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
Q8NEZ5	O75164	1	ubiquitination	down-regulates quantity by destabilization	0.339	SCF(FBXO22) regulates histone H3 lysine 9 and 36 methylation levels by targeting histone demethylase KDM4A for ubiquitin-mediated proteasomal degradation	SIGNOR-273442
P36888	Q13322	2	binding	up-regulates activity	0.364	These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K–Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells.	SIGNOR-255947
P11362	Q9Y2J4	1	phosphorylation	up-regulates activity	0.2	These data support an idea that Amotl2 Tyr-103 can be phosphorylated by FGF receptor tyrosine kinase activity. We then determined whether Amotl2 Tyr-103 is required for its interaction with c-Src. \|Amotl2 promotes MAPK/ERK activation via c-Src, which is dependent on phosphorylation of tyrosine residue at position 103 but independent of the C-terminal PDZ-binding domain.	SIGNOR-271869
O00257	Q9H2X6	0	phosphorylation	up-regulates activity	0.423	In addition, HIPK2 phosphorylates Pc2 at several sites, including threonine 495.	SIGNOR-278484
Q9Y458	P35548	1	transcriptional regulation	down-regulates quantity by repression	0.309	the main function of TBX22 as shown in misexpression experiments is to decrease proliferation. We subsequently uncovered three targets of TBX22, DLX5, MSX2, and TBX22 itself. All are downregulated in the presence of viral-derived hTBX22.	SIGNOR-265567
O43248	P04271	1	transcriptional regulation	up-regulates quantity by expression	0.252	HOXC6 and HOXC11 increase transcription of S100beta gene in BrdU-induced in vitro differentiation of GOTO neuroblastoma cells into Schwannian cells.	SIGNOR-261647
Q8N0W4	P58400	2	binding	up-regulates activity	0.77	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.\|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264150
Q9BZL6	P24723	0	phosphorylation	up-regulates	0.2	Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. Our data suggest a two-step mechanism of activation of pkd2 via endogenously produced diacylglycerol and the activation of pkcs.	SIGNOR-89431
Q96P20	Q9BZY9	0	ubiquitination	down-regulates quantity by destabilization	0.489	Taken together, these data indicated that TRIM31 directly induced the K48-linked ubiquitination of NLRP3 through its E3 ligase activity.\|Taken together, these results indicated that TRIM31 could promote proteasomal degradation of NLRP3.	SIGNOR-278603
P11021	O95260	0	post transcriptional regulation	down-regulates quantity by destabilization	0.295	We showed that the molecular chaperone BiP (also known as GRP78) was short-lived under basal conditions and ER stress. The turnover of BiP was in part driven by its amino-terminal arginylation (Nt-arginylation) by the arginyltransferase ATE1, which generated an autophagic N-degron of the N-end rule pathway.	SIGNOR-261345
P11274	P18031	0	dephosphorylation	down-regulates	0.33	These results illustrate selectivity in the effects of ptps in a cellular context and suggest that ptp1b may function as a specific, negative regulator of p210 bcr-abl signalling in vivo.	SIGNOR-56818
Q05655	P30411	1	phosphorylation	down-regulates activity	0.301	In addition, we found a protein kinase C-dependent phosphorylation of Ser(346) that was mutually exclusive with the basal phosphorylation at Ser(348) and therefore may be implicated in differential regulation of B2 receptor activation. Functional analysis of receptor mutants revealed that a low phosphorylation stoichiometry is sufficient to initiate receptor sequestration while a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation.	SIGNOR-249108
P49327	P04626	0	phosphorylation	up-regulates activity	0.442	Conversely, HER2 directly phosphorylates and activates FASN, while it also promotes FASN gene expression ( xref ; xref ).\|Conversely, HER2 directly phosphorylates and activates FASN, while it also promotes FASN gene expression.	SIGNOR-278399
P01019-PRO_0000420660	P04201	2	binding	up-regulates activity	0.2	Recent advances have improved our understanding of the renin-angiotensin system (RAS). These have included the recognition that angiotensin (Ang)-(1-7) is a biologically active product of the RAS cascade. The identification of the ACE homologue ACE2, which forms Ang-(1-7) from Ang II, and the GPCR Mas as an Ang-(1-7) receptor have provided the necessary biochemical and molecular background and tools to study the biological significance of Ang-(1-7).	SIGNOR-260229
O15111	Q00653	1	phosphorylation	up-regulates activity	0.791	Ikkalfa phosphorylates p100, leading to its proteasomal processing to p52.	SIGNOR-124230
Q15759	O60381	1	phosphorylation	up-regulates	0.428	A mutation of the p38 map kinase phosphorylation site at aa 401 [(s-a)401hbp1] also triggered hbp1 protein instability. While protein stability was compromised by mutation, the specific activities of (s-a)401hbp1 and of wild-type hbp1 appeared comparable for transcriptional repression.	SIGNOR-119134
Q99708	P24941	0	phosphorylation	up-regulates	0.617	Collectively, these findings thereby provided strong support for ctip thr-847 indeed being a cdk target. it is established that both cdk-dependent and checkpoint-dependent phosphorylations are required for activation of sae2/ctip in vivo	SIGNOR-183840
P17612	O95835	1	phosphorylation	up-regulates	0.2	Here, we show that cyclic amp (camp)-dependent protein kinase (pka) phosphorylates lats and thereby enhances its activity sufficiently to phosphorylate yap on ser381.	SIGNOR-236991
P10070	Q8N752	0	phosphorylation	up-regulates	0.333	Gli2 is phosphorylated by gsk3 and ck1 for the fbxw11 (betatrcp2)-mediated degradation ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed	SIGNOR-179972
Q00987	P46531	1	ubiquitination	up-regulates	0.476	Although the interaction between notch1 and mdm2 results in ubiquitination of notch1, this does not result in degradation of notch1, but instead leads to activation of the intracellular domain of notch1.	SIGNOR-200197
P08912	P30679	2	binding	up-regulates activity	0.385	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-257351
Q86WV6	O43318	0	phosphorylation	up-regulates activity	0.2	Activated TAK1 directly mediates STING phosphorylation on serine 355, which facilitates its interaction with STING ER exit protein (STEEP) and thereby promotes its oligomerization and translocation to the ERGIC for subsequent activation	SIGNOR-277887
P43694	Q92833	2	binding	down-regulates activity	0.456	JMJ physically associates with Nkx2.5 and GATA4 in vitro and in vivo as determined by glutathione S-transferase pull-down and immunoprecipitation assays. we show that JMJ represses ANF gene expression by inhibiting transcriptional activities of Nkx2.5 and GATA4.	SIGNOR-224697
Q9BXC1	Q14344	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-257029
