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
O43603	P22466	2	binding	up-regulates	0.862	Galanin showed high affinity for the galr1 (ic(50) = 0.097 nm) and galr2 receptors (ic(50) = 0.48 nm).	SIGNOR-73125
P31751	Q2PPJ7	1	phosphorylation	down-regulates activity	0.453	RGC2 is an endogenous substrate for Akt2 downstream of PI 3-kinase	SIGNOR-269799
P17252	O75385	1	phosphorylation	down-regulates activity	0.2	ULK1 is phosphorylated by PKCalpha at S423 in vivo and in vitro.\|PKC\u03b1 phosphorylation of ULK1 does not change its kinase activity	SIGNOR-279558
P67775	Q16549	0	phosphorylation	up-regulates	0.2	This together with the rapid kinetics of pp1-pp2a activation following p38 activation suggests that pp1 and/or pp2a complexes are direct targets for p38-mediated phosphorylation	SIGNOR-105783
O60291	Q99816	1	monoubiquitination	up-regulates activity	0.492	In the present study, we identified the first substrate of the Mahogunin E3 ubiquitin–protein ligase: TSG101, a key component of the endosomal sorting ESCRT machinery.We find that Mahogunin interacts with the ubiquitin E2 variant (UEV) domain of TSG101 via its PSAP motif and that it catalyzes monoubiquitylation of TSG101 both in vivo and in vitro. Consistent with the results of the biochemical characterization and subcellular localization studies of Mahogunin, our functional studies provide direct evidence that Mahogunin plays an essential role in regulation of endosome-to-lysosome trafficking. We found that siRNA-mediated depletion of Mahogunin in HeLa cells causes enlargement and clustering of EEA1-positive endosomes and LAMP2-positive late endosomes/lysosomes (Figure 8B) and inhibits the endosomal trafficking of internalized EGF–EGFR complexes to lysosomes for degradation (Figures 9 and and10,10, A and B). These results are strikingly similar to the phenotypes that resulted from depletion of TSG101	SIGNOR-271635
P20393	Q99743	1	transcriptional regulation	down-regulates quantity by repression	0.631	In this study, we found that NPAS2, like BMAL1, is a direct target gene of RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding.	SIGNOR-267981
P10243	P19338	2	binding	down-regulates activity	0.417	We identify nucleolin as one of the nuclear polypeptides that interact specifically with the A-Myb and c-Myb. We show that the interaction of nucleolin with Myb is functional because co-transfection of nucleolin down-regulates Myb transcriptional activity.	SIGNOR-221233
P25025	P25098	0	phosphorylation	down-regulates activity	0.2	Upon activation, GRK2 phosphorylates CXCR2 and causes receptor desensitization and internalization, leading to down-regulation of neutrophil chemotaxis	SIGNOR-260647
Q13451	P51608	0	transcriptional regulation	down-regulates quantity by repression	0.306	These results are compatible with the hypothesis that MeCP2 associates with the Sgk and Fkbp5 promoters and has a repressive effect that is over-ridden by elevated glucocorticoids in response to stress.	SIGNOR-264542
P50616	P45984	0	phosphorylation	down-regulates	0.34	Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro.	SIGNOR-91067
P68400	P31749	1	phosphorylation	up-regulates	0.372	CK2 hyperactivates AKT by phosphorylation at Ser129	SIGNOR-252595
Q9NPH9	Q08334	2	binding	up-regulates	0.601	See table 2	SIGNOR-151917
Q01094	Q13315	0	phosphorylation	up-regulates quantity by stabilization	0.679	Selective induction of e2f1 in response to dna damage, mediated by atm-dependent phosphorylation. We identify a site for atm/atr phosphorylation in the amino terminus of e2f1 and we show that this site is required for atm-mediated stabilization of e2f1. Finally, we also show that e2f1 is required for dna damaged induced apoptosis in mouse thymocytes.	SIGNOR-109416
O14842	P09471	2	binding	up-regulates activity	0.2	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257184
P01106	O60885	2	null	down-regulates activity	0.562	Conversely, MYC inhibits BRD4's HAT activity, suggesting that MYC regulates its own transcription by limiting BRD4-mediated chromatin remodeling of its locus.	SIGNOR-262047
P04049	P30086	2	binding	down-regulates	0.762	Suppression of raf-1 kinase activity and map kinase by rkip. Rkip binds to raf-1, mek and erk, but not to ras.	SIGNOR-70838
Q16204	P24941	0	phosphorylation	up-regulates	0.2	Serine 244 phosphorylation is required for h4 apoptotic function.	SIGNOR-121198
P28482	P67775	0	dephosphorylation	down-regulates activity	0.621	P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3).Mapk activity is tightly regulated by phosphorylation and dephosphorylation. The activation of the mapk activity requires the dual phosphorylation of the ser/thr and tyr residues in the txy kinase activation motif (1113), and deactivation occurs through the action of either ser/thr protein phosphatase	SIGNOR-103159
P25490	Q13547	0	deacetylation	down-regulates activity	0.798	Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs.	SIGNOR-268835
P80098	P32246	2	binding	up-regulates	0.742	For example, 11 chemokines are reported to bind to CC chemokine receptor (CCR) 1, including macrophage inflammatory protein (MIP)‐1α , MIP‐1β, MIP‐1δ, regulated upon activation, normal T cell‐expressed and secreted (RANTES), monocyte chemotactic peptide (MCP)‐1, MCP‐2, MCP‐3, MCP‐4, leukotactin‐1 (Lkn‐1), myeloid progenitor inhibitory factor (MPIF)‐1, and hemofiltrate CC chemokine (HCC)‐1	SIGNOR-254368
P17612	Q14738	1	phosphorylation	up-regulates	0.2	Protein kinase a activates protein phosphatase 2a by phosphorylation of the b56delta subunit.	SIGNOR-153218
Q15831	Q9NRH2	1	phosphorylation	up-regulates activity	0.367	We demonstrate that LKB1 activates SNRK by phosphorylating the T‐loop residue (Thr173)	SIGNOR-260824
P31314	P67775	2	binding	down-regulates activity	0.308	HOX11 also inhibited PP2A serine/threonine phosphatase activity concomitant with stimulation of the AKT/PKB signaling cascade.	SIGNOR-240719
P46531	O00587	2	binding	up-regulates	0.72	Manic fringe elongates the o-linked fucose saccharides on full-length notch1 and notch1 egf repeats 1923.	SIGNOR-80555
O95837	P41968	2	binding	up-regulates activity	0.25	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257298
O60934	P24941	0	phosphorylation	up-regulates activity	0.507	Nbs1 is phosphorylated by Cdk2 on Ser432 in human whole-cell extracts.	SIGNOR-279500
Q13557	O15084	1	phosphorylation	down-regulates activity	0.2	We provide evidence for a dual kinase-mediated regulation of the PITK holoenzyme whereby PITK phosphorylation at S1017 is catalyzed by calcium/calmodulin-dependent kinase II-delta (CaMKIIdelta), promoting the subsequent phosphorylation of S1013 by glycogen synthase kinase-3 (GSK3) in vitro.\|the phosphorylation of PITK at these specific residues altered PP1 binding and subsequent PITK-directed dephosphorylation of hnRNP K	SIGNOR-264793
