is associated with decreased nuclear retention of GR and decreased gene transcription.	SIGNOR-248538
Q9Y3C5	Q9HAU4	1	binding	up-regulates activity	0.54	RNF11 recruits AMSH to Smurf2 E3 ligase. Smurf2 promotes ubiquitination of AMSH in the presence of wt RNF11. Previously, we have shown that RNF11 interacts with the HECT-type E3 ligases AIP4 and Smurf2. Here, we show that RNF11 binds to AMSH in mammalian cells and that this interaction is independent of the RNF11 RING-finger domain and the PY motif. Our results also demonstrate that AMSH is ubiquitinated by Smurf2 E3 ligase in the presence of RNF11 and that a consequent reduction in its steady-state level requires both RNF11 and Smurf2. RNF11 therefore recruits AMSH to Smurf2 for ubiquitination, leading to its degradation by the 26S proteasome.	SIGNOR-272952
Q02363	P15172	1	binding	down-regulates activity	0.54	Id1 and Id2 interacted strongly with MyoD and Myf-5.Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-240268
P06493	Q9UNH5	1	phosphorylation	up-regulates activity	0.54	We found that Cdc14A is phosphorylated on Ser411, Ser453 and Ser549 by Cdk1 early in mitosis and becomes dephosphorylated during late mitotic stages.	SIGNOR-278264
Q15910	P10275	1	binding	up-regulates activity	0.54	This study demonstrates that phosphorylation of EZH2 at Ser21, mediated directly or indirectly by the PI3K-Akt pathway, can switch its function from a Polycomb repressor to a transcriptional coactivator of AR (and potentially other factors).	SIGNOR-251542
P62258	P46527	1	binding	down-regulates	0.54	14-3-3_, 14-3-3_, and 14-3-3_ (but not 14-3-3_ and 14-3-3_) could form a complex with p27kip1 / we discovered that akt-mediated p27kip1phosphorylation directly induces p27kip1binding to 14-3-3 and cytoplasmic localization through phosphorylating the newly identified thr198residue.	SIGNOR-88297
P51151	Q8IWJ2	1	null	up-regulates activity	0.54	Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector	SIGNOR-253087
Q99933	Q9UNE7	1	binding	up-regulates activity	0.54	BAG-1 stimulates CHIP-induced degradation of the glucocorticoid hormone receptor (GR). A model for the cooperation of CHIP and BAG-1 in coupling Hsc/Hsp70 to the ubiquitin/proteasome system. CHIP associates with Hsc/Hsp70 via its TPR chaperone adaptor (TPR) and, at the same time, recruits E2 ubiquitin-conjugating enzymes of the Ubc4/5 family to the chaperone complex. BAG-1 binds to Hsp70 via its BAG domain (BAG) and utilizes its ubiquitin-like domain (ubl) for proteasomal association	SIGNOR-272587
Q8TDJ6	Q15042	1	binding	up-regulates quantity	0.54	We isolated here a novel protein that was co-immunoprecipitated with Rab3 GEP and GAP by their respective antibodies from the crude synaptic vesicle fraction of rat brain. The protein, named rabconnectin-3, bound both Rab3 GEP and GAP. These results indicate that rabconnectin-3 serves as a scaffold molecule for both Rab3 GEP and GAP on synaptic vesicles.	SIGNOR-265582
Q13164	P17302	1	phosphorylation	down-regulates activity	0.54	Activated BMK1 selectively phosphorylates Cx43 on Ser-255 in vitro and in vivo. These data demonstrate that BMK1 kinase activity alone is both a necessary and sufficient component in the mediation of EGF-induced Cx43 Ser-255 phosphorylation and subsequent inhibition of GJC.	SIGNOR-250115
P49841	P04150	1	phosphorylation	down-regulates activity	0.54	We found hormone-dependent GR phosphorylation on serine 404 by GSK-3beta [ ]Cells expressing a GR that is incapable of GSK-3beta phosphorylation had a redirection of the global transcriptional response to hormone, including the activation of additional signaling pathways, in part due to the altered ability of unphosphorylatable GR to recruit transcriptional cofactors CBP/p300 and the p65 (RelA) subunit of NF-kappaB	SIGNOR-181541