P01106	Q13309	0	ubiquitination	down-regulates quantity	0.736	The F-box protein Skp2 mediates c-Myc ubiquitylation by binding to the MB2 domain	SIGNOR-243548
Q9Y3S1	Q9H4A3	1	phosphorylation	up-regulates activity	0.546	WNK1, which is activated in response to osmotic stress by phosphorylation of its T-loop residue (Ser382). \| We found that wild-type WNK2 (Figure 8A) or WNK3 (Figure 8B) phosphorylated kinase-inactive WNK1 (1–667, D368A) at Ser382 in vitro.	SIGNOR-260790
Q16236	Q9UPY5	1	transcriptional regulation	up-regulates quantity by expression	0.424	NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification. NFE2L2 directly binds to the promoter region of SLC7A11, leading to increased expression of this transporter, which in turn contributes to the resistance to ferroptosis and to radiotherapy	SIGNOR-279867
P54198	P24941	0	phosphorylation	up-regulates activity	0.326	Hira bound to and was phosphorylated by cyclin a- and e-cdk2 in vitrohira became phosphorylated on threonine 555 in s phase when cyclin-cdk2 kinases are active.ectopic expression of hira in cells caused arrest in s phase and this is consistent with the notion that it is a cyclin-cdk2 substrate that has a role in control of the cell cycle.	SIGNOR-105548
Q96EB6	P17861-2	1	deacetylation	down-regulates activity	0.379	P300 increases the acetylation and protein stability of XBP1s, and enhances its transcriptional activity, whereas SIRT1 deacetylates XBP1s and inhibits its transcriptional activity.. The mRNA encoding the active spliced form of XBP1 (XBP1s) is generated from the unspliced form by IRE1 (inositol-requiring enzyme 1) during the UPR.	SIGNOR-260430
Q9BZI1	P28482	0	phosphorylation	up-regulates activity	0.2	We tested the transcriptional properties of Irx2 by dividing it into amino- and carboxy terminal parts and found that Mek1-mediated phosphorylation activates and derepresses the amino and carboxyl parts, respectively. When Ser46 and Ser65 were mutated to alanine (S46A and S65A), phosphorylation was reduced, whereas substitution of Ser83 and Ser103 (S83A and S103A) did not affect phosphorylation.	SIGNOR-263052
P35558	Q86UZ6	0	transcriptional regulation	up-regulates quantity by expression	0.2	We identified LIF/ZBTB46 signalling as a key promoter of metabolic reprogramming and NE differentiation of PCa cells through interactions with PCK1. We showed that ZBTB46 directly upregulates the expression of PCK1 and NE marker gene through activation of LIF signalling.	SIGNOR-277987
P28482	O15067	1	phosphorylation	up-regulates	0.2	T619 in PFAS is required to mediate ERK2-dependent purine synthesis stimulation. We demonstrate that ERK2, but not ERK1, phosphorylates the purine synthesis enzyme PFAS (phosphoribosylformylglycinamidine synthase) at T619 in cells to stimulate de novo purine synthesis. The expression of nonphosphorylatable PFAS (T619A) decreases purine synthesis, RAS-dependent cancer cell-colony formation, and tumor growth. Thus, ERK2-mediated PFAS phosphorylation facilitates the increase in nucleic acid synthesis required for anabolic cell growth and proliferation.	SIGNOR-267306
P05231	P11831	0	null	up-regulates	0.281	Srf within myofibers modulates Il6 and Cox2/Il4 expressions and, therefore, exerts a paracrine control of satellite cell proliferation and fusion, respectively, which in turn support skeletal muscle hypertrophy.	SIGNOR-255966
P78527	P14859	1	phosphorylation	down-regulates	0.33	Through a similar strategy, t226 and s232 were characterized as the dna-pk phosphorylation sites	SIGNOR-53258
P16949	P06493	0	phosphorylation	up-regulates activity	0.641	null	SIGNOR-279803
Q13469	P45983	0	phosphorylation	down-regulates	0.752	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 jnk directly regulated nuclear factor of activated t-cell (nfat) activation in culture and in transgenic mice containing an nfat-dependent luciferase reporter.	SIGNOR-118217
O43791	O15164	2	binding	down-regulates quantity by destabilization	0.337	Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations.	SIGNOR-272825
O75056	P46531	2	binding	up-regulates activity	0.379	Furthermore, we show that Syndecan-3 interacts with Notch and is required for Notch processing by ADAM17/tumor necrosis factor-converting enzyme (TACE) and signal transduction. Together, our data support the conclusion that Syndecan-3 and Notch cooperate in regulating homeostasis of the satellite cell population and myofiber size.	SIGNOR-244072
P35462	P19086	2	binding	up-regulates activity	0.315	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-257097
Q9BZL6	Q9GZY8	1	phosphorylation	up-regulates activity	0.2	The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.\|PKD directly phosphorylates MFF on serines 155, 172, and 275	SIGNOR-275947
Q9UHD2	P35813	0	dephosphorylation	down-regulates activity	0.41	Furthermore, PPM1A, but not PPM1B, serves as an efficient phosphatase to dephosphorylate Ser 172 residue of both TBK1 and IKKepsilon kinases, which is critical for their kinase activities.\|In a similar in vitro phosphatase assay, incubation of PPM1A also eliminated TBK1 and IKKepsilon phosphorylation at Ser 172 residue, evidenced by phospho-S172 immunoblotting (XREF_FIG, F and G).\|These observations suggest that PPM1A may block kinase activities of TBK1 and IKKepsilon.	SIGNOR-276966
P24941	Q96T88	1	phosphorylation	down-regulates quantity by destabilization	0.303	UHRF1 is phosphorylated by CDK2/cyclin A. In vitro kinase assay was performed with CDK2/cyclin A using recombinant wild-type UHRF1 or UHRF1-S674A mutant	SIGNOR-277192
P25490	P38606	1	transcriptional regulation	up-regulates quantity by expression	0.325	We investigated the relationship between transcription factor YY1 and ATP6V1A, and found that mRNA expression of YY1 had significant correlation with that of ATP6V1A. To validate that YY1 transcriptionally regulates ATP6V1A, we discovered that the ATP6V1A core promoter region contains three YY1 binding sites. Moreover, RNAi-mediated knockdown of YY1 in GC cells significantly decreased ATP6V1A mRNA and protein expression, while YY1 overexpression increased ATP6V1A expression level.	SIGNOR-260635
P08754	P32239	2	binding	up-regulates activity	0.267	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-257150
P31751	P15311	1	phosphorylation	up-regulates	0.375	Purified akt directly phosphorylates recombinant ezrin at threonine 567 in vitro in an atp-dependent manner. ezrin activation after initiation of na+-glucose cotransport requires akt2 expression	SIGNOR-130260
P04150	P06239	2	binding	up-regulates	0.355	The present study shows that the GC receptor is part of a TCR-linked multiprotein complex containing heat-shock protein (HSP)90, LCK and FYN, which is essential for TCR-dependent LCK/FYN activation.	SIGNOR-251685
Q9Y4D8	P01106	2	ubiquitination	down-regulates quantity by destabilization	0.2	We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop.	SIGNOR-267146