O60266	Q13555	0	phosphorylation	down-regulates activity	0.353	Phosphorylation and inhibition of type III adenylyl cyclase by calmodulin-dependent protein kinase II in vivo. \| Site-directed mutagenesis of a CaM kinase II consensus site (Ser-1076 to Ala-1076) in III-AC greatly reduced Ca2+-stimulated phosphorylation and inhibition of III-AC in vivo.	SIGNOR-250691
P06493	Q14790	1	phosphorylation	down-regulates	0.361	In this study, we demonstrate that procaspase-8 is phosphorylated in mitotic cells by cdk1na interference-mediated silencing of cyclin b1 or treatment with the cdk1 inhibitor ro-3306 enhances the fas-mediated activation and processing of procaspase-8 in mitotic cells/cyclin b1 on ser-387	SIGNOR-168446
P24941	P06400	1	phosphorylation	down-regulates	0.884	We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein.	SIGNOR-47895
P31751	Q00987	1	phosphorylation	up-regulates quantity by stabilization	0.56	Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.. Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186.	SIGNOR-109732
Q99801	P53671	0	phosphorylation	down-regulates activity	0.2	LIMK2 also downregulates NKX3.1 mRNA levels.\|While WT-NKX3.1 was efficiently phosphorylated, the S185A mutant showed no phosphorylation ( xref A), confirming that LIMK2 only phosphorylates the S185 site in NKX3.1.	SIGNOR-278951
P06241	P42681	1	phosphorylation	up-regulates activity	0.347	We further demonstrate that Rlk can be phosphorylated and activated by Src kinases, leading to a decrease in its half-life. A specific tyrosine in the activation loop of Rlk, Y420, is required for phosphorylation and activation, as well as for decreased stability, but is not required for lipid RAFT association.	SIGNOR-249341
Q9HCK8	P07197	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-268917
P01588	P19235	2	binding	up-regulates	0.876	Binding of erythropoietin (epo) to the epo receptor (epor) initiates a signaling cascade resulting in tyrosine phosphorylation of several proteins and induction of ap-1 transcription factor(s).	SIGNOR-55300
Q92934	Q86V86	0	phosphorylation	down-regulates activity	0.346	Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells.	SIGNOR-250399
P84103	Q9UBU9	2	binding	up-regulates	0.68	9g8 and srp20 also enhance the tap rna-binding activity	SIGNOR-178111
P04637	P78527	0	phosphorylation	up-regulates	0.793	We demonstrate that phosphorylation of p53 at serines 15 and 37 impairs the ability of mdm2 to inhibit p53-dependent transactivation. We present evidence that these effects are most likely due to a conformational change induced upon phosphorylation of p53. Our studies provide a plausible mechanism by which the induction of p53 can be modulated by dna-pk (or other protein kinases with similar specificity) in response to dna damage.	SIGNOR-53030
P62805	O14929	0	acetylation	down-regulates activity	0.2	Histone acetyltransferase 1 is the founding member of the histone acetyltransferase superfamily and catalyzes lysine acetylation of newly synthesized histone H4\|Lys12 for direct attack of the acetyl group of the cofactor.\| It is postulated that histone acetylation, through charge neutralization of the cationic histone tails, weakens nucleosomal electrostatic interactions with anionic DNA, thus destabilizing internucleosomal contacts and nucleosomal structure and facilitating access to the promoter region for RNA polymerase and transcription factors.	SIGNOR-264790
Q66K74	Q13618	0	ubiquitination	down-regulates quantity	0.242	Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B.	SIGNOR-268947
Q12852	O14733	1	phosphorylation	up-regulates activity	0.556	Collectively, these data suggest the hypothesis that ApoE activates DLK by increasing its levels	SIGNOR-279630
Q92630	P10070	1	phosphorylation	down-regulates quantity by destabilization	0.3	DYRK2 directly phosphorylated Gli2 sequences and resulted in the loss of coexpressed GLI proteins, indicating that DYRK2 acts by inducing the phosphorylation and degradation of GLI proteins via the ubiquitin and proteasome pathway.	SIGNOR-279034
P35226	O43791	2	binding	up-regulates activity	0.4	Here, we describe an E3 ubiquitin ligase consisting of SPOP and CULLIN3 that is able to ubiquitinate the PcG protein BMI1 and the variant histone MACROH2A1. To investigate whether BMI1 can form a complex with SPOP and CULLIN3 in vivo, we reconstituted the complex in 293HEK cells. We find that BMI1 readily immunoprecipitates both hemagglutinin (HA)-SPOP and CULLIN3, and, conversely, CULLIN3 immunoprecipitates BMI1 (Fig. 2a). Complex formation depends on the presence of SPOP, in accordance with BMI1 binding to the MATH domain of SPOP (Fig. 1b) and previously published data showing SPOP–CULLIN interaction by means of the BTB/POZ domain of SPOP (30).	SIGNOR-272658
P04626	Q9BXH1	1	phosphorylation	down-regulates quantity by destabilization	0.281	HER2 phosphorylates and destabilizes pro-apoptotic PUMA. Using an intracellular assay, we found PUMA to be phosphorylated in breast cancer cells with activated HER2. Via cell-free HER2 kinase assay, we observed that PUMA was directly phosphorylated by HER2. Activation of HER2 decreased PUMA protein half-life.	SIGNOR-276474
Q9HC98	P0DMV8	1	phosphorylation	up-regulates activity	0.425	Mitotic phosphorylation of Hsp72 by the kinase NEK6 at Thr66 located in the NBD promotes the localization of Hsp72 to the mitotic spindle and is required for efficient spindle assembly and chromosome congression and segregation.	SIGNOR-273885
Q9ULV5	P52564	0	phosphorylation	up-regulates activity	0.2	Regulation of Hsf4b nuclear translocation and transcription activity by phosphorylation at threonine 472\| At the upstream, MEK6 was found to interact with Hsf4b and enhance Hsf4b's nuclear translocation and transcription activity, probably by phosphorylation at sites such as T472. Taken together, our results suggest that phosphotylation of Hsf4b at T472 by protein kinases such as MEI	SIGNOR-275493
Q4FZB7	P62805	1	methylation	down-regulates activity	0.2	SUV420H1 and SUV420H2 are two highly homologous enzymes that methylate lysine 20 of histone H4 (H4K20), a mark that has been implicated in transcriptional regulation.	SIGNOR-266651
P15882	P63000	1	gtpase-activating protein	down-regulates activity	0.666	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-260499
P08253	P01023	2	cleavage	down-regulates quantity by destabilization	0.636	The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.\|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.	SIGNOR-261739
Q01344	Q06945	2	binding	up-regulates activity	0.417	Sox4 activation by IL-5R_ appears to be direct, with syntenin functioning as an adaptor molecule. Syntenin mediates IL-5induced Sox4 activation.	SIGNOR-223010
P08620	P22455	2	binding	up-regulates	0.672	Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides.	SIGNOR-18567
O75093	Q12857	0	transcriptional regulation	up-regulates quantity	0.257	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268892