O15111	Q13546	1	phosphorylation	down-regulates activity	0.54	Indeed, IKKa and IKKb may directly repress RIPK1 kinase activity by addition of an inhibitory phosphate group on RIPK1.\|Mass spectrometry analysis of kinase assays performed with recombinant proteins allowed us to identify Ser166, Ser331, and Ser416 as highly conserved RIPK1 residues phosphorylated by IKKa and IKKb.	SIGNOR-278927
P51449	Q16552	1	transcriptional regulation	up-regulates	0.54	We found that RORgt is required for the constitutive expression of IL-17 in intestinal lamina propria T cells and for the in vitro differentiation of Th17 cells from naive CD4+ T cells	SIGNOR-255029
Q12923	P12931	1	dephosphorylation	down-regulates activity	0.54	Mechanistically, RIL suppresses Src activation through interacting with Src and PTPL1, allowing PTPL1 dependent dephosphorylation of Src at the activation loop.\|Our results reveal a novel Src inactivation cycle in which reversion-induced LIM preferentially recognizes active Src and facilitates PTPL1-mediated inactivation of Src.	SIGNOR-277125
Q00535	Q13153	1	phosphorylation	down-regulates activity	0.54	Our previous work revealed that the neuronal p35/Cdk5 kinase associates with Pak1 in a RacGTP-dependent manner, causing hyperphosphorylation and down-regulation of Pak1 kinase activity. We have now demonstrated direct phosphorylation of Pak1 on threonine 212 by the p35/Cdk5 kinase.	SIGNOR-249328
P50750	P01106	1	phosphorylation	down-regulates activity	0.54	CDK9 promotes phosphorylation of MYC on Ser 62 .	SIGNOR-279024
Q09013	P26678	1	phosphorylation	up-regulates	0.54	Coimmunoprecipitation studies showed that dmpk and pln can physically associate. Furthermore, purified wild-type dmpk, but not a kinase-deficient mutant (k110a dmpk), phosphorylates pln in vitro	SIGNOR-131371
Q16816	P06737	1	phosphorylation	up-regulates activity	0.54	It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15	SIGNOR-267399
P04629	Q9NRF2	1	binding	up-regulates	0.54	The adapter protein sh2-b has been shown to bind to activated nerve growth factor (ngf) receptor trka and has been implicated in ngf-induced neuronal differentiation and the survival of sympathetic neurons.	SIGNOR-124198
Q13627	Q96EB6	1	phosphorylation	up-regulates activity	0.54	DYRK1A and DYRK3 directly phosphorylate SIRT1 at Thr(522), promoting deacetylation of p53.\|DYRK1A and DYRK3 promote cell survival through phosphorylation and activation of SIRT1.	SIGNOR-278473
Q13976	Q01970	1	phosphorylation	down-regulates activity	0.539	PKG can directly phosphorylate PLC-beta2 and PLC-beta3 in vitro with purified proteins and in vivo with metabolic labeling. Phosphorylation of PLC-beta leads to the inhibition of G-protein-activated PLC-beta3 activity by 50-70% in COS-7 cell transfection assays. By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)). Mutation at these two sites (S26A and S1105A) of PLC-beta3 completely blocked the phosphorylation of PLC-beta3 protein catalyzed by PKG.	SIGNOR-249077
P28482	Q05682	1	phosphorylation	down-regulates	0.539	Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin.	SIGNOR-71037
P42224	P33076	1	transcriptional regulation	up-regulates	0.539	When IFN-γ binds to its receptor, the receptor-associated protein tyrosine kinases Janus kinase I (JAK1) and JAK2 are activated (37). This leads to the phosphorylation of STAT1, which then dimerizes, translocates to the nucleus, and activates its target promoters, including the pIV promoter of Ciita	SIGNOR-256249
P53350	P51587	1	phosphorylation	down-regulates activity	0.539	M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1	SIGNOR-102486
P38405	Q08828	1	binding	up-regulates activity	0.539	D1-class dopamine receptors (D1 and D5) activate the G s/olf family of G proteins to stimulate cAMP produc tion by AC and are found exclusively postsynaptically on dopamine-receptive cells, such as GABA-ergic medium spiny neurons (MSNs) in the striatum.	SIGNOR-264992
Q9ULT6	Q9H461	1	ubiquitination	down-regulates quantity	0.539	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-260111