P12931	P15529	1	phosphorylation	up-regulates activity	0.458	Src kinase phosphorylates CD46 at Y354 of the Cyt2 isoform in vitro.	SIGNOR-280127
Q5S007	O43353	1	phosphorylation	up-regulates activity	0.376	Altogether, our results indicate a scenario that LRRK2 physically interacts with Rip2 and promotes phosphorylation of Rip2.\|Taken together, our results show that LRRK2 enhances Rip2 activity by promoting the phosphorylation of Rip2 at Ser176.	SIGNOR-278953
Q96PM5	Q9UQM7	0	phosphorylation	down-regulates	0.296	Phosphorylation of pirh2 by calmodulin-dependent kinase ii impairs its ability to ubiquitinate p53	SIGNOR-156064
P04626	Q96JA1	0	ubiquitination	down-regulates	0.403	We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation.	SIGNOR-139948
P31751	P55265	1	phosphorylation	down-regulates activity	0.2	AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively	SIGNOR-276192
P29320	Q8NBZ7	1	phosphorylation	up-regulates activity	0.2	However, it is possible that etk is a principal activator of Ugd.\|The phosphorylation of the Ugd protein (a UDP-glucose dehydrogenase) by Etk increases Ugd dehydrogenase activity.	SIGNOR-280006
Q8TDC3	Q8N5S9	0	phosphorylation	up-regulates activity	0.307	In transfected COS-7 cells, kinase activity and Thr (189) phosphorylation of overexpressed SAD-B were significantly enhanced by coexpression of constitutively active CaMKKalpha (residues 1-434) in a manner similar to that observed with coexpression of LKB1, STRAD, and MO25.\|Taken together, these results indicate that CaMKKalpha is capable of activating SAD-B through phosphorylation of Thr (189) both in vitro and in vivo and demonstrate for the first time that CaMKK may be an alternative activating kinase for SAD-B.	SIGNOR-280202
P46531	Q13573	2	binding	up-regulates	0.601	Contact with skip is required for biological activity of notchic. A mutation in the fourth ankyrin repeat that abolished notch signal transduction did not affect interaction with cbf1 but abolished interaction with skip.	SIGNOR-86125
P04626	Q15303	2	binding	up-regulates	0.53	Most breast, skin, lung, ovary, and gastrointestinal tract tumors express erbb-4, and heterodimerization of this receptor with erbb-2, may be involved in some cancer	SIGNOR-43844
P24941	O94761	1	phosphorylation	up-regulates activity	0.329	During S/G2 phases, CDK1 and CDK2 (CDK1/2) phosphorylate RECQL4 on serines 89 and 251, enhancing MRE11/RECQL4 interaction and RECQL4 recruitment to DSBs.	SIGNOR-277374
Q9H422	Q00613	1	phosphorylation	up-regulates activity	0.335	We show that Yak1 directly phosphorylates Hsf1 in vitro, leading to the increase in DNA binding activity of Hsf1.	SIGNOR-279054
P36888	P49771	2	binding	up-regulates	0.885	Flt3 ligand (fl) is an early-acting potent co-stimulatory cytokine that regulates proliferation and differentiation of a number of blood cell lineages. Its receptor flt3/flk2 belongs to class iii receptor tyrosine kinases that also include the receptors for colony-stimulating factor 1	SIGNOR-65564
Q9UBY5	P19086	2	binding	up-regulates activity	0.25	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257229
P10071	P55075	1	transcriptional regulation	down-regulates quantity	0.445	Whereas Fgf8 expression was almost absent in Shh-/- mutants, it was up-regulated in Gli3-/-;Shh-/- double mutants, suggesting that SHH is not required for Fgf8 induction, and that GLI3 normally represses Fgf8 independently of SHH	SIGNOR-268949
Q92908	P49840	0	phosphorylation	down-regulates quantity by destabilization	0.265	Through bioinformatics and cell-based experiments, we identified the AKT-repressed signal as glycogen synthase kinase 3 (GSK3)-catalyzed phosphorylation of Ser(37) on the long form of the transcription factor GATA6. Phosphorylation of GATA6 on Ser(37) promoted its degradation, thereby preventing GATA6 from repressing transcripts that are induced by TNF and attenuated by insulin	SIGNOR-253156
Q9NXA8	P07195	1	deacetylation	up-regulates activity	0.2	In colorectal cancer, SIRT5 binds to lactate dehydrogenase B (LDHB) to deacetylate it at Lysine 329, thereby increasing its enzymatic activity.	SIGNOR-267645
P53779	Q5JR12	1	phosphorylation	down-regulates	0.2	Specific phosphorylation of pp2czeta at ser (92) by stress-activated jnk attenuates its phosphatase activity in cells.	SIGNOR-178926
Q99497	P31749	0	phosphorylation	up-regulates activity	0.465	Using a proteomic approach, we identified on DJ-1 a novel threonine phosphorylation (T125) that was found, by the in-silico tool scansite 4, as part of a putative Akt consensus. \|Deglycase activity of DJ-1 on histones proteins, investigated by coupling 2D tau gel with LC-MS/MS and 2D-TAU (Triton-Acid-Urea)-Western blot, was found correlated with its phosphorylation status that, in turn, depends from Akt activation.	SIGNOR-275582
P50148	P41595	2	binding	up-regulates activity	0.553	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-257138
P63211	Q9NPG1	2	binding	up-regulates	0.398	In the non-canonical wnt signalling pathway, frizzled uses galphaq or galphai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat.	SIGNOR-152606
Q00536	Q00535	0	phosphorylation	up-regulates activity	0.335	Taken together, our findings demonstrate that Pctaire1 interacts with p35, both in vitro and in vivo, and that phosphorylation of Pctaire1 by Cdk5 enhances its kinase activity.	SIGNOR-279149
P78357	Q13882	0	phosphorylation	up-regulates activity	0.2	As a consequence, Brk stimulates p190 and attenuates p120 functions, leading to RhoA inactivation and Ras activation, respectively.\|Brk phosphorylates p190 at the Y (1105) residue both in vitro and in vivo, thereby promoting the association of p190 with p120RasGAP (p120).	SIGNOR-279274
P05107	O60674	0	phosphorylation	up-regulates activity	0.265	PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role.	SIGNOR-254738
Q86Y13	Q9BTM1	1	monoubiquitination	up-regulates activity	0.2	2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271763
Q01484	O94856	0	relocalization	up-regulates quantity	0.694	Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.	SIGNOR-266716
Q13608	O43933	2	binding	up-regulates activity	0.67	Pex26 recruits Pex6–Pex1 complexes to peroxisomes. Pex26 anchors Pex6 and Pex1 through Pex26–Pex6 and Pex6–Pex1 interactions.	SIGNOR-253615
Q02750	Q16584	0	phosphorylation	up-regulates activity	0.335	Here we report that MLK3 can phosphorylate and activate MEK-1 directly in vitro and also can induce MEK phosphorylation on its activation sites in vivo in COS-7 cells.	SIGNOR-280019
P20810	P07384	2	binding	down-regulates activity	0.915	In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains\|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain	SIGNOR-251582
P11802	Q14814	2	binding	down-regulates	0.28	In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms.	SIGNOR-176524
