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
Q9UPU5	Q07812	1	deubiquitination	up-regulates quantity by stabilization	0.2	In this study, several cancer-related proteins (Bax, p300, E2F4 and securin) have been proven to be substrates of ubiquitin-specific peptidase 24 (USP24), and relevance has been shown between USP24 and its substrates in samples from clinical lung cancer patients. \|Knockdown of USP24 decreases Bax and p300 levels	SIGNOR-275606
O60674	P15509	2	phosphorylation	up-regulates activity	0.533	JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation.	SIGNOR-249503
P49715	P27361	0	phosphorylation	down-regulates	0.371	Ccaat/enhancer-binding protein alpha (c/ebpalpha) is one of the key transcription factors that mediate lineage specification and differentiation of multipotent myeloid progenitors into mature granulocytes.Here we report that inducers of monocyte differentiation inhibit the alternate cell fate choice, that of granulopoiesis, through inhibition of c/ebpalpha. This inhibition is mediated by extracellular signal-regulated kinases 1 and/or 2 (erk1/2), which interact with c/ebpalpha through an fxfp docking site and phosphorylate serine 21.	SIGNOR-120570
Q9Y4K3	Q15654	2	binding	up-regulates activity	0.28	Our results revealed that TRIP6 could enhance TRAF6 oligomerization and TRAF6 autoubiquitination through its interaction	SIGNOR-280455
Q9HCE1	Q14164	2	binding	up-regulates activity	0.2	MOV10 enhances IRF3 activation and IRF3-mediated gene induction. This indicated that MOV10-mediated antiviral activity is most likely mediated through IKKε and not through TBK1. Involvement of IKKε was further established by examining the physical interaction of MOV10 and IKKε.	SIGNOR-261138
Q13535	P38398	1	phosphorylation	up-regulates activity	0.8	Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion.	SIGNOR-106432
Q8N2W9	Q05513	0	phosphorylation	down-regulates quantity by destabilization	0.519	In this study, we discovered a new protein isoform encoded by KIAA0317, termed fibrosis-inducing E3 ligase 1 (FIEL1), which potently stimulates the TGFbeta signaling pathway through the site-specific ubiquitination of PIAS4.FIEL1 targets PIAS4 using a double locking mechanism that is facilitated by the kinases PKCzeta and GSK3beta. Specifically, PKCzeta phosphorylation of PIAS4 and GSK3beta phosphorylation of FIEL1 are both essential for the degradation of PIAS4.\|These experiments suggested that PKCzeta is an authentic regulator of PIAS4 protein stability; Q21 and phosphorylated S18 of PIAS4 are both required for FIEL1 interaction.	SIGNOR-275513
P17612	P18846	1	phosphorylation	up-regulates activity	0.451	PKA catalytic subunit phosphorylates ATF-1 at Ser63 and that phosphorylation is essential for efficient DNA binding by ATF-1.	SIGNOR-250336
Q96IV0	Q04323	2	binding	up-regulates activity	0.488	PNGase is directed to polyubiquitinated MGPs via VCP and the adaptor protein SAKS1, allowing PNGase to deglycosylate MGPs, which can then be degraded by the proteasome. PNGase itself is reported to bind to the S4 component of the 19 S proteasome.	SIGNOR-261060
Q09472	P35558	1	acetylation	down-regulates quantity by destabilization	0.546	Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase\|P300 Acetylates and Destabilizes PEPCK1\|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1	SIGNOR-267603
Q96SB4	P54793	1	phosphorylation	up-regulates activity	0.2	Phosphorylation by SRPK1 drives ASF from the cytosol to the nucleus.\|Phosphorylation of ASF by SR protein kinase 1 (SRPK1) in the cytosol results in ASF relocation to the nucleus, whereas phosphorylation of ASF by Clk and Sty releases ASF from speckles and recruits it into nascent transcripts where ASF regulates alternative splicing.	SIGNOR-279765
Q13418	O14974	1	phosphorylation	down-regulates activity	0.584	MYPT1 was phosphorylated by ILK and phosphorylation sites in the N- and C-terminal fragments of MYPT1 were detected. From sequence analyses, three sites were identified: a primary site at Thr(709), and two other sites at Thr(695) and Thr(495). ILK produced an intermediate level of inhibition	SIGNOR-262884
P24588	P17612	1	relocalization	up-regulates activity	0.561	In this report, we demonstrate that glutamate receptors and PKA are recruited into a macromolecular signaling complex through direct interaction between the MAGUK proteins, PSD-95 and SAP97, and AKAP79/150	SIGNOR-261292
Q01196	P01106	1	transcriptional regulation	down-regulates quantity by repression	0.337	RUNX1 represses MYC expression through direct binding at three downstream enhancer elements	SIGNOR-260093
Q00535	P46531	1	phosphorylation	up-regulates activity	0.32	An in vitro kinase reaction demonstrated that T2132, S2136, and S2141 were CDK5\u2010phosphorylated sites in the Notch1 peptide (Figure\u00a02B, C, and D).\|In conclusion, CDK5 positively regulates Notch1 function via phosphorylation, which in turn promotes cell proliferation and migration.	SIGNOR-279401
Q9Y276	O95202	2	binding	up-regulates activity	0.464	LETM1 was co-precipitated with BCS1L and formation of the LETM1 complex depended on BCS1L levels, suggesting that BCS1L stimulates the assembly of the LETM1 complex.	SIGNOR-262543
P47736	Q9Y297	0	ubiquitination	down-regulates	0.342	Here, we demonstrated that rap1gap is ubiquitinated and degraded through proteasome pathway in mitosis. Proteolysis of rap1gap requires the plk1 kinase and _-trcp ubiquitin ligase complex.	SIGNOR-203548
P33981	Q02224	1	phosphorylation	up-regulates activity	0.43	Strikingly, phosphorylation of Cenp-E C tail by wild-type (WT) MPS1 or CDK1-cyclin B completely reverses its inhibitory effect toward Cenp-E motor ATPase in solution.	SIGNOR-278999
P53805	Q14469	0	transcriptional regulation	down-regulates quantity by repression	0.2	Increased Calcineurin/NFAT activity by Notch signaling involves downregulation of Calcipressin, an endogenous Calcineurin inhibitor, through a HES-1-dependent mechanism .... Chromatin immunoprecipitation (ChIP) analysis of keratinocytes overexpressing HES-1 showed that this protein can bind to the HES binding sites present in both distal and proximal promoters	SIGNOR-252026
P31749	P54578	1	phosphorylation	up-regulates activity	0.424	Phosphorylation and activation of ubiquitin-specific protease-14 by Akt regulates the ubiquitin-proteasome system\|These results suggested S432 as a major and S143 as a minor phosphorylation site of Akt.	SIGNOR-265056
Q9UKY1	Q15326	2	binding	down-regulates activity	0.491	Corepressor BS69 interacts with ZHX1, a member of the ZHX family having zinc-fingers and homeoboxes. Although BS69 was originally found as a corepressor interacting with ZHX1, BS69 was also found to function as a transcriptional activator in HEK293 cells, in which the activation required the MYND domain of BS69. Co-transfection of BS69 with a mutant form of ZHX1, which cannot interact with BS69, led to increase the transcriptional activation of BS69, suggesting that transcriptional activation mediated by BS69 is suppressed by ZHX1.	SIGNOR-263898
P01009	Q07954	2	binding	up-regulates	0.322	In vitro binding studies revealed that antithrombin iii (atiii)thrombin, heparin cofactor ii (hcii)thrombin, and ?1-antitrypsin (?1AT)trypsin bound to purified lrp	SIGNOR-41180
P28335	P50148	2	binding	up-regulates activity	0.568	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-257221