Q07912

P10275

1

phosphorylation

up-regulates activity

0.545

Ack1 interacted with and phosphorylated AR protein at Tyr 267 and Ack1 was shown to be required for optimal AR target gene expression and AR recruitment.|Two intracellular tyrosine kinases, Ack1 (activated cdc42 associated kinase) and Src, phosphorylate and enhance AR activity and promote prostate xenograft tumor growth in castrated animals.

SIGNOR-278194

P07948

Q06187

1

phosphorylation

up-regulates

0.545

Phosphorylation at y551 requires lyn kinase activity, indicating that y551 is a transphosphorylation site \ this transphosphorylation at y551 is followed by phosphorylation at a second site, which is dependent on btk catalytic activity.

SIGNOR-41607

P68400

Q6VY07

1

phosphorylation

up-regulates activity

0.545

Phosphorylation of Ser278 by CK2 or a Ser278-->Asp mutation increased the interaction between PACS-1 and cargo, whereas a Ser278-->Ala substitution decreased this interaction. Moreover, the Ser278-->Ala mutation yields a dominant-negative PACS-1 molecule that selectively blocks retrieval of PACS-1-regulated cargo molecules to the TGN.

SIGNOR-250925

Q07812

Q9NR28

1

relocalization

up-regulates

0.545

Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi

SIGNOR-87109

Q96SN8

O43379

1

relocalization

up-regulates activity

0.545

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

SIGNOR-271723

Q6W2J9

Q99496

1

binding

up-regulates activity

0.545

BcoR and Fbxl10/Jhdm1B are among the most abundant Ring1B/Rnf2 interactors identified with the highest confidence, and their association has been validated by coimmunoprecipitation studies; hence we call this the Fbxl10-BcoR complex. In summary, we have widened the set of multiprotein complexes containing the Polycomb group protein Ring1B/Rnf2. The new interactors contain protein motifs whose enzymatic activities and binding properties would expand the regulatory potential and gene target diversity of Ring1B/Rnf2 complexes in terms of recruitment to and modification of chromatin

SIGNOR-252241

O95628

P41229

1

ubiquitination

down-regulates quantity by destabilization

0.545

In our study, we show that the protein level of the yeast histone H3 Lys 4 (H3 K4) demethylase Jhd2/Kdm5 is modulated through polyubiquitination by the E3 ubiquitin ligase Not4 and turnover by the proteasome. Finally, we show that human NOT4 can polyubiquitinate human JARID1C/SMCX, a homolog of Jhd2, suggesting that this is likely a conserved mechanism. We propose that Not4 is an E3 ubiquitin ligase that monitors and controls a precise amount of Jhd2 protein so that the proper balance between histone demethylase and histone methyltransferase activities occur in the cell, ensuring appropriate levels of H3 K4 trimethylation and gene expression.

SIGNOR-271468

P23471

Q9UM73

1

dephosphorylation

down-regulates

0.545

Rptpbeta/zeta dephosphorylates alk at the site(s) in alk that is undergoing autophosphorylation through autoactivation.

SIGNOR-157227

Q96N67

P63000

1

guanine nucleotide exchange factor

up-regulates activity

0.545

As a GEF, Dock7 exchanges GDP for GTP on Cdc42 and Rac1, causing their activation, followed by activation of downstream effectors, including the dephosphorylation (activation) of cofilin, a key regulator of actin turnover.

SIGNOR-261887

Q9Y5Z0

P05067

1

cleavage

up-regulates activity

0.544

BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.|Figure 6 Preferred BACE1 and BACE2 cleavage sites. (A) Sequence of APP indicating Î±- and Î²-cleavage sites, BACE1- and BACE2-cleavage sites, and the location of mutations analyzed here. APP numbering is that of the 770-aa isoform.

SIGNOR-261773

O15111

Q9NQC7

1

phosphorylation

up-regulates activity

0.544

The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.

SIGNOR-204692

Q86XK2

Q9NZJ0

1

binding

down-regulates

0.544

We determined that the f-box protein fbxo11 interacts with cdt2,a dcaf protein that controls cell-cycle progression, and recruits cdt2 to the scf(fbxo11)complex to promote its proteasomal degradation.

SIGNOR-192325

Q9Y297

P46937

1

ubiquitination

down-regulates

0.544

This cascade of phosphorylation allows the binding of scfbetatrcp that promotes the ubiquitination and degradation of yap.

SIGNOR-201138

P01106

P25490

2

binding

down-regulates activity

0.544

Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc.Yin-Yang-1 (YY1) regulates the transcription of many genes, including the oncogenes c-fos and c-myc. Depending on the context, YY1 acts as a transcriptional repressor, a transcriptional activator, or a transcriptional initiator. In cotransfections, c-Myc inhibits both the repressor and the activator functions of YY1, which suggests that one way c-Myc acts is by modulating the activity of YY1.

SIGNOR-268795

Q05209

Q14289

1

dephosphorylation

down-regulates activity

0.544

Inhibition of the catalytic activity of cell adhesion kinase beta by protein-tyrosine phosphatase-pest-mediated dephosphorylation. / dephosphorylation of tyr402 and tyr579/580 by ptp-pest

SIGNOR-107502

Q13131

Q53ET0

1

phosphorylation

down-regulates

0.544

Collectively, these findings suggest ampk suppresses glucose production through two transcriptional effects:reduced expression of creb targets via crtc inactivation and reduced expression of foxo target genes via class iia hdac inactivation

SIGNOR-176426

Q9UI95

Q9UM11

1

binding

down-regulates activity

0.544

The APC is activated in mitosis and G1 by CDC20 and CDH1, and inhibited by the checkpoint protein MAD2, a specific inhibitor of CDC20. We show here that a MAD2 homolog MAD2B also inhibits APC. MAD2B directly inhibits activation of APC by CDC20 and CDH1

SIGNOR-264902

Q96QT4

P04083

1

phosphorylation

up-regulates

0.544

Trpm7 was responsible for phosphorylation of the serine 5 (ser5) residue [29]. In 2009, the study focused on an association between anxa1 and trpm7 confirmed the presence of a trpm7/annexin a1/mg2_+ complex, suggesting a novel pathway in bradykinin signaling, dependent on pkc and c-src [30]. Even though that pathway is not fully characterized, the same team that discovered the ser5 phosphorylation of anxa1 also reported crucial relevance of this modification for anxa1 membrane binding and especially for the interaction between annexin a1 and its known partner, the calcium binding protein s100a11