Q15562	Q9GZV5	2	binding	up-regulates	0.808	When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14.	SIGNOR-201382
Q13627	P46531	1	phosphorylation	down-regulates	0.396	Dyrk1a physically interacts with the nicd inducing its phosphorylation in the ankyrin domain, thereby attenuating notch .	SIGNOR-185494
Q9UBF6	P05412	1	ubiquitination	down-regulates activity	0.324	SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase. by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes.	SIGNOR-271452
Q14694	Q13131	0	phosphorylation	up-regulates activity	0.309	Under energy stress, USP10 activity in turn is enhanced through AMPK-mediated phosphorylation of Ser76 of USP10.	SIGNOR-277207
Q5S007	P15311	1	phosphorylation	up-regulates activity	0.411	LRRK2 also phosphorylated ezrin and radixin, which are related to moesin, at the residue equivalent to Thr558, as well as a peptide (LRRKtide: RLGRDKYKTLRQIRQ) encompassing Thr558.	SIGNOR-279202
O75385	Q9Y4K3	0	ubiquitination	up-regulates quantity by stabilization	0.548	AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function.	SIGNOR-273000
P04049	Q16512	0	phosphorylation	up-regulates	0.2	Interaction between active pak1 and raf-1 is necessary for phosphorylation and activation of raf-1.	SIGNOR-112549
P01160	P16066	2	binding	up-regulates	0.887	Natriuretic peptide receptor-a (npra) is the biological receptor of the peptide hormones atrial natriuretic peptide (anp) and brain natriuretic peptide (bnp)	SIGNOR-137600
Q92529	P62993	1	relocalization	up-regulates	0.819	In addition to direct binding of grb2 to phosphotyrosine residues of receptor kinases, grb2 can also be recruited to the receptor by binding to shc when shc is tyrosine phosphorylated as a result of receptor stimulation.	SIGNOR-146897
P45973	Q16695	2	binding	up-regulates activity	0.2	A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing.	SIGNOR-264489
Q9UNN4	P19784	0	phosphorylation	up-regulates activity	0.414	ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. \| Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled.	SIGNOR-250993
P29350	P07948	2	dephosphorylation	down-regulates activity	0.734	SHP-1 efficiently inhibits Lyn autophosphorylation and suppresses FcϵRI stimulation\|We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397	SIGNOR-248471
O14920	Q13568	1	phosphorylation	up-regulates activity	0.37	Here we present evidence that the kinase IKKbeta phosphorylates and activates IRF5 in response to stimulation in several inflammatory pathways, including those emanated from Toll like receptors and retinoic acid inducible gene I like receptors.\|Recombinant IKK\u03b2 phosphorylated IRF5 at Ser-445 in vitro, and a point mutation of this serine abolished IRF5 activation and cytokine production.	SIGNOR-279466
Q07820	Q9Y4K3	0	ubiquitination	up-regulates activity	0.396	TRAF6 likely directly ubiquitinates MCL-1 since purified TRAF6 promoted the ubiquitination of recombinant GST-MCL-1 and co-expression of Tax with TRAF6 further enhanced MCL-1 ubiquitination .\|Therefore, TRAF6 mediated MCL-1 stabilization appears to be a common mechanism of cell survival usurped by both viral and non viral cancers.	SIGNOR-278726
P46734	O43318	0	phosphorylation	up-regulates activity	0.505	Taken together, our data indicate that TAK1 and TAB1 play a pivotal role as upstream signal transducers activating the MKK3-p38 MAPK signaling cascade that leads to the induction of type I collagen expression by TGF-beta(1). In addition, our findings also suggest that TAK1 has a novel function in regulation of the steady-state protein levels of MKK3 and p38 MAPK.	SIGNOR-42402
P16298	O00429	1	dephosphorylation	up-regulates activity	0.278	When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis.	SIGNOR-248361
P68400	P45973	1	phosphorylation	up-regulates	0.368	Hp1_ was multiply phosphorylated at n-terminal serine residues (s11-14) in human and mouse cells and that this phosphorylation enhanced hp1_'s affinity for h3k9me. Unphosphorylatable mutant hp1_ exhibited severe heterochromatin localization defects in vivo, and its prolonged expression led to increased chromosomal instability.	SIGNOR-171707
P35240	Q9Y4B6	2	binding	down-regulates quantity by destabilization	0.2	VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation. In this study, we provide evidence to show that Merlin is regulated in a Roc1-Cullin4A-DDB1-dependent manner. Following serum stimulation, Merlin is recruited to the E3 ligase complex through a direct interaction with the WD40-containing adaptor protein VprBP. Loading of Merlin to the E3 ubiquitin ligase complex resulted in its polyubiquitination, and consequently its proteasome-mediated degradation.	SIGNOR-271673
P52945	P49841	0	phosphorylation	down-regulates quantity	0.2	We show that glucose levels modulate PDX1 protein phosphorylation at a novel C-terminal GSK3 consensus that maps to serines 268 and 272. A decrease in glucose levels triggers increased turnover of the PDX1 protein in a GSK3-dependent manner, such that PDX1 phosphomutants are refractory to the destabilizing effect of low glucose	SIGNOR-255566
Q14814	Q09472	2	binding	up-regulates	0.743	Once released from associated repressors, MEF2 is bound by the p300 coactivator, which possesses histone acetyltransferase activity. Thus, the net result of CaMK signaling to MEF2 complexes is increased histone acetylation (Ac), which relaxes chromatin and stimulates MEF2 target gene transcription.	SIGNOR-232162
Q6VAB6	P48454	0	dephosphorylation	up-regulates activity	0.259	These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.\|the negative regulators 14-3-3	SIGNOR-248527
P49407	Q9Y496	2	binding	up-regulates	0.55	Kif3a is essential for shh-mediated signaling in mammalian systems (5), and we identified kif3a as a arr1 binding partner in a proteomics screen (18). To test whether arrs, smo, and kif3a might work in concert.	SIGNOR-178672
O43324	Q05086	0	ubiquitination	down-regulates quantity	0.2	These results strongly suggest that Ube3a decreases p18 levels via ubiquitination followed by proteasomal degradation.\|We demonstrate that Ube3a directly ubiquitinates p18 and targets it for proteasomal degradation, which normally limits mTORC1 signaling and activity dependent synaptic remodeling.	SIGNOR-278680
P04637	Q9Y4K3	0	ubiquitination	up-regulates activity	0.61	Here, we show that TRAF6 E3 ligase is a crucial factor to restrict mitochondrial translocation of p53 and spontaneous apoptosis by promoting K63-linked ubiquitination of p53 at K24 in cytosol, and such ubiquitination limits the interaction between p53 and MCL-1/BAK.\|We mutated every conserved lysine (K) residue on p53 and found that TRAF6 preferentially ubiquitinates p53 at K24 in the in vivo ubiquitination assay (XREF_FIG, XREF_SUPPLEMENTARY, XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY).	SIGNOR-278728