Q13501	Q9Y4E8	0	deubiquitination	down-regulates activity	0.26	SQSTM1 Is a Substrate for RNF26 and the DUB USP15. Catalytically competent RNF26 (light red) recruits SQSTM1 (blue) and mediates ubiquitin ligation (red), which serves to attract UBDs of specific vesicle-associated adaptors. Dissociation of the RNF26/SQSTM1 complex, promoted by the DUB USP15 (yellow), releases target vesicles for (4) fast transport into the cell periphery.	SIGNOR-269829
Q9GZM8	Q14204	2	binding	up-regulates activity	0.72	LIS1 specifically binds the P1 loop domain of CDHC, while NUDEL binds the C-terminal region as well as a distinct binding site in the P1 loop domain. LIS1 and NUDEL regulate CDHC localization and motor function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex	SIGNOR-252159
Q9Y4K3	P36897	2	binding	up-regulates activity	0.428	We report here that TRAF6 is specifically required for the Smad-independent activation of JNK and p38 and its carboxyl TRAF homology domain physically interacts with TGF-² receptors	SIGNOR-241918
P06239	Q9UQQ2	1	phosphorylation	up-regulates	0.569	In vitro tyrosine phosphorylation of lnk by lck and zap-70. Tyrosine 297 would appear to be an attractive target for phosphorylation within the c-terminal domain. Our studies suggest that although lnk may participate in tcr signaling, its functions are in no way limiting during t cell development or activation.	SIGNOR-48850
P01222	P16473	2	binding	up-regulates	0.722	Two novel human glycoprotein hormonelike genes, alpha2 (a2) and beta5 (b5), recently have been identified. Using a yeast two-hybrid assay, the two subunits were found as potential heterodimerization partners.	SIGNOR-88653
P18146	P68400	0	phosphorylation	down-regulates activity	0.464	Casein kinase II associates with Egr-1 and acts as a negative modulator of its DNA binding and transcription activities in NIH 3T3 cells. \| There are three CKII recognition sites (S376XXD, T389XE, and T516XXXD) in fragment 10.	SIGNOR-250858
O95622	O14775	2	binding	down-regulates activity	0.456	The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC	SIGNOR-264998
P05198	Q86TM6	0	ubiquitination	down-regulates quantity by destabilization	0.2	HRD1 overexpression also decreased the expression of eIF2alpha and p-eIF2alpha in HKC-8 cells.\|HRD1 promoted eIF2alpha ubiquitylation and degradation, thereby providing a protective mechanism that suppressed tubular epithelial cell apoptosis.	SIGNOR-278671
Q9H0K1	Q15831	0	phosphorylation	up-regulates	0.481	A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold.	SIGNOR-122788
P41212	Q16549	0	phosphorylation	down-regulates	0.2	In vivo p38-dependent phosphorylation reduced trans-repressional abilities of tel through ets-binding consensus site	SIGNOR-95622
P48729	Q8NEG4	2	binding	up-regulates quantity	0.2	We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates.	SIGNOR-273751
Q9H1C0	Q14344	2	binding	up-regulates activity	0.35	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-257284
Q9NYD6	P55268	1	transcriptional regulation	up-regulates quantity by expression	0.2	The specificity of binding of these two proteins to the Lamin B2 origin is confirmed by both band-shift and in vitro footprinting assays. In addition, the ability of HOXC10 and HOXC13 to increase the activity of a promoter containing the 74 bp sequence, as assayed by CAT-assay experiments, demonstrates a direct interaction of these homeoproteins with the origin sequence in mammalian cells.	SIGNOR-261645
O00238	O95630	1	phosphorylation	up-regulates activity	0.29	BMP type I receptor activation stimulates AMSH phosphorylation \| The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. \| Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads.	SIGNOR-250600
Q9GZZ0	P05556	1	transcriptional regulation	up-regulates quantity by expression	0.2	Consistently, ITGB1 promoter activity was decreased by HOXD1 knockdown in ECs. Furthermore, we identified the putative HOXD1-binding sites in the promoter region of ITGB1. Together, these findings suggest that HOXD1 plays a significant role in EC functions by regulating the expression of ITGB1.	SIGNOR-261648
Q15326	Q9UKY1	2	binding	down-regulates activity	0.491	Corepressor BS69 interacts with ZHX1, a member of the ZHX family having zinc-fingers and homeoboxes. Although BS69 was originally found as a corepressor interacting with ZHX1, BS69 was also found to function as a transcriptional activator in HEK293 cells, in which the activation required the MYND domain of BS69. Co-transfection of BS69 with a mutant form of ZHX1, which cannot interact with BS69, led to increase the transcriptional activation of BS69, suggesting that transcriptional activation mediated by BS69 is suppressed by ZHX1.	SIGNOR-263898
P01106	P45983	0	phosphorylation	up-regulates activity	0.556	The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71.	SIGNOR-236018
Q8NFU7	Q96SR6	1	transcriptional regulation	up-regulates quantity by expression	0.2	Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9.	SIGNOR-259095
Q9UQM7	P51790	1	phosphorylation	up-regulates activity	0.337	Identification of an N-terminal amino acid of the CLC-3 chloride channel critical in phosphorylation-dependent activation of a CaMKII-activated chloride current\|The N-terminus of CLC-3, which contains a CaMKII consensus sequence, was phosphorylated by CaMKII in vitro, and mutation of the serine at position 109 (S109A) abolished the CaMKII-dependent Cl(-) conductance, indicating that this residue is important in the gating of CLC-3 at the plasma membrane.	SIGNOR-275863
Q9UNA0	P16112	1	cleavage	down-regulates quantity by destabilization	0.765	Aggrecan Degradation in Human Cartilage Evidence for both Matrix Metalloproteinase and Aggrecanase Activity in Normal, Osteoarthritic, and Rheumatoid Joints\|Stromelysin-1 (MMP-3), as well as other MMPs, cleave aggrecan in the interglobular domain between Asn341 and Phe342 to generate a G1 fragment with the COOH terminus VDIPEN341 (11–13). This fragment has been isolated and identified by NH2-terminal sequence analysis from human OA cartilage (11). A second proteolytic activity identified as “aggrecanase” also cleaves aggrecan in the interglobular domain, but between Glu373 and Ala374 (19–24), generating a G1 fragment with a COOH terminus of NITEGE374	SIGNOR-266985
P08069	Q9Y5X3	2	binding	down-regulates quantity	0.269	Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures.	SIGNOR-269444
P46531	Q6UY11	2	binding	down-regulates activity	0.29	Moreover, the interaction of DLK1 with NOTCH1 caused an inhibition of basal NOTCH signaling in preadipocytes and mesenchymal multipotent cells. In this work, we demonstrate, for the first time, that DLK2 interacts with itself, with DLK1, and with the same NOTCH1 receptor region as DLK1 does. We demonstrate also that the interaction of DLK2 with NOTCH1 similarly results in an inhibition of NOTCH signaling in preadipocytes and Mouse Embryo fibloblasts.	SIGNOR-219377
P31277	O00470	2	binding	up-regulates activity	0.407	We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets.	SIGNOR-241229
Q8NEZ5	O14867	1	ubiquitination	down-regulates quantity	0.282	Here, we show that heme triggers the degradation of Bach1, a pro-metastatic transcription factor, by promoting its interaction with the ubiquitin ligase Fbxo22.	SIGNOR-259331