SIGNOR-202804

Q92633

P50148

1

binding

up-regulates activity

0.544

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-257091

P68036

P46934

1

ubiquitination

up-regulates activity

0.544

Only UbcH5 and Related Class I E2s Support Ubiquitination of S5a—UbcH5 belongs to the Class I family of E2s which contains a catalytic core (UBC domain) without a distinct Ub binding domain (38). To test whether other Class I E2s can also support ubiquitination of S5a, we assayed the ubiquitination of S5a with UbcH7 and the E3s, Nedd4, or Parkin. With either of these E3s, UbcH7 supported ubiquitination of S5a (Fig. 8, A and B). In addition, another Class I E2, Ubc4, a close homolog of UbcH5, supported ubiquitination of S5a by the APC, a multimeric Ring finger E3 responsible for cell cycle progression through mitosis (39) (Fig. 8C). Thus, multiple Class I E2s can support ubiquitination of S5a by various types of E3s (Table 1).

SIGNOR-272735

Q9ULX6

Q08211

1

binding

up-regulates activity

0.544

We report evidence for a novel nuclear export signal in HAP95 and showed that the domains involved in RHA binding and nuclear localization are required for CTE activation. Finally, we showed that HAP95 synergizes significantly with RHA on CTE-mediated reporter gene expression and promotes nuclear export of unspliced mRNA in transfected cells. Taken together, these data support the proposal that HAP95 specifically facilitates CTE-mediated gene expression by directly binding to RHA.

SIGNOR-260950

Q92823

P16157

1

relocalization

up-regulates quantity

0.544

Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.

SIGNOR-266721

P06241

Q07666

1

phosphorylation

up-regulates activity

0.544

The tyrosine kinase Fyn modulates Sam68 mediated alternative splicing of Bcl-x mRNA.|Tyrosine phosphorylation of Sam68 by Fyn inverted this effect and favored the Bcl-x(L) splice site selection.

SIGNOR-279462

P25490

P01106

2

transcriptional regulation

down-regulates quantity by repression

0.544

Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc.Yin-Yang-1 (YY1) regulates the transcription of many genes, including the oncogenes c-fos and c-myc. Depending on the context, YY1 acts as a transcriptional repressor, a transcriptional activator, or a transcriptional initiator. In cotransfections, c-Myc inhibits both the repressor and the activator functions of YY1, which suggests that one way c-Myc acts is by modulating the activity of YY1.

SIGNOR-268794

P18075

Q13705

1

binding

up-regulates

0.544

We show that bmp7 and activin bind to the same type ii receptors, actrii and iib, but recruit distinct type i receptors into heteromeric receptor complexes.

SIGNOR-60240

Q70E73

Q8N8S7

1

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

P45452

P02458

1

cleavage

down-regulates quantity by destabilization

0.544

Although it appears that MMP-1 and MMP-13 both cleave type II collagen initially at the same site, MMP-13 affects a secondary cleavage to produce a 1/4-size collagen fragment with an NH2 terminus three amino acids removed from the primary cleavage site.The present work has demonstrated expression of MMP-13 in human osteoarthritic cartilage and shown that MMP-13 has significant type II collagen degrading activity.

SIGNOR-256340

Q8WWW0

Q9NS23

1

binding

up-regulates activity

0.543

NORE1A can heterodimerize with RASSF1A and, thus, mediate K-Ras regulation of RASSF1A

SIGNOR-249587

Q9Y371

Q14457

1

binding

up-regulates

0.543

Bif-1 forms a complex with beclin1 through uvrag and promotes the activation of the class iii pi3 kinase, vps34, in mammalian cells.

SIGNOR-171899

Q7Z5H3

P60953

1

gtpase-activating protein

down-regulates activity

0.543

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-260478

P84022

P46531

1

binding

up-regulates

0.543

Nicd and smad3 were shown to interact directly, both in vitro and in cells, in a ligand-dependent manner, and smad3 could be recruited to csl-binding sites on dna in the presence of csl and nicd

SIGNOR-119374

O00444

Q969U6

1

phosphorylation

down-regulates activity

0.543

The activity of SCF-FBXW5 is in turn negatively regulated by Polo-like kinase 4 (PLK4), which phosphorylates FBXW5 at Ser 151 to suppress its ability to ubiquitylate HsSAS-6.