P41595	O95837	2	binding	up-regulates activity	0.435	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-257228
Q00535	Q9ULW0	1	phosphorylation	up-regulates quantity by stabilization	0.272	CDK5-mediated phosphorylation and stabilization of TPX2 promotes hepatocellular tumorigenesis	SIGNOR-265100
P12931	P29350	2	phosphorylation	up-regulates	0.527	Recombinant shp-1 had elevated activity subsequent to phosphorylation by src in vitro, and shp-1 variants with mutated phosphorylation sites in the c terminus, shp-1 y538f, and shp-1 y538f,y566f were less active toward src-generated phosphoproteins in intact cells.	SIGNOR-120492
Q9Y6X9	P17612	0	phosphorylation	up-regulates quantity by stabilization	0.2	Mechanistically, GPER1 activates PRKACA (protein kinase cAMP-activated catalytic subunit alpha), which in turn phosphorylates MORC2 at threonine 582 (T582). Phosphorylated MORC2 decreases its interaction with HSPA8 (heat shock protein family A [Hsp70] member 8) and LAMP2A (lysosomal associated membrane protein 2A), two core components of the chaperone-mediated autophagy (CMA) machinery, thus protecting MORC2 from lysosomal degradation by CMA.	SIGNOR-273781
P45983	Q9Y6W6	0	dephosphorylation	down-regulates	0.705	Mkp-5 directly dephosphorylates sapk/jnk and p38 in vitromkp-5 binds to p38 and sapk/jnk, but not to mapk/erk, and inactivates p38 and sapk/jnk	SIGNOR-68986
P17706	P40763	1	dephosphorylation	down-regulates	0.735	The nuclear isoform of protein-tyrosine phosphatase tc-ptp regulates interleukin-6-mediated signaling pathway through stat3 dephosphorylation.	SIGNOR-90818
P51170	P27361	0	phosphorylation	down-regulates quantity by destabilization	0.28	Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4.	SIGNOR-249449
O75376	P41182	2	binding	up-regulates activity	0.57	The POZ domains of BCL-6 and several other POZ proteins interact with corepressors N-CoR and SMRT.	SIGNOR-252239
P33032	O95837	2	binding	up-regulates activity	0.268	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-257393
P07948	Q9NWQ8	1	phosphorylation	up-regulates activity	0.725	Here we show that Lyn interacts with C-terminal Src kinase-binding protein (Cbp), an adaptor protein that recruits negative regulators C-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk). Lyn phosphorylated Cbp on several tyrosine residues, including Tyr314, which recruited Csk/Ctk to suppress Lyn kinase activity.Thus, a single phosphotyrosine residue on Cbp coordinates a two-phase process involving distinct negative regulatory pathways to inactivate, then degrade, Lyn.	SIGNOR-262898
P61586	O60890	0	gtpase-activating protein	up-regulates activity	0.636	OPHN-1 colocalized with the actin cytoskeleton in neuronal and glial cells. We have previously shown that OPHN1 stimulates GTPases activity of RhoA, Cdc42, and Rac1 in vitro	SIGNOR-268397
Q9UBE8	Q8N122	1	phosphorylation	down-regulates activity	0.327	NLK inhibits mTORC1 lysosomal localization and thereby suppresses mTORC1 activation. Mechanistically, NLK phosphorylates Raptor on S863 to disrupt its interaction with the Rag GTPase, which is important for mTORC1 lysosomal recruitment.	SIGNOR-273908
Q9H1B7	P01213	1	transcriptional regulation	down-regulates quantity by repression	0.263	EAP1 encoded a nuclear protein expressed in neurons involved in the inhibitory and facilitatory control of reproduction. EAP1 transactivated genes required for reproductive function, such as GNRH1, and repressed inhibitory genes, such as preproenkephalin. It contained a RING finger domain of the C3HC4 subclass required for this dual transcriptional activity.These results suggest that EAP1 is a transcriptional regulator that, acting within the neuroendocrine brain, contributes to controlling female reproductive function.	SIGNOR-267156
Q9NWQ8	P07948	0	phosphorylation	up-regulates activity	0.725	Here we show that Lyn interacts with C-terminal Src kinase-binding protein (Cbp), an adaptor protein that recruits negative regulators C-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk). Lyn phosphorylated Cbp on several tyrosine residues, including Tyr314, which recruited Csk/Ctk to suppress Lyn kinase activity.Thus, a single phosphotyrosine residue on Cbp coordinates a two-phase process involving distinct negative regulatory pathways to inactivate, then degrade, Lyn.	SIGNOR-262898
Q13144	P49841	0	phosphorylation	down-regulates activity	0.579	The largest (epsilon) subunit of eIF2B is a substrate for glycogen synthase kinase (GSK)-3 in vitro, and phosphorylation by GSK3 inhibits the activity of eIF2B. The site of phosphorylation has previously been identified as Ser(535).	SIGNOR-251236
O00755	Q9NPG1	2	binding	up-regulates activity	0.646	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-131897
Q15418	P35568	1	phosphorylation	down-regulates quantity by destabilization	0.358	Negative feedback involves s6k, which inactivates irs by phosphorylation at multiple sites, thus inducing its degradation and altered cell localization.	SIGNOR-175687
P09211	Q9NRD0	2	binding	down-regulates quantity by destabilization	0.2	Here, we show that loss of FBX8 accelerates chemical-induced colon tumorigenesis. FBX8 directly targets GSTP1 for ubiquitin-mediated proteasome degradation in CRC.	SIGNOR-272304
P19022	O60716	2	binding	up-regulates quantity by stabilization	0.736	To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member.	SIGNOR-252125
Q15797	Q09472	2	binding	up-regulates	0.405	Thus, Ski/SnoN represses TGFβ signaling by multiple mechanisms. In addition to recruitment of a transcriptional repressor complex and dissociation of the transcriptional coactivator p300/CBP from the Smads	SIGNOR-95462
P08254	Q99075	1	cleavage	up-regulates	0.517	It was concluded that mmp-3 cleaves hb-egf at a specific site in the jm domain and that this enzyme might regulate the conversion of hb-egf from being a juxtacrine to a paracrine/autocrine growth factor.	SIGNOR-83339
Q12926	O14672	1	post transcriptional regulation	up-regulates quantity	0.2	Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). The experiments show for the first time that ADAM10mRNA represents a nELAV target and that these RNA-binding proteins can play a role in the post-transcriptional regulation of ADAM10 expression. nELAV proteins specifically bind the ADAM10 mRNA and this binding is disrupted following Aβ exposure	SIGNOR-266863
Q9NQT8	Q7KZI7	0	phosphorylation	down-regulates activity	0.415	We report here the identification of GAKIN/KIF13B as a novel in vivo substrate for Par1b and present evidence that GAKIN/KIF13B plays a critical role in axon formation in neurons, which is negatively regulated by Par1b-mediated phosphorylation. Par1b phosphorylates GAKIN/KIF13B at both Ser1381 and Ser1410.	SIGNOR-262956
Q92793	P15172	1	acetylation	up-regulates	0.616	Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo.	SIGNOR-81050