P29120	P01189-PRO_0000024969	1	cleavage	up-regulates quantity	0.2	POMC is post-translationally cleaved by prohormone convertase enzymes 1 and 2 (PC1, PC2) into ACTH, an N-terminal glycopeptide	SIGNOR-268724
P28223	O95837	2	binding	up-regulates activity	0.449	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-257227
O14492	P22681	2	binding	up-regulates	0.647	Aps couples c-cbl to theinsulinreceptor, resulting in ubiquitination of theinsulinreceptor. The aps adapter protein couples theinsulinreceptor to the phosphorylation of c-cbl and facilitates ligand-stimulated ubiquitination of theinsulinreceptor.	SIGNOR-109691
Q9Y463	P46527	1	phosphorylation	up-regulates	0.355	Mirk phosphorylates p27 at ser-10, thus stabilizing p27 and blocking its nuclear export and degradation	SIGNOR-235805
Q5T0W9	P49674	2	binding	up-regulates quantity	0.256	We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates.	SIGNOR-273762
Q9UBR4	Q96A47	2	binding	up-regulates activity	0.433	a direct NLI-independent interaction between Lhx3 and the related proteins Isl1 and Isl2 was observed. The combinatorial expression of the LIM homeodomain proteins Isl1, Isl2, Lhx1, and Lhx3 in subsets of developing motor neurons correlates with the future organization of these neurons into motor columns with distinct innervation targets, implying a functional role for LIM homeodomain protein combinations in the specification of neuronal identity	SIGNOR-236836
Q8IU54	Q8IU57	2	binding	up-regulates	0.873	Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha.	SIGNOR-96174
Q13464	P61587	1	phosphorylation	up-regulates	0.707	We show that rock phosphorylates endogenous rhoe at serine 11 upon cell stimulation with platelet-derived growth factor. Phosphorylation has no effect on rhoe binding to rock i, but instead increases rhoe protein stability.	SIGNOR-134703
Q9Y5I2	Q9Y5F8	2	binding	up-regulates activity	0.2	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265711
P01106	P00519	0	phosphorylation	up-regulates activity	0.469	Altogether, our data demonstrate that Pin1 and Abl cooperate to enhance the interaction of Myc with p300 and its resulting acetylation.\|These experiments confirmed that Myc Y74 is phosphorylated by Abl, and provided us with a reagent to detect this form of Myc in cells (see below).	SIGNOR-278196
Q9NQA5	Q5T4S7	0	ubiquitination	down-regulates quantity by destabilization	0.246	Cytomix induced interaction between TRPV5 and UBR4 (Ubiquitin recoginition 4), an E3 ubiquitin ligase; knockdown of UBR4 with small interfering RNAs prevented cytomix-induced degradation of TRPV5. UBR4/p600 ubiquitin ligase is responsible for TRPV5 ubiquitination and proteasomal degradation in response to cytomix	SIGNOR-272117
Q9Y572	P00367	2	binding	up-regulates	0.446	Rip3 directly interacts with glycogen phosphorylase (pygl), glutamate ammonia ligase (glul), and glutamate dehydrogenase 1 (glud1). Rip kinase activity is required to enhance the activities of all three enzymes both in vivo and in vitro.	SIGNOR-187314
Q5T197	P52630	1	ubiquitination	down-regulates activity	0.448	DCST1 promotes ubiquitination of STAT2.\|The ability of DCST1 to degrade STAT2 levels was visible both in the presence and absence of IFNbetastimulation.\|In our study, DCST1 was found to interact with and promote ubiquitination of STAT2, leading to reduced STAT2 expression and attenuated activation of the ISG induction pathway.	SIGNOR-278747
Q8NHW3	P49840	0	phosphorylation	up-regulates activity	0.2	We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity.	SIGNOR-159377
P04637	O15151	0	ubiquitination	down-regulates quantity by destabilization	0.948	Here we demonstrate that MdmX acts as a ubiquitin ligase in vitro, being capable of autoubiquitination, as well as mediating the ubiquitination of p53.	SIGNOR-271389
P67870	P35222	1	phosphorylation	up-regulates activity	0.601	We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin	SIGNOR-251067
P05362	P20702	2	binding	up-regulates	0.679	Using assays to quantify cd11c-mediated cell adhesion, we demonstrate that cd11c recognizes icam-2 and vcam-1. The cd11c-binding site on vcam-1 appears to be different from that used by the integrin alpha4.	SIGNOR-31388
P18850	P35638	1	transcriptional regulation	up-regulates quantity by expression	0.658	Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network	SIGNOR-260180
P09132	P61011	2	binding	up-regulates activity	0.962	Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure (Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54.	SIGNOR-261168
O15105	Q6ZNA4	0	ubiquitination	down-regulates	0.736	Axin is a scaffold protein in tgf-beta signaling that promotes degradation of smad7 by arkadia	SIGNOR-119666
O75928	Q15759	0	phosphorylation	up-regulates activity	0.264	The switch between the coactivating and inhibitory actions of PIASxα is controlled, at least in part, through PIASxα phosphorylation. PIASxα is itself phosphorylated by p38 in vitro and in vivo in response to the activation of stress signaling pathways (Figure 2, Figure 3, Figure 4). We identify Ser113 and Ser 116 as two residues that are phosphorylated by p38 and have important functional roles	SIGNOR-262947
Q9Y5X1	Q07912	0	phosphorylation	up-regulates	0.505	We have previously shown that sh3px1, phosphorylated by ack2 (activated cdc42-associated tyrosine kinase 2), regulates the degradation of egf (epidermal growth factor) receptor.	SIGNOR-142569
P52565	P12931	0	phosphorylation	down-regulates	0.399	We show here that src kinase binds and phosphorylates rhogdi both in vitro and in vivo at tyr156. analysis of rho gtpase-rhogdi complexes using in vitro assays of complexation and in vivo by coimmunoprecipitation analysis indicates that src-mediated phosphorylation of tyr156 causes a dramatic decrease in the ability of rhogdi to form a complex with rhoa, rac1, or cdc42.	SIGNOR-149282
P51812	P67809	1	phosphorylation	up-regulates	0.538	We therefore conclude that rsk1/rsk2 are novel activators of yb-1, able to phosphorylate the serine 102 residue.	SIGNOR-182165
Q16665	P13500	1	transcriptional regulation	up-regulates quantity by expression	0.403	These findings suggest that both MCP-1 and MCP-5 are HIF-1 target genes and that HIF-1α is involved in transcriptional induction of these two chemokines in astrocytes by hypoxia.	SIGNOR-251719
Q86YT6	O00548	1	ubiquitination	up-regulates activity	0.743	Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity.	SIGNOR-209750
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
P11474	Q92785	2	binding	down-regulates activity	0.2	DPF2 directly bound to ERRalpha and suppressed the transactivation function of nuclear receptors such as androgen receptor. DPF2 was recruited to ERR target gene promoters in myoblast cells, and knockdown of DPF2 derepressed the level of mRNA expressed by target genes of ERRalpha. These results show that DPF2 acts as a nuclear receptor-selective co-repressor for ERRalpha by associating with both acetylated histone H3 and HDAC1.	SIGNOR-239539
P43146	P06241	0	phosphorylation	up-regulates activity	0.572	Fyn tyrosine kinase, but not Src, regulates the phosphorylation of DCC in N1E-115 neuroblastoma cells.Both DCC phosphorylation and Netrin-1-induced axon outgrowth are impaired in Fyn(-/-) CN and spinal cord explants. We propose that DCC is regulated by tyrosine phosphorylation and that Fyn is essential for the response of axons to Netrin-1. these results show that DCC is phosphorylated by Fyn, but not Src, in N1E-115 cells, and that tyrosines 1261 and 1418 are the major phosphorylation sites of Fyn in vivo.	SIGNOR-268176