Q9UGL1	P78317	0	sumoylation	down-regulates quantity by destabilization	0.3	Hendriks and coworkers showed that, in response to alkylation damage by methyl methanesulfonate (MMS), SUMOylated JARID1B (KDM5B) is ubiquitylated by the SUMOtargeted ubiquitin ligase RNF4 and degraded by the proteasome, whereas JARID1C (KDM5C) is SUMOylated and recruited to the chromatin to demethylate histone H3K4 (Hendriks et al., 2015).	SIGNOR-271575
P08151	P28482	0	phosphorylation	up-regulates activity	0.323	We conclude that multisite phosphorylation of GLI1 by ERK2 or other MAP kinases weakens GLI1-SUFU binding, thereby facilitating GLI1 activation and contributing to both physiological and pathological crosstalk.	SIGNOR-277601
P08908	Q00535	0	phosphorylation	down-regulates quantity by destabilization	0.27	Cyclin-dependent kinase 5 promotes proteasomal degradation of the 5-HT 1A receptor via phosphorylation\|5-HT1AR was phosphorylated by the Cdk5-p35 complex at Thr314 in the third cytoplasmic loop.	SIGNOR-264406
P0DTD1-PRO_0000449619	P23396	2	binding	down-regulates activity	0.2	Nsp1 Locks the 40S in a Conformation Incompatible with mRNA Loading and Disrupts Initiation Factor Binding. Molecular interactions between C-Nsp1 and 40S ribosome components, including uS3, h18, and uS5.	SIGNOR-262507
P37173	P10600	2	binding	up-regulates	0.866	T?RII Is known to bind the isoforms tgf??1 And tgf??3. Binding of these ligands causes recruitment of the type i receptor (t?RI) into a signalling receptor complex followed by activation of t?RI Through transphosphorylation	SIGNOR-104798
P31749	O60858	0	polyubiquitination	down-regulates quantity by destabilization	0.353	Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT. We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro.	SIGNOR-271852
Q8WXX7	Q8TCU6	2	binding	up-regulates activity	0.252	Mutations in the Autism susceptibility candidate 2 gene (AUTS2), whose protein is believed to act in neuronal cell nuclei, have been associated with multiple psychiatric illnesses, including autism spectrum disorders, intellectual disability, and schizophrenia. Here we show that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development. AUTS2 activates Rac1 to induce lamellipodia but downregulates Cdc42 to suppress filopodia. Our loss-of-function and rescue experiments show that a cytoplasmic AUTS2-Rac1 pathway is involved in cortical neuronal migration and neuritogenesis in the developing brain. These results suggest that FL-AUTS2 can activate Rac1 via interaction with P-Rex1 and the Elmo2/Dock180 complex to regulate actin dynamics in N1E-115 cells.	SIGNOR-266817
Q13588	P00519	2	binding	up-regulates	0.267	We show that the grb2-related adapter protein, gads, also associates with bcr-abl, specifically through y177 and demonstrate that bcr-abl-driven lymphoid disease requires gads	SIGNOR-200871
Q01094	P45983	0	phosphorylation	down-regulates activity	0.277	JNK1 phosphorylates E2F1 in vitro, and co-transfection of JNK1 reduces the DNA binding activity of E2F1	SIGNOR-279218
P67775	P63151	2	binding	down-regulates activity	0.912	Since B_ suppresses the association of the catalytic C and regulatory A subunits of protein phosphatase 2A [94], the B_ interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity	SIGNOR-217875
Q96A08	Q14493	0	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265393
P29597	P08575	0	dephosphorylation	down-regulates activity	0.407	CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling\|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells	SIGNOR-248357
Q9H461	P04628	2	binding	up-regulates	0.725	Wnt signaling is mediated by the frizzled (fz) family of seven-pass transmembrane receptors that bind wnt via the conserved amino-terminal cysteine-rich domain (crd)	SIGNOR-109250
P60900	P17861	2	binding	down-regulates quantity by destabilization	0.303	We saw preferential binding of XBP-1u to subunits _5, _6 and _7.2. We demonstrate that XBP-1u undergoes efficient degradation in vitro by 20S proteasomes in the absence of ubiquitination.	SIGNOR-239039
P0CG48	Q9BXM7	0	phosphorylation	up-regulates activity	0.604	Ubiquitin is phosphorylated by PINK1 to activate parkin\|PINK1 phosphorylated ubiquitin at Ser65 both in vitro and in cells	SIGNOR-249691
Q86Y13	Q6FI13	1	monoubiquitination	up-regulates activity	0.2	2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271755
Q9BXW9	P51587	2	binding	up-regulates activity	0.812	Fanconi anemia complementation group FANCD2 protein serine 331 phosphorylation is important for fanconi anemia pathway function and BRCA2 interaction	SIGNOR-263238
O15027	P28482	0	phosphorylation	up-regulates activity	0.352	Recombinant active ERK2 also phosphorylated Sec16 (XREF_FIG).	SIGNOR-280022
Q9Y5G0	Q9Y5H9	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-265692
P23588	P31749	0	phosphorylation	up-regulates	0.393	Using an in vitro kinase assay, we found that pkb can directly phosphorylate eif4b on serine 422 (ser422). This was prevented by pretreatment of cells with the phosphatidylinositol 3-kinase (pi3k) inhibitor ly294002 or pharmacological inhibition of pkb. Phosphorylation regultes the activation of eukaryotic translation initiation factor 4b.	SIGNOR-252520
Q13315	Q9UQ84	1	phosphorylation	up-regulates	0.83	The phosphorylation of exo1 by atm appears to regulate the activity of exo1 following resection, allowing optimal rad51 loading and the completion of hr repair.	SIGNOR-162304
P24864	P24941	2	binding	up-regulates	0.955	Our results suggest that ad-induced cyclin e activates cdk2 that targets the transcriptional repressor prb/cyclin e activates the cdk2 kinase necessary for the actual initiation of dna replication	SIGNOR-201506
P28482	Q8IUX7	1	phosphorylation	up-regulates activity	0.2	We show that DNA binding by AEBP1 requires both the N- and C-terminal domains of AEBP1, and MAPK interaction with AEBP1 (through its N terminus) results in enhanced DNA binding. A threonine at position 623 within the C-terminal domain of AEBP1 plays an important role in DNA binding by AEBP1, because the mutation results in decreased DNA binding by AEBP1, which leads to a decrease in the transcriptional repression ability of AEBP1. We also show that in vitro phosphorylation of AEBP1 by MAPK is greatly reduced upon mutation of T623. These results suggest that MAPK regulates the transcriptional activity of AEBP1 by a novel dual mechanism, in which MAPK interaction enhances and subsequent phosphorylation decreases the DNA-binding ability of AEBP1.	SIGNOR-262897
Q9NR19	P11279	1	transcriptional regulation	up-regulates quantity by expression	0.2	Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy\|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1\|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants	SIGNOR-276556