O43603

P22466

2

binding

up-regulates

0.862

Galanin showed high affinity for the galr1 (ic(50) = 0.097 nm) and galr2 receptors (ic(50) = 0.48 nm).

SIGNOR-73125

P31751

Q2PPJ7

1

phosphorylation

down-regulates activity

0.453

RGC2 is an endogenous substrate for Akt2 downstream of PI 3-kinase

SIGNOR-269799

P17252

O75385

1

phosphorylation

down-regulates activity

0.2

ULK1 is phosphorylated by PKCalpha at S423 in vivo and in vitro.|PKC\u03b1 phosphorylation of ULK1 does not change its kinase activity

SIGNOR-279558

P67775

Q16549

0

phosphorylation

up-regulates

0.2

This together with the rapid kinetics of pp1-pp2a activation following p38 activation suggests that pp1 and/or pp2a complexes are direct targets for p38-mediated phosphorylation

SIGNOR-105783

O60291

Q99816

1

monoubiquitination

up-regulates activity

0.492

In the present study, we identified the first substrate of the Mahogunin E3 ubiquitin–protein ligase: TSG101, a key component of the endosomal sorting ESCRT machinery.We find that Mahogunin interacts with the ubiquitin E2 variant (UEV) domain of TSG101 via its PSAP motif and that it catalyzes monoubiquitylation of TSG101 both in vivo and in vitro. Consistent with the results of the biochemical characterization and subcellular localization studies of Mahogunin, our functional studies provide direct evidence that Mahogunin plays an essential role in regulation of endosome-to-lysosome trafficking. We found that siRNA-mediated depletion of Mahogunin in HeLa cells causes enlargement and clustering of EEA1-positive endosomes and LAMP2-positive late endosomes/lysosomes (Figure 8B) and inhibits the endosomal trafficking of internalized EGF–EGFR complexes to lysosomes for degradation (Figures 9 and and10,10, A and B). These results are strikingly similar to the phenotypes that resulted from depletion of TSG101

SIGNOR-271635

P20393

Q99743

1

transcriptional regulation

down-regulates quantity by repression

0.631

In this study, we found that NPAS2, like BMAL1, is a direct target gene of RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding.

SIGNOR-267981

P10243

P19338

2

binding

down-regulates activity

0.417

We identify nucleolin as one of the nuclear polypeptides that interact specifically with the A-Myb and c-Myb. We show that the interaction of nucleolin with Myb is functional because co-transfection of nucleolin down-regulates Myb transcriptional activity.

SIGNOR-221233

P25025

P25098

0

phosphorylation

down-regulates activity

0.2

Upon activation, GRK2 phosphorylates CXCR2 and causes receptor desensitization and internalization, leading to down-regulation of neutrophil chemotaxis

SIGNOR-260647

Q13451

P51608

0

transcriptional regulation

down-regulates quantity by repression

0.306

These results are compatible with the hypothesis that MeCP2 associates with the Sgk and Fkbp5 promoters and has a repressive effect that is over-ridden by elevated glucocorticoids in response to stress.

SIGNOR-264542

P50616

P45984

0

phosphorylation

down-regulates

0.34

Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro.

SIGNOR-91067

P68400

P31749

1

phosphorylation

up-regulates

0.372

CK2 hyperactivates AKT by phosphorylation at Ser129

SIGNOR-252595

Q9NPH9

Q08334

2

binding

up-regulates

0.601

See table 2

SIGNOR-151917

Q01094

Q13315

0

phosphorylation

up-regulates quantity by stabilization

0.679

Selective induction of e2f1 in response to dna damage, mediated by atm-dependent phosphorylation. We identify a site for atm/atr phosphorylation in the amino terminus of e2f1 and we show that this site is required for atm-mediated stabilization of e2f1. Finally, we also show that e2f1 is required for dna damaged induced apoptosis in mouse thymocytes.

SIGNOR-109416

O14842

P09471

2

binding

up-regulates activity

0.2

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

SIGNOR-257184

P01106

O60885

2

null

down-regulates activity

0.562

Conversely, MYC inhibits BRD4's HAT activity, suggesting that MYC regulates its own transcription by limiting BRD4-mediated chromatin remodeling of its locus.

SIGNOR-262047

P04049

P30086

2

binding

down-regulates

0.762

Suppression of raf-1 kinase activity and map kinase by rkip. Rkip binds to raf-1, mek and erk, but not to ras.

SIGNOR-70838

Q16204

P24941

0

phosphorylation

up-regulates

0.2

Serine 244 phosphorylation is required for h4 apoptotic function.

SIGNOR-121198

P28482

P67775

0

dephosphorylation

down-regulates activity

0.621

P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3).Mapk activity is tightly regulated by phosphorylation and dephosphorylation. The activation of the mapk activity requires the dual phosphorylation of the ser/thr and tyr residues in the txy kinase activation motif (1113), and deactivation occurs through the action of either ser/thr protein phosphatase

SIGNOR-103159

P25490

Q13547

0

deacetylation

down-regulates activity

0.798

Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs.

SIGNOR-268835

P80098

P32246

2

binding

up-regulates

0.742

For example, 11 chemokines are reported to bind to CC chemokine receptor (CCR) 1, including macrophage inflammatory protein (MIP)‐1α , MIP‐1β, MIP‐1δ, regulated upon activation, normal T cell‐expressed and secreted (RANTES), monocyte chemotactic peptide (MCP)‐1, MCP‐2, MCP‐3, MCP‐4, leukotactin‐1 (Lkn‐1), myeloid progenitor inhibitory factor (MPIF)‐1, and hemofiltrate CC chemokine (HCC)‐1

SIGNOR-254368

P17612

Q14738

1

phosphorylation

up-regulates

0.2

Protein kinase a activates protein phosphatase 2a by phosphorylation of the b56delta subunit.

SIGNOR-153218

Q15831

Q9NRH2

1

phosphorylation

up-regulates activity

0.367

We demonstrate that LKB1 activates SNRK by phosphorylating the T‐loop residue (Thr173)

SIGNOR-260824

P31314

P67775

2

binding

down-regulates activity

0.308

HOX11 also inhibited PP2A serine/threonine phosphatase activity concomitant with stimulation of the AKT/PKB signaling cascade.

SIGNOR-240719

P46531

O00587

2

binding

up-regulates

0.72

Manic fringe elongates the o-linked fucose saccharides on full-length notch1 and notch1 egf repeats 1923.

SIGNOR-80555

O95837

P41968

2

binding

up-regulates activity

0.25

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

SIGNOR-257298

O60934

P24941

0

phosphorylation

up-regulates activity

0.507

Nbs1 is phosphorylated by Cdk2 on Ser432 in human whole-cell extracts.