Q9UBK2	P05019	1	transcriptional regulation	up-regulates quantity by expression	0.34	PGC-1 alpha specifically induces IGF1 and represses myostatin, and expression of PGC-1a 4 in vitro and in vivo induces robust skeletal muscle hypertrophy	SIGNOR-256152
O75581	P56705	2	binding	up-regulates	0.648	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-131835
P42229	Q9NPD5	1	transcriptional regulation	up-regulates quantity by expression	0.2	PRL enhanced the binding of Stat5a to the OATP1B3 promoter and DNA-protein binding was inhibited in competition assays by excess OATP1B3 and Stat5 consensus oligomers but not by mutant Stat5 oligomers.\|PRL and GH induction of Oatp1b2 and OATP1B3 promoter activity required cotransfection of Stat5a and PRLRL or GHR.	SIGNOR-268990
P23528	P60484	0	dephosphorylation	up-regulates activity	0.441	Unexpectedly, cofilin-1 activation by PGE 2 was mediated by the protein phosphatase activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10), with which it directly associated.\|Unexpectedly, cofilin-1 dephosphorylation and activation in our model was mediated by the protein phosphatase activity of PTEN.	SIGNOR-276980
Q12834	Q9UI95	2	binding	down-regulates activity	0.459	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-264903
P27695	O60260	0	ubiquitination	down-regulates quantity by destabilization	0.2	Based on these results, we conclude that Parkin directly ubiquitinates APE1.\|These results indicated that degradation of APE1 by Parkin was limited compared to the transiently expressed APE1, suggesting that a large portion of APE1 is not in contact with the Parkin and PINK1 without induction of stresses such as oxidative stress.	SIGNOR-278531
P20042	Q9UI10	0	guanine nucleotide exchange factor	up-regulates activity	0.754	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.	SIGNOR-269132
Q92793	P41240	2	binding	up-regulates	0.535	Here we present cbp--a transmembrane phosphoprotein that is ubiquitously expressed and binds specifically to the sh2 domain of csk. Cbp is involved in the membrane localization of csk and in the csk-mediated inhibition of c-src.	SIGNOR-77139
Q14145	Q9NY33	0	cleavage	down-regulates quantity by destabilization	0.599	The influence of DPP3 on the Keap1-Nrf2/ARE signal pathway suggest a direct involvement of DPP3 in the oxidative stress response [8,14,31,53,99,100]. It was shown that DPP3 competes with Nrf2 through the ETGE motif to bind to Keap1 and consequently enhances the translocation of Nrf2 to the nucleus, thereby driving the expression of an array of genes encoding antioxidative enzymes [99]. More specifically, binding of DPP3 to Keap1 releases Nrf2, and thus, prevents its degradation through the 26S proteasome	SIGNOR-268464
Q12834	P51955	0	phosphorylation	up-regulates activity	0.945	In summary, we have demonstrated that Nek2 can associate with and phosphorylate Mad2 and Cdc20.\|The results presented here support a model in which Nek2 modulates the functions of Mad2 and Cdc20 in the mitotic checkpoint and elevation of Nek2 levels may contribute to chromosome instability by interfering with the control of the checkpoint.	SIGNOR-278366
P48436	Q05086	0	ubiquitination	down-regulates quantity by destabilization	0.261	We show that E6-AP ubiquitinates SOX9 in vitro and in vivo and that SOX9 levels are enhanced after addition of the proteasome inhibitor bortezomib. Similar, siRNA knockdown of E6-AP and the E2 ligase Ubc9 increased cellular SOX9 amounts, supporting the notion that SOX9 may be ubiquitinated in hypertrophic chondrocytes by E6-AP and degraded by proteasomes.	SIGNOR-272134
Q15750	Q01974	1	phosphorylation	down-regulates	0.278	Tak1 (tgf-beta activated kinase 1), a map3k, interacts with ror2 and phosphorylates its intracellular carboxyterminal serine/thronine/proline-rich (stp) domain	SIGNOR-180566
P56524	Q02078	2	binding	down-regulates	0.564	We discovered that mef2 interacts with histone deacetylases (hdacs) 4 and 5, resulting in repression of the transcriptional activity of mef2.	SIGNOR-76231
P46527	Q13309	0	ubiquitination	down-regulates	0.766	Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase. ;the recognition of p27 by skp2/cks1 of the scfskp2 complex is dictated by cycline/cdk2, providing a high affinity binding site and the phosphorylation of p27 at t187, serving here we provide evidence suggesting that both cdk2/e and phosphorylation of thr(187) on p27 are essential for the recognition of p27 by the scf(skp2/cks1) complex, the ubiquitin-protein isopeptide ligase (e3).	SIGNOR-154194
Q6P4F7	P61586	1	gtpase-activating protein	down-regulates activity	0.549	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-260466
Q15910	P31749	0	phosphorylation	down-regulates activity	0.594	Enhancer of zeste homolog 2 (ezh2) is a methyltransferase that plays an important role in many biological processes through its ability to trimethylate lysine 27 in histone h3. Here, we show that akt phosphorylates ezh2 at serine 21 and suppresses its methyltransferase activity by impeding ezh2 binding to histone h3	SIGNOR-141043
Q01094	P49336	0	phosphorylation	down-regulates	0.483	E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8), a colorectal oncoprotein. Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription from inhibition by E2F1.	SIGNOR-181078
P07949	O15530	1	phosphorylation	up-regulates activity	0.2	Ret/ptc (rearranged in transformation/papillary thyroid carcinomas) tyrosine kinase phosphorylates and activates phosphoinositide-dependent kinase 1 (pdk1) ret/ptc phosphorylates a specific tyrosine (y9) residue located in the n-terminal region of pdk1.	SIGNOR-235863
Q13131	Q9H2X6	1	phosphorylation	up-regulates activity	0.2	These results indicate that HIPK2 is a substrate of AMPKα2 in vitro and in vivo. Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKα2 in vitro (Figure S5J).	SIGNOR-276469
P01106	P34896	1	transcriptional regulation	up-regulates quantity by expression	0.276	Myc regulates the de novo purine and pyrimidine synthetic genes in multiple biological systems. Intriguingly, MYC was found to directly activate the expression of SHMT1, and SHMT2, which are enzymes involved in single carbon metabolism and are essential for dNTP synthesis	SIGNOR-267379
P17252	P17252	2	phosphorylation	up-regulates	0.2	Pkc is frequently autophosphorylated on two c-terminal sites, the turn motif (thr- 638 in human pkc) and the hydrophobic site (ser-657 in human pkc). Thus, it is becoming clear that autophosphorylation of pkc can be a regulated event and that it has significant impact on pkc function	SIGNOR-127253
P01178-PRO_0000020496	Q92824	0	cleavage	up-regulates quantity	0.2	Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension.	SIGNOR-270336
P19525	P10636	1	phosphorylation	up-regulates quantity	0.2	Interestingly, PKR phosphorylated tau directly and no detectable labeling occurred when tau was incubated with 32 P\u2010ATP alone (Figure\u00a0 xref right).\|PKR kinase directly regulates tau expression and Alzheimer's disease-related tau phosphorylation.	SIGNOR-279735
O75925	Q5U5R9	0	polyubiquitination	down-regulates quantity by destabilization	0.389	We discovered a ubiquitin E3 ligase, HECTD2, which ubiquitinated and mediated the degradation of PIAS1, thus increasing inflammation in an experimental pneumonia model.	SIGNOR-272421