Q8NEZ5

O75164

1

ubiquitination

down-regulates quantity by destabilization

0.339

SCF(FBXO22) regulates histone H3 lysine 9 and 36 methylation levels by targeting histone demethylase KDM4A for ubiquitin-mediated proteasomal degradation

SIGNOR-273442

P36888

Q13322

2

binding

up-regulates activity

0.364

These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K–Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells.

SIGNOR-255947

P11362

Q9Y2J4

1

phosphorylation

up-regulates activity

0.2

These data support an idea that Amotl2 Tyr-103 can be phosphorylated by FGF receptor tyrosine kinase activity. We then determined whether Amotl2 Tyr-103 is required for its interaction with c-Src. |Amotl2 promotes MAPK/ERK activation via c-Src, which is dependent on phosphorylation of tyrosine residue at position 103 but independent of the C-terminal PDZ-binding domain.

SIGNOR-271869

O00257

Q9H2X6

0

phosphorylation

up-regulates activity

0.423

In addition, HIPK2 phosphorylates Pc2 at several sites, including threonine 495.

SIGNOR-278484

Q9Y458

P35548

1

transcriptional regulation

down-regulates quantity by repression

0.309

the main function of TBX22 as shown in misexpression experiments is to decrease proliferation. We subsequently uncovered three targets of TBX22, DLX5, MSX2, and TBX22 itself. All are downregulated in the presence of viral-derived hTBX22.

SIGNOR-265567

O43248

P04271

1

transcriptional regulation

up-regulates quantity by expression

0.252

HOXC6 and HOXC11 increase transcription of S100beta gene in BrdU-induced in vitro differentiation of GOTO neuroblastoma cells into Schwannian cells.

SIGNOR-261647

Q8N0W4

P58400

2

binding

up-regulates activity

0.77

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

SIGNOR-264150

Q9BZL6

P24723

0

phosphorylation

up-regulates

0.2

Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. Our data suggest a two-step mechanism of activation of pkd2 via endogenously produced diacylglycerol and the activation of pkcs.