SIGNOR-275476

Q9UPQ7

O15146

1

ubiquitination

down-regulates quantity

0.543

We have identified a PDZ domain containing RING finger 3 (PDZRN3) as a synapse-associated E3 ubiquitin ligase and have demonstrated that it regulates the surface expression of muscle-specific receptor tyrosine kinase (MuSK), the key organizer of postsynaptic development at the mammalian neuromuscular junction. PDZRN3 binds to MuSK and promotes its ubiquitination. Together, these data demonstrate that PDZRN3 is a catalytically active RING-type E3 ubiquitin ligase

SIGNOR-271664

O43312

P08151

1

binding

up-regulates

0.543

Mim is a shh-responsive gene that can potentiate gli transcriptional activity.MIM Appears to regulate target gene expression through its association with the gli complex

SIGNOR-157650

P15531

Q8IVT5

1

phosphorylation

down-regulates

0.543

Autophosphorylated recombinant nm23-h1 phosphorylated ksr in vitro. Using site-directed mutagenesis, we found that nm23-h1 phosphorylated ksr serine 392, a 14-3-3-binding site, consistent with the recent identification of c-tak1 as a kinase for this site.

SIGNOR-90390

P00519

Q9H3D4

1

phosphorylation

up-regulates quantity by stabilization

0.543

In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters.

SIGNOR-260934

P06493

Q5BJF6

1

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

P07949

Q13322

1

binding

up-regulates

0.543

Grb7 and grb10, likely relay signals emanating from ret to other, as yet, unidentified targets within the cell

SIGNOR-41699

Q15418

P67809

1

phosphorylation

up-regulates

0.543

We therefore conclude that rsk1/rsk2 are novel activators of yb-1, able to phosphorylate the serine 102 residue.

SIGNOR-182497

P41143

P63096

1

binding

up-regulates activity

0.543

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-256683

P46695

Q13362

1

binding

down-regulates

0.542

Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit.

SIGNOR-144309

P25101

P50148

1

binding

up-regulates

0.542

The response to endothelin-1 (et-1) consisted of two phases in both cell types. The initial, transient phase of contraction and phosphorylation of 20-kda myosin light chain (mlc20) was mediated additively by eta and etb receptors and initiated by galphaq-, ca2+/calmodulin-dependent activation of mlc kinase.

SIGNOR-129817

Q06187

O43516

1

phosphorylation

up-regulates activity

0.542

Based on previous reports and the present data we suggest that Btk can induce WASP activation and also facilitates its subsequent inactivation through WIP phosphorylation.|We confirmed that Btk can indeed phosphorylate Y468 of baculovirus-generated human His-tagged WIP ( xref ), but that this is more difficult to show in cell extracts where WIP would be purified along with cellular WASP ().

SIGNOR-279801

Q9UKB1

P25963

1

ubiquitination

down-regulates

0.542

We report here the identification of an ikappab-ubiquitin (ub) ligase complex containing the f-box/wd40-repeat protein, beta-trcp, a vertebrate homolog of drosophila slimb. beta-trcp binds to ikappabalpha only when the latter is specifically phosphorylated by an ikappab kinase complex. here we provide evidence that lysine residues 21 and 22 serve as the primary sites for signal-induced ubiquitination of i kappa b alpha.

SIGNOR-64317

P17612

Q92934

1

phosphorylation

down-regulates

0.542

Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo.

SIGNOR-67387

P27361

O75030

1

phosphorylation

down-regulates quantity by destabilization

0.542

More interestingly, ERK-dependent phosphorylation of MITF at Ser 73 is essential for MITF ubiquitinilation and degradation (87). Putting together all these findings, it can be proposed that MAPK activation inhibits melanogenesis due to an increased MITF degradation which is dependent on the MAPK-induced MITF phosphorylation and ubiquitinilation. In summary, although the phosphorylation of MITF at Ser73 increases its intrinsic transcriptional activity, this phosphorylation also targets MITF to the proteasome for its degradation. Consequently, the decrease in MITF levels leads to a down-regulation of melanogenic enzymes expression and to an inhibition of melanogenesis.

SIGNOR-249620

Q05209

P12931

1

dephosphorylation

up-regulates activity

0.542

PTP-PEST increases dephosphorylation of Src at Y527 and activates it.|The data presented here supports our hypothesis that PTP-PEST activates Src via dephosphorylating it at Y527 (Tyr530 in human c-Src equivalent to Tyr527 in chicken Src).

SIGNOR-277086

P62136

Q9GZV5

1

dephosphorylation

up-regulates activity

0.542

PP1A dephosphorylates TAZ at Ser-89 and Ser-311, promotes TAZ nuclear translocation, and stabilizes TAZ by disrupting the binding to the SCF E3 ubiquitin ligase.

SIGNOR-277116

P53778

P15336

1

phosphorylation

up-regulates

0.542

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

SIGNOR-65589

Q9Y243

Q92934

1

phosphorylation

down-regulates

0.542

Ser-136 is the major phosphoacceptor site for akt;akt can weakly phosphorilate ser-155.

SIGNOR-81122

P12931

Q9Y2X7

1

phosphorylation

up-regulates activity

0.542

Tyrosines 246 and 293 are required to hold GIT1 in a closed conformation.Hyperphosphorylation of GIT1-N by Src and pervanadate does not affect its binding in vitro to full length GIT1 proteins. Mutations Y246E and Y293E of GIT1 enhance binding to paxillin.