SIGNOR-279500

Q13557

O15084

1

phosphorylation

down-regulates activity

0.2

We provide evidence for a dual kinase-mediated regulation of the PITK holoenzyme whereby PITK phosphorylation at S1017 is catalyzed by calcium/calmodulin-dependent kinase II-delta (CaMKIIdelta), promoting the subsequent phosphorylation of S1013 by glycogen synthase kinase-3 (GSK3) in vitro.|the phosphorylation of PITK at these specific residues altered PP1 binding and subsequent PITK-directed dephosphorylation of hnRNP K

SIGNOR-264793

O60266

Q13555

0

phosphorylation

down-regulates activity

0.353

Phosphorylation and inhibition of type III adenylyl cyclase by calmodulin-dependent protein kinase II in vivo. | Site-directed mutagenesis of a CaM kinase II consensus site (Ser-1076 to Ala-1076) in III-AC greatly reduced Ca2+-stimulated phosphorylation and inhibition of III-AC in vivo.

SIGNOR-250691

P06493

Q14790

1

phosphorylation

down-regulates

0.361

In this study, we demonstrate that procaspase-8 is phosphorylated in mitotic cells by cdk1na interference-mediated silencing of cyclin b1 or treatment with the cdk1 inhibitor ro-3306 enhances the fas-mediated activation and processing of procaspase-8 in mitotic cells/cyclin b1 on ser-387

SIGNOR-168446

P24941

P06400

1

phosphorylation

down-regulates

0.884

We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein.

SIGNOR-47895

P31751

Q00987

1

phosphorylation

up-regulates quantity by stabilization

0.56

Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.. Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186.

SIGNOR-109732

Q99801

P53671

0

phosphorylation

down-regulates activity

0.2

LIMK2 also downregulates NKX3.1 mRNA levels.|While WT-NKX3.1 was efficiently phosphorylated, the S185A mutant showed no phosphorylation ( xref A), confirming that LIMK2 only phosphorylates the S185 site in NKX3.1.

SIGNOR-278951

P06241

P42681

1

phosphorylation

up-regulates activity

0.347

We further demonstrate that Rlk can be phosphorylated and activated by Src kinases, leading to a decrease in its half-life. A specific tyrosine in the activation loop of Rlk, Y420, is required for phosphorylation and activation, as well as for decreased stability, but is not required for lipid RAFT association.

SIGNOR-249341

Q9HCK8

P07197

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-268917

P01588

P19235

2

binding

up-regulates

0.876

Binding of erythropoietin (epo) to the epo receptor (epor) initiates a signaling cascade resulting in tyrosine phosphorylation of several proteins and induction of ap-1 transcription factor(s).

SIGNOR-55300

Q92934

Q86V86

0

phosphorylation

down-regulates activity

0.346

Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells.

SIGNOR-250399

P84103

Q9UBU9

2

binding

up-regulates

0.68

9g8 and srp20 also enhance the tap rna-binding activity

SIGNOR-178111

P04637

P78527

0

phosphorylation

up-regulates

0.793

We demonstrate that phosphorylation of p53 at serines 15 and 37 impairs the ability of mdm2 to inhibit p53-dependent transactivation. We present evidence that these effects are most likely due to a conformational change induced upon phosphorylation of p53. Our studies provide a plausible mechanism by which the induction of p53 can be modulated by dna-pk (or other protein kinases with similar specificity) in response to dna damage.

SIGNOR-53030

P62805

O14929

0

acetylation

down-regulates activity

0.2

Histone acetyltransferase 1 is the founding member of the histone acetyltransferase superfamily and catalyzes lysine acetylation of newly synthesized histone H4|Lys12 for direct attack of the acetyl group of the cofactor.| It is postulated that histone acetylation, through charge neutralization of the cationic histone tails, weakens nucleosomal electrostatic interactions with anionic DNA, thus destabilizing internucleosomal contacts and nucleosomal structure and facilitating access to the promoter region for RNA polymerase and transcription factors.

SIGNOR-264790

Q66K74

Q13618

0

ubiquitination

down-regulates quantity

0.242

Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B.

SIGNOR-268947

Q12852

O14733

1

phosphorylation

up-regulates activity

0.556

Collectively, these data suggest the hypothesis that ApoE activates DLK by increasing its levels

SIGNOR-279630

Q92630

P10070

1

phosphorylation

down-regulates quantity by destabilization

0.3

DYRK2 directly phosphorylated Gli2 sequences and resulted in the loss of coexpressed GLI proteins, indicating that DYRK2 acts by inducing the phosphorylation and degradation of GLI proteins via the ubiquitin and proteasome pathway.

SIGNOR-279034

P35226

O43791

2

binding

up-regulates activity

0.4

Here, we describe an E3 ubiquitin ligase consisting of SPOP and CULLIN3 that is able to ubiquitinate the PcG protein BMI1 and the variant histone MACROH2A1. To investigate whether BMI1 can form a complex with SPOP and CULLIN3 in vivo, we reconstituted the complex in 293HEK cells. We find that BMI1 readily immunoprecipitates both hemagglutinin (HA)-SPOP and CULLIN3, and, conversely, CULLIN3 immunoprecipitates BMI1 (Fig. 2a). Complex formation depends on the presence of SPOP, in accordance with BMI1 binding to the MATH domain of SPOP (Fig. 1b) and previously published data showing SPOP–CULLIN interaction by means of the BTB/POZ domain of SPOP (30).

SIGNOR-272658

P04626

Q9BXH1

1

phosphorylation

down-regulates quantity by destabilization

0.281

HER2 phosphorylates and destabilizes pro-apoptotic PUMA. Using an intracellular assay, we found PUMA to be phosphorylated in breast cancer cells with activated HER2. Via cell-free HER2 kinase assay, we observed that PUMA was directly phosphorylated by HER2. Activation of HER2 decreased PUMA protein half-life.

SIGNOR-276474

Q9HC98

P0DMV8

1

phosphorylation

up-regulates activity

0.425

Mitotic phosphorylation of Hsp72 by the kinase NEK6 at Thr66 located in the NBD promotes the localization of Hsp72 to the mitotic spindle and is required for efficient spindle assembly and chromosome congression and segregation.

SIGNOR-273885

Q9ULV5

P52564

0

phosphorylation

up-regulates activity

0.2

Regulation of Hsf4b nuclear translocation and transcription activity by phosphorylation at threonine 472| At the upstream, MEK6 was found to interact with Hsf4b and enhance Hsf4b's nuclear translocation and transcription activity, probably by phosphorylation at sites such as T472. Taken together, our results suggest that phosphotylation of Hsf4b at T472 by protein kinases such as MEI

SIGNOR-275493

Q4FZB7

P62805

1

methylation

down-regulates activity

0.2

SUV420H1 and SUV420H2 are two highly homologous enzymes that methylate lysine 20 of histone H4 (H4K20), a mark that has been implicated in transcriptional regulation.

SIGNOR-266651

P15882

P63000

1

gtpase-activating protein

down-regulates activity

0.666

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-260499

P08253

P01023

2

cleavage

down-regulates quantity by destabilization

0.636

The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.

SIGNOR-261739

Q01344

Q06945

2

binding

up-regulates activity

0.417

Sox4 activation by IL-5R_ appears to be direct, with syntenin functioning as an adaptor molecule. Syntenin mediates IL-5induced Sox4 activation.

SIGNOR-223010

P08620

P22455

2

binding

up-regulates

0.672

Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides.