SIGNOR-89431

Q96P20

Q9BZY9

0

ubiquitination

down-regulates quantity by destabilization

0.489

Taken together, these data indicated that TRIM31 directly induced the K48-linked ubiquitination of NLRP3 through its E3 ligase activity.|Taken together, these results indicated that TRIM31 could promote proteasomal degradation of NLRP3.

SIGNOR-278603

P11021

O95260

0

post transcriptional regulation

down-regulates quantity by destabilization

0.295

We showed that the molecular chaperone BiP (also known as GRP78) was short-lived under basal conditions and ER stress. The turnover of BiP was in part driven by its amino-terminal arginylation (Nt-arginylation) by the arginyltransferase ATE1, which generated an autophagic N-degron of the N-end rule pathway.

SIGNOR-261345

P11274

P18031

0

dephosphorylation

down-regulates

0.33

These results illustrate selectivity in the effects of ptps in a cellular context and suggest that ptp1b may function as a specific, negative regulator of p210 bcr-abl signalling in vivo.

SIGNOR-56818

Q05655

P30411

1

phosphorylation

down-regulates activity

0.301

In addition, we found a protein kinase C-dependent phosphorylation of Ser(346) that was mutually exclusive with the basal phosphorylation at Ser(348) and therefore may be implicated in differential regulation of B2 receptor activation. Functional analysis of receptor mutants revealed that a low phosphorylation stoichiometry is sufficient to initiate receptor sequestration while a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation.

SIGNOR-249108

P49327

P04626

0

phosphorylation

up-regulates activity

0.442

Conversely, HER2 directly phosphorylates and activates FASN, while it also promotes FASN gene expression ( xref ; xref ).|Conversely, HER2 directly phosphorylates and activates FASN, while it also promotes FASN gene expression.

SIGNOR-278399

P01019-PRO_0000420660

P04201

2

binding

up-regulates activity

0.2

Recent advances have improved our understanding of the renin-angiotensin system (RAS). These have included the recognition that angiotensin (Ang)-(1-7) is a biologically active product of the RAS cascade. The identification of the ACE homologue ACE2, which forms Ang-(1-7) from Ang II, and the GPCR Mas as an Ang-(1-7) receptor have provided the necessary biochemical and molecular background and tools to study the biological significance of Ang-(1-7).

SIGNOR-260229

O15111

Q00653

1

phosphorylation

up-regulates activity

0.791

Ikkalfa phosphorylates p100, leading to its proteasomal processing to p52.

SIGNOR-124230

Q15759

O60381

1

phosphorylation

up-regulates

0.428

A mutation of the p38 map kinase phosphorylation site at aa 401 [(s-a)401hbp1] also triggered hbp1 protein instability. While protein stability was compromised by mutation, the specific activities of (s-a)401hbp1 and of wild-type hbp1 appeared comparable for transcriptional repression.

SIGNOR-119134

Q99708

P24941

0

phosphorylation

up-regulates

0.617

Collectively, these findings thereby provided strong support for ctip thr-847 indeed being a cdk target. it is established that both cdk-dependent and checkpoint-dependent phosphorylations are required for activation of sae2/ctip in vivo

SIGNOR-183840

P17612

O95835

1

phosphorylation

up-regulates

0.2

Here, we show that cyclic amp (camp)-dependent protein kinase (pka) phosphorylates lats and thereby enhances its activity sufficiently to phosphorylate yap on ser381.

SIGNOR-236991

P10070

Q8N752

0

phosphorylation

up-regulates

0.333

Gli2 is phosphorylated by gsk3 and ck1 for the fbxw11 (betatrcp2)-mediated degradation ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed

SIGNOR-179972

Q00987

P46531

1

ubiquitination

up-regulates

0.476

Although the interaction between notch1 and mdm2 results in ubiquitination of notch1, this does not result in degradation of notch1, but instead leads to activation of the intracellular domain of notch1.

SIGNOR-200197

P08912

P30679

2

binding

up-regulates activity

0.385

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-257351

Q86WV6

O43318

0

phosphorylation

up-regulates activity

0.2

Activated TAK1 directly mediates STING phosphorylation on serine 355, which facilitates its interaction with STING ER exit protein (STEEP) and thereby promotes its oligomerization and translocation to the ERGIC for subsequent activation

SIGNOR-277887

P43694

Q92833

2

binding

down-regulates activity

0.456

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

SIGNOR-224697

Q9BXC1

Q14344

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-257029

P01106

Q13309

0

ubiquitination

down-regulates quantity

0.736

The F-box protein Skp2 mediates c-Myc ubiquitylation by binding to the MB2 domain

SIGNOR-243548

Q9Y3S1

Q9H4A3

1

phosphorylation

up-regulates activity

0.546

WNK1, which is activated in response to osmotic stress by phosphorylation of its T-loop residue (Ser382). | We found that wild-type WNK2 (Figure 8A) or WNK3 (Figure 8B) phosphorylated kinase-inactive WNK1 (1–667, D368A) at Ser382 in vitro.

SIGNOR-260790

Q16236

Q9UPY5

1

transcriptional regulation

up-regulates quantity by expression

0.424

NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification. NFE2L2 directly binds to the promoter region of SLC7A11, leading to increased expression of this transporter, which in turn contributes to the resistance to ferroptosis and to radiotherapy

SIGNOR-279867

P54198

P24941

0

phosphorylation

up-regulates activity

0.326

Hira bound to and was phosphorylated by cyclin a- and e-cdk2 in vitrohira became phosphorylated on threonine 555 in s phase when cyclin-cdk2 kinases are active.ectopic expression of hira in cells caused arrest in s phase and this is consistent with the notion that it is a cyclin-cdk2 substrate that has a role in control of the cell cycle.

SIGNOR-105548

Q96EB6

P17861-2

1

deacetylation

down-regulates activity

0.379

P300 increases the acetylation and protein stability of XBP1s, and enhances its transcriptional activity, whereas SIRT1 deacetylates XBP1s and inhibits its transcriptional activity.. The mRNA encoding the active spliced form of XBP1 (XBP1s) is generated from the unspliced form by IRE1 (inositol-requiring enzyme 1) during the UPR.