SIGNOR-276627

P27361

P04150

1

phosphorylation

down-regulates

0.542

Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action.

SIGNOR-154409

Q9UPT6

Q13233

1

binding

up-regulates

0.542

Overexpression of full-length jsap1 in cos-7 cells led to a considerable enhancement of jnk3 activation, and modest enhancement of jnk1 and jnk2 activation, by the mekk1-sek1 pathwaythe regions of jsap1 that bound jnk, sek1, and mekk1 were distinct from one another. Jnk and mekk1 also bound jsap1 in vitro, suggesting that these interactions are direct.

SIGNOR-71471

Q8N6P7

P29597

1

binding

up-regulates

0.542

Il-22 activates jak1 and tyk2

SIGNOR-90165

Q99708

Q96T58

1

binding

down-regulates

0.542

We identify the ctip and ctbp corepressors as novel components of the human rbp-jk/sharp-corepressor complex and show that ctip binds directly to the sharp repression domain.

SIGNOR-141616

Q13315

Q9NUW8

1

phosphorylation

up-regulates

0.542

Optimal function of the dna repair enzyme tdp1 requires its phosphorylation by atm and/or dna-pk. Here we show that top1-associated dna double-stranded breaks (dsbs) induce the phosphorylation of tdp1 at s81. This phosphorylation is mediated by the protein kinases: ataxia-telangiectasia-mutated (atm) and dna-dependent protein kinase (dna-pk)

SIGNOR-188772

Q9UBV4

O75581

1

binding

up-regulates

0.542

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

SIGNOR-131677

Q9UBS3

P11021

1

binding

up-regulates activity

0.542

When BAP was added to BiP (2:1 molar ratio of BAP:BiP), it increased the ATPase activity of BiP by about 2-fold, which was similar to the increase observed when the J domain of ERdj4 was added to BiP (Fig.5). When both BAP and the J domain were added to BiP, the rate of ATP hydrolysis by BiP was stimulated by about 4-fold over basal levels, indicating that both BAP and ERdj4 positively regulate the ATPase activity of BiP

SIGNOR-261044

P05412

P01137

1

transcriptional regulation

up-regulates quantity by expression

0.542

MAPKs have cis-acting regulatory elements in the mouse-TGF promoter region, which respond to various transcription factors, including specificity protein-1 and activating protein 1. Thus, it is possible that apoptotic cell-induced TGF-beta mRNA expression is mediated through activation of these transcription factors via MAPK signaling. Xiao et al. reported that all of the MAPK members, including p38/ERK/JNK, are required for apoptotic Jurkat cells up-regulation of TGF-beta production

SIGNOR-251713

Q14004

P24928

1

phosphorylation

up-regulates activity

0.541

Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence

SIGNOR-273054

P06239

P06127

1

phosphorylation

up-regulates activity

0.541

Tyrosine phosphorylation of cd5 requires lck activity. We propose that t cell activation mediates cd5 tyrosine phosphorylation at residues y429 and y463 mainly through the activation of lck

SIGNOR-106799

P21554

P08754

1

binding

up-regulates activity

0.541

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-256867

P63096

O43306

1

binding

down-regulates activity

0.541

Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3

SIGNOR-278077

P08709

P00742

2

binding

up-regulates activity

0.541

TF has a high affinity for FVII and enables the trace levels (∼1% of the total FVII) of activated FVII (FVIIa) in the blood to cleave specific sites in the serine proteases FIX and FX, activating them into FIXa and FXa, respectively.

SIGNOR-263545

O14965

P25963

1

phosphorylation

down-regulates activity

0.541

The results of the in vitro kinase assay, using purified human recombinant AURKA and IkappaBalpha proteins, confirmed that AURKA can directly phosphorylate IkappaBalpha (Ser32) at a concentration as low as 2.5 ng/mul (XREF_FIG).|While an earlier study suggested that AURKA down-regulates IkappaBalpha indirectly through activation of the PI3K and AKT pathway 35, our data demonstrate, for the first time, that AURKA directly binds and phosphorylates the IkappaBalpha subunit, leading to activation of NF-kappaB.

SIGNOR-278912

P21554

P63096

1

binding

up-regulates activity

0.541

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-256724

Q13459

P63000

1

gtpase-activating protein

down-regulates activity

0.541

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-260510

Q9UHD2

Q13568

1

phosphorylation

up-regulates

0.541

Activation of interferon regulatory factor 5 by site specific phosphorylation. Although the gene induction by irf5 in the presence of tbk-1 was modest, phosphorylation by tbk-1 produced a significant shift in the mobility of irf5 in sds-page. For this reason we identified the residues that are phosphorylated on irf5 by tbk-1 with mass spectrometry. Ser-158 and ser-309 were found to be phosphorylated

SIGNOR-196528

P45984

Q13469

1

phosphorylation

down-regulates

0.541

Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin

SIGNOR-118223

P0DP24

Q96RR4

1

binding

up-regulates

0.541

The ca2+-calmodulin-dependent protein kinase (cam kinase) cascade includes three kinases: cam-kinase kinase (camkk);and the cam kinases camki and camkiv, which are phosphorylated and activated by camkk.