SIGNOR-18567

O75093

Q12857

0

transcriptional regulation

up-regulates quantity

0.257

For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)

SIGNOR-268892

Q15562

Q9GZV5

2

binding

up-regulates

0.808

When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14.

SIGNOR-201382

Q13627

P46531

1

phosphorylation

down-regulates

0.396

Dyrk1a physically interacts with the nicd inducing its phosphorylation in the ankyrin domain, thereby attenuating notch .

SIGNOR-185494

Q9UBF6

P05412

1

ubiquitination

down-regulates activity

0.324

SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase. by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes.

SIGNOR-271452

Q14694

Q13131

0

phosphorylation

up-regulates activity

0.309

Under energy stress, USP10 activity in turn is enhanced through AMPK-mediated phosphorylation of Ser76 of USP10.

SIGNOR-277207

Q5S007

P15311

1

phosphorylation

up-regulates activity

0.411

LRRK2 also phosphorylated ezrin and radixin, which are related to moesin, at the residue equivalent to Thr558, as well as a peptide (LRRKtide: RLGRDKYKTLRQIRQ) encompassing Thr558.

SIGNOR-279202

O75385

Q9Y4K3

0

ubiquitination

up-regulates quantity by stabilization

0.548

AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function.

SIGNOR-273000

P04049

Q16512

0

phosphorylation

up-regulates

0.2

Interaction between active pak1 and raf-1 is necessary for phosphorylation and activation of raf-1.

SIGNOR-112549

P01160

P16066

2

binding

up-regulates

0.887

Natriuretic peptide receptor-a (npra) is the biological receptor of the peptide hormones atrial natriuretic peptide (anp) and brain natriuretic peptide (bnp)

SIGNOR-137600

Q92529

P62993

1

relocalization

up-regulates

0.819

In addition to direct binding of grb2 to phosphotyrosine residues of receptor kinases, grb2 can also be recruited to the receptor by binding to shc when shc is tyrosine phosphorylated as a result of receptor stimulation.

SIGNOR-146897

P45973

Q16695

2

binding

up-regulates activity

0.2

A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing.

SIGNOR-264489

Q9UNN4

P19784

0

phosphorylation

up-regulates activity

0.414

ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled.

SIGNOR-250993

P29350

P07948

2

dephosphorylation

down-regulates activity

0.734

SHP-1 efficiently inhibits Lyn autophosphorylation and suppresses FcϵRI stimulation|We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397

SIGNOR-248471

O14920

Q13568

1

phosphorylation

up-regulates activity

0.37

Here we present evidence that the kinase IKKbeta phosphorylates and activates IRF5 in response to stimulation in several inflammatory pathways, including those emanated from Toll like receptors and retinoic acid inducible gene I like receptors.|Recombinant IKK\u03b2 phosphorylated IRF5 at Ser-445 in vitro, and a point mutation of this serine abolished IRF5 activation and cytokine production.

SIGNOR-279466

Q07820

Q9Y4K3

0

ubiquitination

up-regulates activity

0.396

TRAF6 likely directly ubiquitinates MCL-1 since purified TRAF6 promoted the ubiquitination of recombinant GST-MCL-1 and co-expression of Tax with TRAF6 further enhanced MCL-1 ubiquitination .|Therefore, TRAF6 mediated MCL-1 stabilization appears to be a common mechanism of cell survival usurped by both viral and non viral cancers.

SIGNOR-278726

P46734

O43318

0

phosphorylation

up-regulates activity

0.505

Taken together, our data indicate that TAK1 and TAB1 play a pivotal role as upstream signal transducers activating the MKK3-p38 MAPK signaling cascade that leads to the induction of type I collagen expression by TGF-beta(1). In addition, our findings also suggest that TAK1 has a novel function in regulation of the steady-state protein levels of MKK3 and p38 MAPK.

SIGNOR-42402

P16298

O00429

1

dephosphorylation

up-regulates activity

0.278

When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis.

SIGNOR-248361

P68400

P45973

1

phosphorylation

up-regulates

0.368

Hp1_ was multiply phosphorylated at n-terminal serine residues (s11-14) in human and mouse cells and that this phosphorylation enhanced hp1_'s affinity for h3k9me. Unphosphorylatable mutant hp1_ exhibited severe heterochromatin localization defects in vivo, and its prolonged expression led to increased chromosomal instability.

SIGNOR-171707

P35240

Q9Y4B6

2

binding

down-regulates quantity by destabilization

0.2

VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation. In this study, we provide evidence to show that Merlin is regulated in a Roc1-Cullin4A-DDB1-dependent manner. Following serum stimulation, Merlin is recruited to the E3 ligase complex through a direct interaction with the WD40-containing adaptor protein VprBP. Loading of Merlin to the E3 ubiquitin ligase complex resulted in its polyubiquitination, and consequently its proteasome-mediated degradation.

SIGNOR-271673

P52945

P49841

0

phosphorylation

down-regulates quantity

0.2

We show that glucose levels modulate PDX1 protein phosphorylation at a novel C-terminal GSK3 consensus that maps to serines 268 and 272. A decrease in glucose levels triggers increased turnover of the PDX1 protein in a GSK3-dependent manner, such that PDX1 phosphomutants are refractory to the destabilizing effect of low glucose

SIGNOR-255566

Q14814

Q09472

2

binding

up-regulates

0.743

Once released from associated repressors, MEF2 is bound by the p300 coactivator, which possesses histone acetyltransferase activity. Thus, the net result of CaMK signaling to MEF2 complexes is increased histone acetylation (Ac), which relaxes chromatin and stimulates MEF2 target gene transcription.

SIGNOR-232162

Q6VAB6

P48454

0

dephosphorylation

up-regulates activity

0.259

These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3

SIGNOR-248527

P49407

Q9Y496

2

binding

up-regulates

0.55

Kif3a is essential for shh-mediated signaling in mammalian systems (5), and we identified kif3a as a arr1 binding partner in a proteomics screen (18). To test whether arrs, smo, and kif3a might work in concert.

SIGNOR-178672

O43324

Q05086

0

ubiquitination

down-regulates quantity

0.2

These results strongly suggest that Ube3a decreases p18 levels via ubiquitination followed by proteasomal degradation.|We demonstrate that Ube3a directly ubiquitinates p18 and targets it for proteasomal degradation, which normally limits mTORC1 signaling and activity dependent synaptic remodeling.

SIGNOR-278680

P04637

Q9Y4K3

0

ubiquitination

up-regulates activity

0.61

Here, we show that TRAF6 E3 ligase is a crucial factor to restrict mitochondrial translocation of p53 and spontaneous apoptosis by promoting K63-linked ubiquitination of p53 at K24 in cytosol, and such ubiquitination limits the interaction between p53 and MCL-1/BAK.|We mutated every conserved lysine (K) residue on p53 and found that TRAF6 preferentially ubiquitinates p53 at K24 in the in vivo ubiquitination assay (XREF_FIG, XREF_SUPPLEMENTARY, XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY).