SIGNOR-260430

Q9BZI1

P28482

0

phosphorylation

up-regulates activity

0.2

We tested the transcriptional properties of Irx2 by dividing it into amino- and carboxy terminal parts and found that Mek1-mediated phosphorylation activates and derepresses the amino and carboxyl parts, respectively. When Ser46 and Ser65 were mutated to alanine (S46A and S65A), phosphorylation was reduced, whereas substitution of Ser83 and Ser103 (S83A and S103A) did not affect phosphorylation.

SIGNOR-263052

P35558

Q86UZ6

0

transcriptional regulation

up-regulates quantity by expression

0.2

We identified LIF/ZBTB46 signalling as a key promoter of metabolic reprogramming and NE differentiation of PCa cells through interactions with PCK1. We showed that ZBTB46 directly upregulates the expression of PCK1 and NE marker gene through activation of LIF signalling.

SIGNOR-277987

P28482

O15067

1

phosphorylation

up-regulates

0.2

T619 in PFAS is required to mediate ERK2-dependent purine synthesis stimulation. We demonstrate that ERK2, but not ERK1, phosphorylates the purine synthesis enzyme PFAS (phosphoribosylformylglycinamidine synthase) at T619 in cells to stimulate de novo purine synthesis. The expression of nonphosphorylatable PFAS (T619A) decreases purine synthesis, RAS-dependent cancer cell-colony formation, and tumor growth. Thus, ERK2-mediated PFAS phosphorylation facilitates the increase in nucleic acid synthesis required for anabolic cell growth and proliferation.

SIGNOR-267306

P05231

P11831

0

null

up-regulates

0.281

Srf within myofibers modulates Il6 and Cox2/Il4 expressions and, therefore, exerts a paracrine control of satellite cell proliferation and fusion, respectively, which in turn support skeletal muscle hypertrophy.

SIGNOR-255966

P78527

P14859

1

phosphorylation

down-regulates

0.33

Through a similar strategy, t226 and s232 were characterized as the dna-pk phosphorylation sites

SIGNOR-53258

P16949

P06493

0

phosphorylation

up-regulates activity

0.641

null

SIGNOR-279803

Q13469

P45983

0

phosphorylation

down-regulates

0.752

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 jnk directly regulated nuclear factor of activated t-cell (nfat) activation in culture and in transgenic mice containing an nfat-dependent luciferase reporter.

SIGNOR-118217

O43791

O15164

2

binding

down-regulates quantity by destabilization

0.337

Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations.

SIGNOR-272825

O75056

P46531

2

binding

up-regulates activity

0.379

Furthermore, we show that Syndecan-3 interacts with Notch and is required for Notch processing by ADAM17/tumor necrosis factor-converting enzyme (TACE) and signal transduction. Together, our data support the conclusion that Syndecan-3 and Notch cooperate in regulating homeostasis of the satellite cell population and myofiber size.

SIGNOR-244072

P35462

P19086

2

binding

up-regulates activity

0.315

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-257097

Q9BZL6

Q9GZY8

1

phosphorylation

up-regulates activity

0.2

The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275

SIGNOR-275947

Q9UHD2

P35813

0

dephosphorylation

down-regulates activity

0.41

Furthermore, PPM1A, but not PPM1B, serves as an efficient phosphatase to dephosphorylate Ser 172 residue of both TBK1 and IKKepsilon kinases, which is critical for their kinase activities.|In a similar in vitro phosphatase assay, incubation of PPM1A also eliminated TBK1 and IKKepsilon phosphorylation at Ser 172 residue, evidenced by phospho-S172 immunoblotting (XREF_FIG, F and G).|These observations suggest that PPM1A may block kinase activities of TBK1 and IKKepsilon.

SIGNOR-276966

P24941

Q96T88

1

phosphorylation

down-regulates quantity by destabilization

0.303

UHRF1 is phosphorylated by CDK2/cyclin A. In vitro kinase assay was performed with CDK2/cyclin A using recombinant wild-type UHRF1 or UHRF1-S674A mutant

SIGNOR-277192

P25490

P38606

1

transcriptional regulation

up-regulates quantity by expression

0.325

We investigated the relationship between transcription factor YY1 and ATP6V1A, and found that mRNA expression of YY1 had significant correlation with that of ATP6V1A. To validate that YY1 transcriptionally regulates ATP6V1A, we discovered that the ATP6V1A core promoter region contains three YY1 binding sites. Moreover, RNAi-mediated knockdown of YY1 in GC cells significantly decreased ATP6V1A mRNA and protein expression, while YY1 overexpression increased ATP6V1A expression level.

SIGNOR-260635

P08754

P32239

2

binding

up-regulates activity

0.267

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-257150

P31751

P15311

1

phosphorylation

up-regulates

0.375

Purified akt directly phosphorylates recombinant ezrin at threonine 567 in vitro in an atp-dependent manner. ezrin activation after initiation of na+-glucose cotransport requires akt2 expression

SIGNOR-130260

P04150

P06239

2

binding

up-regulates

0.355

The present study shows that the GC receptor is part of a TCR-linked multiprotein complex containing heat-shock protein (HSP)90, LCK and FYN, which is essential for TCR-dependent LCK/FYN activation.

SIGNOR-251685

Q9Y4D8

P01106

2

ubiquitination

down-regulates quantity by destabilization

0.2

We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop.

SIGNOR-267146

P12931

P15529

1

phosphorylation

up-regulates activity

0.458

Src kinase phosphorylates CD46 at Y354 of the Cyt2 isoform in vitro.

SIGNOR-280127

Q5S007

O43353

1

phosphorylation

up-regulates activity

0.376

Altogether, our results indicate a scenario that LRRK2 physically interacts with Rip2 and promotes phosphorylation of Rip2.|Taken together, our results show that LRRK2 enhances Rip2 activity by promoting the phosphorylation of Rip2 at Ser176.