SIGNOR-266329

P28827

O60716

1

dephosphorylation

down-regulates quantity

0.541

Specifically, RPTP\u03bc dephosphorylated p120 catenin, subsequently leading to a lower level of cytoplasmic protein compared with that observed with the vector control and RPTP\u03bc-CS.

SIGNOR-277042

P00742

P08709

2

cleavage

up-regulates activity

0.541

The factor VII zymogen is cleaved at arginine 152 by a variety of proteases, including thrombin, factor IXa, factor Xa, and factor VIIa–tissue factor to produce the serine protease factor VIIa.

SIGNOR-263523

Q96HW7

P24928

1

binding

up-regulates activity

0.541

The Integrator Complex Can Directly Associate with the C-Terminal Domain of RNA Polymerase II Largest Subunit

SIGNOR-261185

O00221

P19838

1

binding

down-regulates

0.541

Nf-kb is normally sequestered in the cell cytoplasm by binding to ikbx, ikbb, ikbe

SIGNOR-102774

P53041

P04150

1

dephosphorylation

down-regulates activity

0.541

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

SIGNOR-248538

Q9Y3C5

Q9HAU4

1

binding

up-regulates activity

0.54

RNF11 recruits AMSH to Smurf2 E3 ligase. Smurf2 promotes ubiquitination of AMSH in the presence of wt RNF11. Previously, we have shown that RNF11 interacts with the HECT-type E3 ligases AIP4 and Smurf2. Here, we show that RNF11 binds to AMSH in mammalian cells and that this interaction is independent of the RNF11 RING-finger domain and the PY motif. Our results also demonstrate that AMSH is ubiquitinated by Smurf2 E3 ligase in the presence of RNF11 and that a consequent reduction in its steady-state level requires both RNF11 and Smurf2. RNF11 therefore recruits AMSH to Smurf2 for ubiquitination, leading to its degradation by the 26S proteasome.

SIGNOR-272952

Q02363

P15172

1

binding

down-regulates activity

0.54

Id1 and Id2 interacted strongly with MyoD and Myf-5.Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.

SIGNOR-240268

P06493

Q9UNH5

1

phosphorylation

up-regulates activity

0.54

We found that Cdc14A is phosphorylated on Ser411, Ser453 and Ser549 by Cdk1 early in mitosis and becomes dephosphorylated during late mitotic stages.

SIGNOR-278264

Q15910

P10275

1

binding

up-regulates activity

0.54

This study demonstrates that phosphorylation of EZH2 at Ser21, mediated directly or indirectly by the PI3K-Akt pathway, can switch its function from a Polycomb repressor to a transcriptional coactivator of AR (and potentially other factors).

SIGNOR-251542

P62258

P46527

1

binding

down-regulates

0.54

14-3-3_, 14-3-3_, and 14-3-3_ (but not 14-3-3_ and 14-3-3_) could form a complex with p27kip1 / we discovered that akt-mediated p27kip1phosphorylation directly induces p27kip1binding to 14-3-3 and cytoplasmic localization through phosphorylating the newly identified thr198residue.

SIGNOR-88297

P51151

Q8IWJ2

1

null

up-regulates activity

0.54

Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector

SIGNOR-253087

Q99933

Q9UNE7

1

binding

up-regulates activity

0.54

BAG-1 stimulates CHIP-induced degradation of the glucocorticoid hormone receptor (GR). A model for the cooperation of CHIP and BAG-1 in coupling Hsc/Hsp70 to the ubiquitin/proteasome system. CHIP associates with Hsc/Hsp70 via its TPR chaperone adaptor (TPR) and, at the same time, recruits E2 ubiquitin-conjugating enzymes of the Ubc4/5 family to the chaperone complex. BAG-1 binds to Hsp70 via its BAG domain (BAG) and utilizes its ubiquitin-like domain (ubl) for proteasomal association

SIGNOR-272587

Q8TDJ6

Q15042

1

binding

up-regulates quantity

0.54

We isolated here a novel protein that was co-immunoprecipitated with Rab3 GEP and GAP by their respective antibodies from the crude synaptic vesicle fraction of rat brain. The protein, named rabconnectin-3, bound both Rab3 GEP and GAP. These results indicate that rabconnectin-3 serves as a scaffold molecule for both Rab3 GEP and GAP on synaptic vesicles.

SIGNOR-265582

Q13164

P17302

1

phosphorylation

down-regulates activity

0.54

Activated BMK1 selectively phosphorylates Cx43 on Ser-255 in vitro and in vivo. These data demonstrate that BMK1 kinase activity alone is both a necessary and sufficient component in the mediation of EGF-induced Cx43 Ser-255 phosphorylation and subsequent inhibition of GJC.