SIGNOR-278728

P41595

O95837

2

binding

up-regulates activity

0.435

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-257228

Q00535

Q9ULW0

1

phosphorylation

up-regulates quantity by stabilization

0.272

CDK5-mediated phosphorylation and stabilization of TPX2 promotes hepatocellular tumorigenesis

SIGNOR-265100

P12931

P29350

2

phosphorylation

up-regulates

0.527

Recombinant shp-1 had elevated activity subsequent to phosphorylation by src in vitro, and shp-1 variants with mutated phosphorylation sites in the c terminus, shp-1 y538f, and shp-1 y538f,y566f were less active toward src-generated phosphoproteins in intact cells.

SIGNOR-120492

Q9Y6X9

P17612

0

phosphorylation

up-regulates quantity by stabilization

0.2

Mechanistically, GPER1 activates PRKACA (protein kinase cAMP-activated catalytic subunit alpha), which in turn phosphorylates MORC2 at threonine 582 (T582). Phosphorylated MORC2 decreases its interaction with HSPA8 (heat shock protein family A [Hsp70] member 8) and LAMP2A (lysosomal associated membrane protein 2A), two core components of the chaperone-mediated autophagy (CMA) machinery, thus protecting MORC2 from lysosomal degradation by CMA.

SIGNOR-273781

P45983

Q9Y6W6

0

dephosphorylation

down-regulates

0.705

Mkp-5 directly dephosphorylates sapk/jnk and p38 in vitromkp-5 binds to p38 and sapk/jnk, but not to mapk/erk, and inactivates p38 and sapk/jnk

SIGNOR-68986

P17706

P40763

1

dephosphorylation

down-regulates

0.735

The nuclear isoform of protein-tyrosine phosphatase tc-ptp regulates interleukin-6-mediated signaling pathway through stat3 dephosphorylation.

SIGNOR-90818

P51170

P27361

0

phosphorylation

down-regulates quantity by destabilization

0.28

Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4.

SIGNOR-249449

O75376

P41182

2

binding

up-regulates activity

0.57

The POZ domains of BCL-6 and several other POZ proteins interact with corepressors N-CoR and SMRT.

SIGNOR-252239

P33032

O95837

2

binding

up-regulates activity

0.268

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-257393

P07948

Q9NWQ8

1

phosphorylation

up-regulates activity

0.725

Here we show that Lyn interacts with C-terminal Src kinase-binding protein (Cbp), an adaptor protein that recruits negative regulators C-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk). Lyn phosphorylated Cbp on several tyrosine residues, including Tyr314, which recruited Csk/Ctk to suppress Lyn kinase activity.Thus, a single phosphotyrosine residue on Cbp coordinates a two-phase process involving distinct negative regulatory pathways to inactivate, then degrade, Lyn.

SIGNOR-262898

P61586

O60890

0

gtpase-activating protein

up-regulates activity

0.636

OPHN-1 colocalized with the actin cytoskeleton in neuronal and glial cells. We have previously shown that OPHN1 stimulates GTPases activity of RhoA, Cdc42, and Rac1 in vitro

SIGNOR-268397

Q9UBE8

Q8N122

1

phosphorylation

down-regulates activity

0.327

NLK inhibits mTORC1 lysosomal localization and thereby suppresses mTORC1 activation. Mechanistically, NLK phosphorylates Raptor on S863 to disrupt its interaction with the Rag GTPase, which is important for mTORC1 lysosomal recruitment.

SIGNOR-273908

Q9H1B7

P01213

1

transcriptional regulation

down-regulates quantity by repression

0.263

EAP1 encoded a nuclear protein expressed in neurons involved in the inhibitory and facilitatory control of reproduction. EAP1 transactivated genes required for reproductive function, such as GNRH1, and repressed inhibitory genes, such as preproenkephalin. It contained a RING finger domain of the C3HC4 subclass required for this dual transcriptional activity.These results suggest that EAP1 is a transcriptional regulator that, acting within the neuroendocrine brain, contributes to controlling female reproductive function.

SIGNOR-267156

Q9NWQ8

P07948

0

phosphorylation

up-regulates activity

0.725

Here we show that Lyn interacts with C-terminal Src kinase-binding protein (Cbp), an adaptor protein that recruits negative regulators C-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk). Lyn phosphorylated Cbp on several tyrosine residues, including Tyr314, which recruited Csk/Ctk to suppress Lyn kinase activity.Thus, a single phosphotyrosine residue on Cbp coordinates a two-phase process involving distinct negative regulatory pathways to inactivate, then degrade, Lyn.

SIGNOR-262898

Q13144

P49841

0

phosphorylation

down-regulates activity

0.579

The largest (epsilon) subunit of eIF2B is a substrate for glycogen synthase kinase (GSK)-3 in vitro, and phosphorylation by GSK3 inhibits the activity of eIF2B. The site of phosphorylation has previously been identified as Ser(535).

SIGNOR-251236

O00755

Q9NPG1

2

binding

up-regulates activity

0.646

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-131897

Q15418

P35568

1

phosphorylation

down-regulates quantity by destabilization

0.358

Negative feedback involves s6k, which inactivates irs by phosphorylation at multiple sites, thus inducing its degradation and altered cell localization.

SIGNOR-175687

P09211

Q9NRD0

2

binding

down-regulates quantity by destabilization

0.2

Here, we show that loss of FBX8 accelerates chemical-induced colon tumorigenesis. FBX8 directly targets GSTP1 for ubiquitin-mediated proteasome degradation in CRC.

SIGNOR-272304

P19022

O60716

2

binding

up-regulates quantity by stabilization

0.736

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

SIGNOR-252125

Q15797

Q09472

2

binding

up-regulates

0.405

Thus, Ski/SnoN represses TGFβ signaling by multiple mechanisms. In addition to recruitment of a transcriptional repressor complex and dissociation of the transcriptional coactivator p300/CBP from the Smads

SIGNOR-95462

P08254

Q99075

1

cleavage

up-regulates

0.517

It was concluded that mmp-3 cleaves hb-egf at a specific site in the jm domain and that this enzyme might regulate the conversion of hb-egf from being a juxtacrine to a paracrine/autocrine growth factor.

SIGNOR-83339

Q12926

O14672

1

post transcriptional regulation

up-regulates quantity

0.2

Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). The experiments show for the first time that ADAM10mRNA represents a nELAV target and that these RNA-binding proteins can play a role in the post-transcriptional regulation of ADAM10 expression. nELAV proteins specifically bind the ADAM10 mRNA and this binding is disrupted following Aβ exposure

SIGNOR-266863

Q9NQT8

Q7KZI7

0

phosphorylation

down-regulates activity

0.415

We report here the identification of GAKIN/KIF13B as a novel in vivo substrate for Par1b and present evidence that GAKIN/KIF13B plays a critical role in axon formation in neurons, which is negatively regulated by Par1b-mediated phosphorylation. Par1b phosphorylates GAKIN/KIF13B at both Ser1381 and Ser1410.

SIGNOR-262956

Q92793

P15172

1

acetylation

up-regulates

0.616

Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo.

SIGNOR-81050