Q9UPU5

Q07812

1

deubiquitination

up-regulates quantity by stabilization

0.2

In this study, several cancer-related proteins (Bax, p300, E2F4 and securin) have been proven to be substrates of ubiquitin-specific peptidase 24 (USP24), and relevance has been shown between USP24 and its substrates in samples from clinical lung cancer patients. |Knockdown of USP24 decreases Bax and p300 levels

SIGNOR-275606

O60674

P15509

2

phosphorylation

up-regulates activity

0.533

JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation.

SIGNOR-249503

P49715

P27361

0

phosphorylation

down-regulates

0.371

Ccaat/enhancer-binding protein alpha (c/ebpalpha) is one of the key transcription factors that mediate lineage specification and differentiation of multipotent myeloid progenitors into mature granulocytes.Here we report that inducers of monocyte differentiation inhibit the alternate cell fate choice, that of granulopoiesis, through inhibition of c/ebpalpha. This inhibition is mediated by extracellular signal-regulated kinases 1 and/or 2 (erk1/2), which interact with c/ebpalpha through an fxfp docking site and phosphorylate serine 21.

SIGNOR-120570

Q9Y4K3

Q15654

2

binding

up-regulates activity

0.28

Our results revealed that TRIP6 could enhance TRAF6 oligomerization and TRAF6 autoubiquitination through its interaction

SIGNOR-280455

Q9HCE1

Q14164

2

binding

up-regulates activity

0.2

MOV10 enhances IRF3 activation and IRF3-mediated gene induction. This indicated that MOV10-mediated antiviral activity is most likely mediated through IKKε and not through TBK1. Involvement of IKKε was further established by examining the physical interaction of MOV10 and IKKε.

SIGNOR-261138

Q13535

P38398

1

phosphorylation

up-regulates activity

0.8

Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion.

SIGNOR-106432

Q8N2W9

Q05513

0

phosphorylation

down-regulates quantity by destabilization

0.519

In this study, we discovered a new protein isoform encoded by KIAA0317, termed fibrosis-inducing E3 ligase 1 (FIEL1), which potently stimulates the TGFbeta signaling pathway through the site-specific ubiquitination of PIAS4.FIEL1 targets PIAS4 using a double locking mechanism that is facilitated by the kinases PKCzeta and GSK3beta. Specifically, PKCzeta phosphorylation of PIAS4 and GSK3beta phosphorylation of FIEL1 are both essential for the degradation of PIAS4.|These experiments suggested that PKCzeta is an authentic regulator of PIAS4 protein stability; Q21 and phosphorylated S18 of PIAS4 are both required for FIEL1 interaction.

SIGNOR-275513

P17612

P18846

1

phosphorylation

up-regulates activity

0.451

PKA catalytic subunit phosphorylates ATF-1 at Ser63 and that phosphorylation is essential for efficient DNA binding by ATF-1.

SIGNOR-250336

Q96IV0

Q04323

2

binding

up-regulates activity

0.488

PNGase is directed to polyubiquitinated MGPs via VCP and the adaptor protein SAKS1, allowing PNGase to deglycosylate MGPs, which can then be degraded by the proteasome. PNGase itself is reported to bind to the S4 component of the 19 S proteasome.

SIGNOR-261060

Q09472

P35558

1

acetylation

down-regulates quantity by destabilization

0.546

Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase|P300 Acetylates and Destabilizes PEPCK1|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1

SIGNOR-267603

Q96SB4

P54793

1

phosphorylation

up-regulates activity

0.2

Phosphorylation by SRPK1 drives ASF from the cytosol to the nucleus.|Phosphorylation of ASF by SR protein kinase 1 (SRPK1) in the cytosol results in ASF relocation to the nucleus, whereas phosphorylation of ASF by Clk and Sty releases ASF from speckles and recruits it into nascent transcripts where ASF regulates alternative splicing.

SIGNOR-279765

Q13418

O14974

1

phosphorylation

down-regulates activity

0.584

MYPT1 was phosphorylated by ILK and phosphorylation sites in the N- and C-terminal fragments of MYPT1 were detected. From sequence analyses, three sites were identified: a primary site at Thr(709), and two other sites at Thr(695) and Thr(495). ILK produced an intermediate level of inhibition

SIGNOR-262884

P24588

P17612

1

relocalization

up-regulates activity

0.561

In this report, we demonstrate that glutamate receptors and PKA are recruited into a macromolecular signaling complex through direct interaction between the MAGUK proteins, PSD-95 and SAP97, and AKAP79/150

SIGNOR-261292

Q01196

P01106

1

transcriptional regulation

down-regulates quantity by repression

0.337

RUNX1 represses MYC expression through direct binding at three downstream enhancer elements

SIGNOR-260093

Q00535

P46531

1

phosphorylation

up-regulates activity

0.32

An in vitro kinase reaction demonstrated that T2132, S2136, and S2141 were CDK5\u2010phosphorylated sites in the Notch1 peptide (Figure\u00a02B, C, and D).|In conclusion, CDK5 positively regulates Notch1 function via phosphorylation, which in turn promotes cell proliferation and migration.

SIGNOR-279401

Q9Y276

O95202

2

binding

up-regulates activity

0.464

LETM1 was co-precipitated with BCS1L and formation of the LETM1 complex depended on BCS1L levels, suggesting that BCS1L stimulates the assembly of the LETM1 complex.

SIGNOR-262543

P47736

Q9Y297

0

ubiquitination

down-regulates

0.342

Here, we demonstrated that rap1gap is ubiquitinated and degraded through proteasome pathway in mitosis. Proteolysis of rap1gap requires the plk1 kinase and _-trcp ubiquitin ligase complex.

SIGNOR-203548

P33981

Q02224

1

phosphorylation

up-regulates activity

0.43

Strikingly, phosphorylation of Cenp-E C tail by wild-type (WT) MPS1 or CDK1-cyclin B completely reverses its inhibitory effect toward Cenp-E motor ATPase in solution.

SIGNOR-278999

P53805

Q14469

0

transcriptional regulation

down-regulates quantity by repression

0.2

Increased Calcineurin/NFAT activity by Notch signaling involves downregulation of Calcipressin, an endogenous Calcineurin inhibitor, through a HES-1-dependent mechanism .... Chromatin immunoprecipitation (ChIP) analysis of keratinocytes overexpressing HES-1 showed that this protein can bind to the HES binding sites present in both distal and proximal promoters

SIGNOR-252026

P31749

P54578

1

phosphorylation

up-regulates activity

0.424

Phosphorylation and activation of ubiquitin-specific protease-14 by Akt regulates the ubiquitin-proteasome system|These results suggested S432 as a major and S143 as a minor phosphorylation site of Akt.

SIGNOR-265056

Q9UKY1

Q15326

2

binding

down-regulates activity

0.491

Corepressor BS69 interacts with ZHX1, a member of the ZHX family having zinc-fingers and homeoboxes. Although BS69 was originally found as a corepressor interacting with ZHX1, BS69 was also found to function as a transcriptional activator in HEK293 cells, in which the activation required the MYND domain of BS69. Co-transfection of BS69 with a mutant form of ZHX1, which cannot interact with BS69, led to increase the transcriptional activation of BS69, suggesting that transcriptional activation mediated by BS69 is suppressed by ZHX1.