SIGNOR-250115

P49841

P04150

1

phosphorylation

down-regulates activity

0.54

We found hormone-dependent GR phosphorylation on serine 404 by GSK-3beta [ ]Cells expressing a GR that is incapable of GSK-3beta phosphorylation had a redirection of the global transcriptional response to hormone, including the activation of additional signaling pathways, in part due to the altered ability of unphosphorylatable GR to recruit transcriptional cofactors CBP/p300 and the p65 (RelA) subunit of NF-kappaB

SIGNOR-181541

O15111

Q13546

1

phosphorylation

down-regulates activity

0.54

Indeed, IKKa and IKKb may directly repress RIPK1 kinase activity by addition of an inhibitory phosphate group on RIPK1.|Mass spectrometry analysis of kinase assays performed with recombinant proteins allowed us to identify Ser166, Ser331, and Ser416 as highly conserved RIPK1 residues phosphorylated by IKKa and IKKb.

SIGNOR-278927

P51449

Q16552

1

transcriptional regulation

up-regulates

0.54

We found that RORgt is required for the constitutive expression of IL-17 in intestinal lamina propria T cells and for the in vitro differentiation of Th17 cells from naive CD4+ T cells

SIGNOR-255029

Q12923

P12931

1

dephosphorylation

down-regulates activity

0.54

Mechanistically, RIL suppresses Src activation through interacting with Src and PTPL1, allowing PTPL1 dependent dephosphorylation of Src at the activation loop.|Our results reveal a novel Src inactivation cycle in which reversion-induced LIM preferentially recognizes active Src and facilitates PTPL1-mediated inactivation of Src.

SIGNOR-277125

Q00535

Q13153

1

phosphorylation

down-regulates activity

0.54

Our previous work revealed that the neuronal p35/Cdk5 kinase associates with Pak1 in a RacGTP-dependent manner, causing hyperphosphorylation and down-regulation of Pak1 kinase activity. We have now demonstrated direct phosphorylation of Pak1 on threonine 212 by the p35/Cdk5 kinase.

SIGNOR-249328

P50750

P01106

1

phosphorylation

down-regulates activity

0.54

CDK9 promotes phosphorylation of MYC on Ser 62 .

SIGNOR-279024

Q09013

P26678

1

phosphorylation

up-regulates

0.54

Coimmunoprecipitation studies showed that dmpk and pln can physically associate. Furthermore, purified wild-type dmpk, but not a kinase-deficient mutant (k110a dmpk), phosphorylates pln in vitro

SIGNOR-131371

Q16816

P06737

1

phosphorylation

up-regulates activity

0.54

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

SIGNOR-267399

P04629

Q9NRF2

1

binding

up-regulates

0.54

The adapter protein sh2-b has been shown to bind to activated nerve growth factor (ngf) receptor trka and has been implicated in ngf-induced neuronal differentiation and the survival of sympathetic neurons.

SIGNOR-124198

Q13627

Q96EB6

1

phosphorylation

up-regulates activity

0.54

DYRK1A and DYRK3 directly phosphorylate SIRT1 at Thr(522), promoting deacetylation of p53.|DYRK1A and DYRK3 promote cell survival through phosphorylation and activation of SIRT1.

SIGNOR-278473

Q13976

Q01970

1

phosphorylation

down-regulates activity

0.539

PKG can directly phosphorylate PLC-beta2 and PLC-beta3 in vitro with purified proteins and in vivo with metabolic labeling. Phosphorylation of PLC-beta leads to the inhibition of G-protein-activated PLC-beta3 activity by 50-70% in COS-7 cell transfection assays. By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)). Mutation at these two sites (S26A and S1105A) of PLC-beta3 completely blocked the phosphorylation of PLC-beta3 protein catalyzed by PKG.

SIGNOR-249077

P28482

Q05682

1

phosphorylation

down-regulates

0.539

Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin.

SIGNOR-71037

P42224

P33076

1

transcriptional regulation

up-regulates

0.539

When IFN-γ binds to its receptor, the receptor-associated protein tyrosine kinases Janus kinase I (JAK1) and JAK2 are activated (37). This leads to the phosphorylation of STAT1, which then dimerizes, translocates to the nucleus, and activates its target promoters, including the pIV promoter of Ciita

SIGNOR-256249

P53350

P51587

1

phosphorylation

down-regulates activity

0.539

M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1

SIGNOR-102486

P38405

Q08828

1

binding

up-regulates activity

0.539

D1-class dopamine receptors (D1 and D5) activate the G s/olf family of G proteins to stimulate cAMP produc tion by AC and are found exclusively postsynaptically on dopamine-receptive cells, such as GABA-ergic medium spiny neurons (MSNs) in the striatum.

SIGNOR-264992

Q9ULT6

Q9H461

1

ubiquitination

down-regulates quantity

0.539

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-260111