SIGNOR-263898

P01009

Q07954

2

binding

up-regulates

0.322

In vitro binding studies revealed that antithrombin iii (atiii)thrombin, heparin cofactor ii (hcii)thrombin, and ?1-antitrypsin (?1AT)trypsin bound to purified lrp

SIGNOR-41180

P28335

P50148

2

binding

up-regulates activity

0.568

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-257221

Q13501

Q9Y4E8

0

deubiquitination

down-regulates activity

0.26

SQSTM1 Is a Substrate for RNF26 and the DUB USP15. Catalytically competent RNF26 (light red) recruits SQSTM1 (blue) and mediates ubiquitin ligation (red), which serves to attract UBDs of specific vesicle-associated adaptors. Dissociation of the RNF26/SQSTM1 complex, promoted by the DUB USP15 (yellow), releases target vesicles for (4) fast transport into the cell periphery.

SIGNOR-269829

Q9GZM8

Q14204

2

binding

up-regulates activity

0.72

LIS1 specifically binds the P1 loop domain of CDHC, while NUDEL binds the C-terminal region as well as a distinct binding site in the P1 loop domain. LIS1 and NUDEL regulate CDHC localization and motor function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex

SIGNOR-252159

Q9Y4K3

P36897

2

binding

up-regulates activity

0.428

We report here that TRAF6 is specifically required for the Smad-independent activation of JNK and p38 and its carboxyl TRAF homology domain physically interacts with TGF-² receptors

SIGNOR-241918

P06239

Q9UQQ2

1

phosphorylation

up-regulates

0.569

In vitro tyrosine phosphorylation of lnk by lck and zap-70. Tyrosine 297 would appear to be an attractive target for phosphorylation within the c-terminal domain. Our studies suggest that although lnk may participate in tcr signaling, its functions are in no way limiting during t cell development or activation.

SIGNOR-48850

P01222

P16473

2

binding

up-regulates

0.722

Two novel human glycoprotein hormonelike genes, alpha2 (a2) and beta5 (b5), recently have been identified. Using a yeast two-hybrid assay, the two subunits were found as potential heterodimerization partners.

SIGNOR-88653

P18146

P68400

0

phosphorylation

down-regulates activity

0.464

Casein kinase II associates with Egr-1 and acts as a negative modulator of its DNA binding and transcription activities in NIH 3T3 cells. | There are three CKII recognition sites (S376XXD, T389XE, and T516XXXD) in fragment 10.

SIGNOR-250858

O95622

O14775

2

binding

down-regulates activity

0.456

The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC

SIGNOR-264998

P05198

Q86TM6

0

ubiquitination

down-regulates quantity by destabilization

0.2

HRD1 overexpression also decreased the expression of eIF2alpha and p-eIF2alpha in HKC-8 cells.|HRD1 promoted eIF2alpha ubiquitylation and degradation, thereby providing a protective mechanism that suppressed tubular epithelial cell apoptosis.

SIGNOR-278671

Q9H0K1

Q15831

0

phosphorylation

up-regulates

0.481

A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold.

SIGNOR-122788

P41212

Q16549

0

phosphorylation

down-regulates

0.2

In vivo p38-dependent phosphorylation reduced trans-repressional abilities of tel through ets-binding consensus site

SIGNOR-95622

P48729

Q8NEG4

2

binding

up-regulates quantity

0.2

We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates.

SIGNOR-273751

Q9H1C0

Q14344

2

binding

up-regulates activity

0.35

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-257284

Q9NYD6

P55268

1

transcriptional regulation

up-regulates quantity by expression

0.2

The specificity of binding of these two proteins to the Lamin B2 origin is confirmed by both band-shift and in vitro footprinting assays. In addition, the ability of HOXC10 and HOXC13 to increase the activity of a promoter containing the 74 bp sequence, as assayed by CAT-assay experiments, demonstrates a direct interaction of these homeoproteins with the origin sequence in mammalian cells.

SIGNOR-261645

O00238

O95630

1

phosphorylation

up-regulates activity

0.29

BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads.

SIGNOR-250600

Q9GZZ0

P05556

1

transcriptional regulation

up-regulates quantity by expression

0.2

Consistently, ITGB1 promoter activity was decreased by HOXD1 knockdown in ECs. Furthermore, we identified the putative HOXD1-binding sites in the promoter region of ITGB1. Together, these findings suggest that HOXD1 plays a significant role in EC functions by regulating the expression of ITGB1.

SIGNOR-261648

Q15326

Q9UKY1

2

binding

down-regulates activity

0.491

Corepressor BS69 interacts with ZHX1, a member of the ZHX family having zinc-fingers and homeoboxes. Although BS69 was originally found as a corepressor interacting with ZHX1, BS69 was also found to function as a transcriptional activator in HEK293 cells, in which the activation required the MYND domain of BS69. Co-transfection of BS69 with a mutant form of ZHX1, which cannot interact with BS69, led to increase the transcriptional activation of BS69, suggesting that transcriptional activation mediated by BS69 is suppressed by ZHX1.

SIGNOR-263898

P01106

P45983

0

phosphorylation

up-regulates activity

0.556

The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71.

SIGNOR-236018

Q8NFU7

Q96SR6

1

transcriptional regulation

up-regulates quantity by expression

0.2

Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9.

SIGNOR-259095

Q9UQM7

P51790

1

phosphorylation

up-regulates activity

0.337

Identification of an N-terminal amino acid of the CLC-3 chloride channel critical in phosphorylation-dependent activation of a CaMKII-activated chloride current|The N-terminus of CLC-3, which contains a CaMKII consensus sequence, was phosphorylated by CaMKII in vitro, and mutation of the serine at position 109 (S109A) abolished the CaMKII-dependent Cl(-) conductance, indicating that this residue is important in the gating of CLC-3 at the plasma membrane.

SIGNOR-275863

Q9UNA0

P16112

1

cleavage

down-regulates quantity by destabilization

0.765

Aggrecan Degradation in Human Cartilage Evidence for both Matrix Metalloproteinase and Aggrecanase Activity in Normal, Osteoarthritic, and Rheumatoid Joints|Stromelysin-1 (MMP-3), as well as other MMPs, cleave aggrecan in the interglobular domain between Asn341 and Phe342 to generate a G1 fragment with the COOH terminus VDIPEN341 (11–13). This fragment has been isolated and identified by NH2-terminal sequence analysis from human OA cartilage (11). A second proteolytic activity identified as “aggrecanase” also cleaves aggrecan in the interglobular domain, but between Glu373 and Ala374 (19–24), generating a G1 fragment with a COOH terminus of NITEGE374

SIGNOR-266985

P08069

Q9Y5X3

2

binding

down-regulates quantity

0.269

Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures.

SIGNOR-269444

P46531

Q6UY11

2

binding

down-regulates activity

0.29

Moreover, the interaction of DLK1 with NOTCH1 caused an inhibition of basal NOTCH signaling in preadipocytes and mesenchymal multipotent cells. In this work, we demonstrate, for the first time, that DLK2 interacts with itself, with DLK1, and with the same NOTCH1 receptor region as DLK1 does. We demonstrate also that the interaction of DLK2 with NOTCH1 similarly results in an inhibition of NOTCH signaling in preadipocytes and Mouse Embryo fibloblasts.

SIGNOR-219377

P31277

O00470

2

binding

up-regulates activity

0.407

We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets.

SIGNOR-241229

Q8NEZ5

O14867

1

ubiquitination

down-regulates quantity

0.282

Here, we show that heme triggers the degradation of Bach1, a pro-metastatic transcription factor, by promoting its interaction with the ubiquitin ligase Fbxo22.

SIGNOR-259331

P29120

P01189-PRO_0000024969

1

cleavage

up-regulates quantity

0.2

POMC is post-translationally cleaved by prohormone convertase enzymes 1 and 2 (PC1, PC2) into ACTH, an N-terminal glycopeptide

SIGNOR-268724

P28223

O95837

2

binding

up-regulates activity

0.449

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-257227

O14492

P22681

2

binding

up-regulates

0.647

Aps couples c-cbl to theinsulinreceptor, resulting in ubiquitination of theinsulinreceptor. The aps adapter protein couples theinsulinreceptor to the phosphorylation of c-cbl and facilitates ligand-stimulated ubiquitination of theinsulinreceptor.

SIGNOR-109691

Q9Y463

P46527

1

phosphorylation

up-regulates

0.355

Mirk phosphorylates p27 at ser-10, thus stabilizing p27 and blocking its nuclear export and degradation

SIGNOR-235805

Q5T0W9

P49674

2

binding

up-regulates quantity

0.256

We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates.

SIGNOR-273762

Q9UBR4

Q96A47

2

binding

up-regulates activity

0.433

a direct NLI-independent interaction between Lhx3 and the related proteins Isl1 and Isl2 was observed. The combinatorial expression of the LIM homeodomain proteins Isl1, Isl2, Lhx1, and Lhx3 in subsets of developing motor neurons correlates with the future organization of these neurons into motor columns with distinct innervation targets, implying a functional role for LIM homeodomain protein combinations in the specification of neuronal identity

SIGNOR-236836

Q8IU54

Q8IU57

2

binding

up-regulates

0.873

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

SIGNOR-96174

Q13464

P61587

1

phosphorylation

up-regulates

0.707

We show that rock phosphorylates endogenous rhoe at serine 11 upon cell stimulation with platelet-derived growth factor. Phosphorylation has no effect on rhoe binding to rock i, but instead increases rhoe protein stability.

SIGNOR-134703

Q9Y5I2

Q9Y5F8

2

binding

up-regulates activity

0.2

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

SIGNOR-265711

P01106

P00519

0

phosphorylation

up-regulates activity

0.469

Altogether, our data demonstrate that Pin1 and Abl cooperate to enhance the interaction of Myc with p300 and its resulting acetylation.|These experiments confirmed that Myc Y74 is phosphorylated by Abl, and provided us with a reagent to detect this form of Myc in cells (see below).

SIGNOR-278196

Q9NQA5

Q5T4S7

0

ubiquitination

down-regulates quantity by destabilization

0.246

Cytomix induced interaction between TRPV5 and UBR4 (Ubiquitin recoginition 4), an E3 ubiquitin ligase; knockdown of UBR4 with small interfering RNAs prevented cytomix-induced degradation of TRPV5. UBR4/p600 ubiquitin ligase is responsible for TRPV5 ubiquitination and proteasomal degradation in response to cytomix

SIGNOR-272117

Q9Y572

P00367

2

binding

up-regulates

0.446

Rip3 directly interacts with glycogen phosphorylase (pygl), glutamate ammonia ligase (glul), and glutamate dehydrogenase 1 (glud1). Rip kinase activity is required to enhance the activities of all three enzymes both in vivo and in vitro.

SIGNOR-187314

Q5T197

P52630

1

ubiquitination

down-regulates activity

0.448

DCST1 promotes ubiquitination of STAT2.|The ability of DCST1 to degrade STAT2 levels was visible both in the presence and absence of IFNbetastimulation.|In our study, DCST1 was found to interact with and promote ubiquitination of STAT2, leading to reduced STAT2 expression and attenuated activation of the ISG induction pathway.

SIGNOR-278747

Q8NHW3

P49840

0

phosphorylation

up-regulates activity

0.2

We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity.

SIGNOR-159377

P04637

O15151

0

ubiquitination

down-regulates quantity by destabilization

0.948

Here we demonstrate that MdmX acts as a ubiquitin ligase in vitro, being capable of autoubiquitination, as well as mediating the ubiquitination of p53.

SIGNOR-271389

P67870

P35222

1

phosphorylation

up-regulates activity

0.601

We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin

SIGNOR-251067

P05362

P20702

2

binding

up-regulates

0.679

Using assays to quantify cd11c-mediated cell adhesion, we demonstrate that cd11c recognizes icam-2 and vcam-1. The cd11c-binding site on vcam-1 appears to be different from that used by the integrin alpha4.

SIGNOR-31388

P18850

P35638

1

transcriptional regulation

up-regulates quantity by expression

0.658

Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network

SIGNOR-260180

P09132

P61011

2

binding

up-regulates activity

0.962

Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure (Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54.

SIGNOR-261168

O15105

Q6ZNA4

0

ubiquitination

down-regulates

0.736

Axin is a scaffold protein in tgf-beta signaling that promotes degradation of smad7 by arkadia

SIGNOR-119666

O75928

Q15759

0

phosphorylation

up-regulates activity

0.264

The switch between the coactivating and inhibitory actions of PIASxα is controlled, at least in part, through PIASxα phosphorylation. PIASxα is itself phosphorylated by p38 in vitro and in vivo in response to the activation of stress signaling pathways (Figure 2, Figure 3, Figure 4). We identify Ser113 and Ser 116 as two residues that are phosphorylated by p38 and have important functional roles

SIGNOR-262947

Q9Y5X1

Q07912

0

phosphorylation

up-regulates

0.505

We have previously shown that sh3px1, phosphorylated by ack2 (activated cdc42-associated tyrosine kinase 2), regulates the degradation of egf (epidermal growth factor) receptor.

SIGNOR-142569

P52565

P12931

0

phosphorylation

down-regulates

0.399

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

SIGNOR-149282

P51812

P67809

1

phosphorylation

up-regulates

0.538

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

SIGNOR-182165

Q16665

P13500

1

transcriptional regulation

up-regulates quantity by expression

0.403

These findings suggest that both MCP-1 and MCP-5 are HIF-1 target genes and that HIF-1α is involved in transcriptional induction of these two chemokines in astrocytes by hypoxia.

SIGNOR-251719

Q86YT6

O00548

1

ubiquitination

up-regulates activity

0.743

Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity.

SIGNOR-209750

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

P11474

Q92785

2

binding

down-regulates activity

0.2

DPF2 directly bound to ERRalpha and suppressed the transactivation function of nuclear receptors such as androgen receptor. DPF2 was recruited to ERR target gene promoters in myoblast cells, and knockdown of DPF2 derepressed the level of mRNA expressed by target genes of ERRalpha. These results show that DPF2 acts as a nuclear receptor-selective co-repressor for ERRalpha by associating with both acetylated histone H3 and HDAC1.

SIGNOR-239539

P43146

P06241

0

phosphorylation

up-regulates activity

0.572

Fyn tyrosine kinase, but not Src, regulates the phosphorylation of DCC in N1E-115 neuroblastoma cells.Both DCC phosphorylation and Netrin-1-induced axon outgrowth are impaired in Fyn(-/-) CN and spinal cord explants. We propose that DCC is regulated by tyrosine phosphorylation and that Fyn is essential for the response of axons to Netrin-1. these results show that DCC is phosphorylated by Fyn, but not Src, in N1E-115 cells, and that tyrosines 1261 and 1418 are the major phosphorylation sites of Fyn in vivo.

SIGNOR-268176

Q9UBK2

P05019

1

transcriptional regulation

up-regulates quantity by expression

0.34

PGC-1 alpha specifically induces IGF1 and represses myostatin, and expression of PGC-1a 4 in vitro and in vivo induces robust skeletal muscle hypertrophy

SIGNOR-256152

O75581

P56705

2

binding

up-regulates

0.648

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-131835

P42229

Q9NPD5

1

transcriptional regulation

up-regulates quantity by expression

0.2

PRL enhanced the binding of Stat5a to the OATP1B3 promoter and DNA-protein binding was inhibited in competition assays by excess OATP1B3 and Stat5 consensus oligomers but not by mutant Stat5 oligomers.|PRL and GH induction of Oatp1b2 and OATP1B3 promoter activity required cotransfection of Stat5a and PRLRL or GHR.

SIGNOR-268990

P23528

P60484

0

dephosphorylation

up-regulates activity

0.441

Unexpectedly, cofilin-1 activation by PGE 2 was mediated by the protein phosphatase activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10), with which it directly associated.|Unexpectedly, cofilin-1 dephosphorylation and activation in our model was mediated by the protein phosphatase activity of PTEN.

SIGNOR-276980

Q12834

Q9UI95

2

binding

down-regulates activity

0.459

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-264903

P27695

O60260

0

ubiquitination

down-regulates quantity by destabilization

0.2

Based on these results, we conclude that Parkin directly ubiquitinates APE1.|These results indicated that degradation of APE1 by Parkin was limited compared to the transiently expressed APE1, suggesting that a large portion of APE1 is not in contact with the Parkin and PINK1 without induction of stresses such as oxidative stress.

SIGNOR-278531

P20042

Q9UI10

0

guanine nucleotide exchange factor

up-regulates activity

0.754

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

SIGNOR-269132

Q92793

P41240

2

binding

up-regulates

0.535

Here we present cbp--a transmembrane phosphoprotein that is ubiquitously expressed and binds specifically to the sh2 domain of csk. Cbp is involved in the membrane localization of csk and in the csk-mediated inhibition of c-src.

SIGNOR-77139

Q14145

Q9NY33

0

cleavage

down-regulates quantity by destabilization

0.599

The influence of DPP3 on the Keap1-Nrf2/ARE signal pathway suggest a direct involvement of DPP3 in the oxidative stress response [8,14,31,53,99,100]. It was shown that DPP3 competes with Nrf2 through the ETGE motif to bind to Keap1 and consequently enhances the translocation of Nrf2 to the nucleus, thereby driving the expression of an array of genes encoding antioxidative enzymes [99]. More specifically, binding of DPP3 to Keap1 releases Nrf2, and thus, prevents its degradation through the 26S proteasome

SIGNOR-268464

Q12834

P51955

0

phosphorylation

up-regulates activity

0.945

In summary, we have demonstrated that Nek2 can associate with and phosphorylate Mad2 and Cdc20.|The results presented here support a model in which Nek2 modulates the functions of Mad2 and Cdc20 in the mitotic checkpoint and elevation of Nek2 levels may contribute to chromosome instability by interfering with the control of the checkpoint.

SIGNOR-278366

P48436

Q05086

0

ubiquitination

down-regulates quantity by destabilization

0.261

We show that E6-AP ubiquitinates SOX9 in vitro and in vivo and that SOX9 levels are enhanced after addition of the proteasome inhibitor bortezomib. Similar, siRNA knockdown of E6-AP and the E2 ligase Ubc9 increased cellular SOX9 amounts, supporting the notion that SOX9 may be ubiquitinated in hypertrophic chondrocytes by E6-AP and degraded by proteasomes.

SIGNOR-272134

Q15750

Q01974

1

phosphorylation

down-regulates

0.278

Tak1 (tgf-beta activated kinase 1), a map3k, interacts with ror2 and phosphorylates its intracellular carboxyterminal serine/thronine/proline-rich (stp) domain

SIGNOR-180566

P56524

Q02078

2

binding

down-regulates

0.564

We discovered that mef2 interacts with histone deacetylases (hdacs) 4 and 5, resulting in repression of the transcriptional activity of mef2.

SIGNOR-76231

P46527

Q13309

0

ubiquitination

down-regulates

0.766

Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase. ;the recognition of p27 by skp2/cks1 of the scfskp2 complex is dictated by cycline/cdk2, providing a high affinity binding site and the phosphorylation of p27 at t187, serving here we provide evidence suggesting that both cdk2/e and phosphorylation of thr(187) on p27 are essential for the recognition of p27 by the scf(skp2/cks1) complex, the ubiquitin-protein isopeptide ligase (e3).

SIGNOR-154194

Q6P4F7

P61586

1

gtpase-activating protein

down-regulates activity

0.549

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-260466

Q15910

P31749

0

phosphorylation

down-regulates activity

0.594

Enhancer of zeste homolog 2 (ezh2) is a methyltransferase that plays an important role in many biological processes through its ability to trimethylate lysine 27 in histone h3. Here, we show that akt phosphorylates ezh2 at serine 21 and suppresses its methyltransferase activity by impeding ezh2 binding to histone h3

SIGNOR-141043

Q01094

P49336

0

phosphorylation

down-regulates

0.483

E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8), a colorectal oncoprotein. Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription from inhibition by E2F1.

SIGNOR-181078

P07949

O15530

1

phosphorylation

up-regulates activity

0.2

Ret/ptc (rearranged in transformation/papillary thyroid carcinomas) tyrosine kinase phosphorylates and activates phosphoinositide-dependent kinase 1 (pdk1) ret/ptc phosphorylates a specific tyrosine (y9) residue located in the n-terminal region of pdk1.

SIGNOR-235863

Q13131

Q9H2X6

1

phosphorylation

up-regulates activity

0.2

These results indicate that HIPK2 is a substrate of AMPKα2 in vitro and in vivo. Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKα2 in vitro (Figure S5J).

SIGNOR-276469

P01106

P34896

1

transcriptional regulation

up-regulates quantity by expression

0.276

Myc regulates the de novo purine and pyrimidine synthetic genes in multiple biological systems. Intriguingly, MYC was found to directly activate the expression of SHMT1, and SHMT2, which are enzymes involved in single carbon metabolism and are essential for dNTP synthesis

SIGNOR-267379

P17252

2

phosphorylation

up-regulates

0.2

Pkc is frequently autophosphorylated on two c-terminal sites, the turn motif (thr- 638 in human pkc) and the hydrophobic site (ser-657 in human pkc). Thus, it is becoming clear that autophosphorylation of pkc can be a regulated event and that it has significant impact on pkc function

SIGNOR-127253

P01178-PRO_0000020496

Q92824

0

cleavage

up-regulates quantity

0.2

Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension.

SIGNOR-270336

P19525

P10636

1

phosphorylation

up-regulates quantity

0.2

Interestingly, PKR phosphorylated tau directly and no detectable labeling occurred when tau was incubated with 32 P\u2010ATP alone (Figure\u00a0 xref right).|PKR kinase directly regulates tau expression and Alzheimer's disease-related tau phosphorylation.

SIGNOR-279735

O75925

Q5U5R9

0

polyubiquitination

down-regulates quantity by destabilization

0.389

We discovered a ubiquitin E3 ligase, HECTD2, which ubiquitinated and mediated the degradation of PIAS1, thus increasing inflammation in an experimental pneumonia model.

SIGNOR-272421