SIGNOR-278953

Q96PM5

Q9UQM7

0

phosphorylation

down-regulates

0.296

Phosphorylation of pirh2 by calmodulin-dependent kinase ii impairs its ability to ubiquitinate p53

SIGNOR-156064

P04626

Q96JA1

0

ubiquitination

down-regulates

0.403

We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation.

SIGNOR-139948

P31751

P55265

1

phosphorylation

down-regulates activity

0.2

AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively

SIGNOR-276192

P29320

Q8NBZ7

1

phosphorylation

up-regulates activity

0.2

However, it is possible that etk is a principal activator of Ugd.|The phosphorylation of the Ugd protein (a UDP-glucose dehydrogenase) by Etk increases Ugd dehydrogenase activity.

SIGNOR-280006

Q8TDC3

Q8N5S9

0

phosphorylation

up-regulates activity

0.307

In transfected COS-7 cells, kinase activity and Thr (189) phosphorylation of overexpressed SAD-B were significantly enhanced by coexpression of constitutively active CaMKKalpha (residues 1-434) in a manner similar to that observed with coexpression of LKB1, STRAD, and MO25.|Taken together, these results indicate that CaMKKalpha is capable of activating SAD-B through phosphorylation of Thr (189) both in vitro and in vivo and demonstrate for the first time that CaMKK may be an alternative activating kinase for SAD-B.

SIGNOR-280202

P46531

Q13573

2

binding

up-regulates

0.601

Contact with skip is required for biological activity of notchic. A mutation in the fourth ankyrin repeat that abolished notch signal transduction did not affect interaction with cbf1 but abolished interaction with skip.

SIGNOR-86125

P04626

Q15303

2

binding

up-regulates

0.53

Most breast, skin, lung, ovary, and gastrointestinal tract tumors express erbb-4, and heterodimerization of this receptor with erbb-2, may be involved in some cancer

SIGNOR-43844

P24941

O94761

1

phosphorylation

up-regulates activity

0.329

During S/G2 phases, CDK1 and CDK2 (CDK1/2) phosphorylate RECQL4 on serines 89 and 251, enhancing MRE11/RECQL4 interaction and RECQL4 recruitment to DSBs.

SIGNOR-277374

Q9H422

Q00613

1

phosphorylation

up-regulates activity

0.335

We show that Yak1 directly phosphorylates Hsf1 in vitro, leading to the increase in DNA binding activity of Hsf1.

SIGNOR-279054

P36888

P49771

2

binding

up-regulates

0.885

Flt3 ligand (fl) is an early-acting potent co-stimulatory cytokine that regulates proliferation and differentiation of a number of blood cell lineages. Its receptor flt3/flk2 belongs to class iii receptor tyrosine kinases that also include the receptors for colony-stimulating factor 1

SIGNOR-65564

Q9UBY5

P19086

2

binding

up-regulates activity

0.25

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

SIGNOR-257229

P10071

P55075

1

transcriptional regulation

down-regulates quantity

0.445

Whereas Fgf8 expression was almost absent in Shh-/- mutants, it was up-regulated in Gli3-/-;Shh-/- double mutants, suggesting that SHH is not required for Fgf8 induction, and that GLI3 normally represses Fgf8 independently of SHH

SIGNOR-268949

Q92908

P49840

0

phosphorylation

down-regulates quantity by destabilization

0.265

Through bioinformatics and cell-based experiments, we identified the AKT-repressed signal as glycogen synthase kinase 3 (GSK3)-catalyzed phosphorylation of Ser(37) on the long form of the transcription factor GATA6. Phosphorylation of GATA6 on Ser(37) promoted its degradation, thereby preventing GATA6 from repressing transcripts that are induced by TNF and attenuated by insulin

SIGNOR-253156

Q9NXA8

P07195

1

deacetylation

up-regulates activity

0.2

In colorectal cancer, SIRT5 binds to lactate dehydrogenase B (LDHB) to deacetylate it at Lysine 329, thereby increasing its enzymatic activity.

SIGNOR-267645

P53779

Q5JR12

1

phosphorylation

down-regulates

0.2

Specific phosphorylation of pp2czeta at ser (92) by stress-activated jnk attenuates its phosphatase activity in cells.

SIGNOR-178926

Q99497

P31749

0

phosphorylation

up-regulates activity

0.465

Using a proteomic approach, we identified on DJ-1 a novel threonine phosphorylation (T125) that was found, by the in-silico tool scansite 4, as part of a putative Akt consensus. |Deglycase activity of DJ-1 on histones proteins, investigated by coupling 2D tau gel with LC-MS/MS and 2D-TAU (Triton-Acid-Urea)-Western blot, was found correlated with its phosphorylation status that, in turn, depends from Akt activation.

SIGNOR-275582

P50148

P41595

2

binding

up-regulates activity

0.553

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-257138

P63211

Q9NPG1

2

binding

up-regulates

0.398

In the non-canonical wnt signalling pathway, frizzled uses galphaq or galphai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat.

SIGNOR-152606

Q00536

Q00535

0

phosphorylation

up-regulates activity

0.335

Taken together, our findings demonstrate that Pctaire1 interacts with p35, both in vitro and in vivo, and that phosphorylation of Pctaire1 by Cdk5 enhances its kinase activity.

SIGNOR-279149

P78357

Q13882

0

phosphorylation

up-regulates activity

0.2

As a consequence, Brk stimulates p190 and attenuates p120 functions, leading to RhoA inactivation and Ras activation, respectively.|Brk phosphorylates p190 at the Y (1105) residue both in vitro and in vivo, thereby promoting the association of p190 with p120RasGAP (p120).

SIGNOR-279274

P05107

O60674

0

phosphorylation

up-regulates activity

0.265

PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role.

SIGNOR-254738

Q86Y13

Q9BTM1

1

monoubiquitination

up-regulates activity

0.2

2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.

SIGNOR-271763

Q01484

O94856

0

relocalization

up-regulates quantity

0.694

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

SIGNOR-266716

Q13608

O43933

2

binding

up-regulates activity

0.67

Pex26 recruits Pex6–Pex1 complexes to peroxisomes. Pex26 anchors Pex6 and Pex1 through Pex26–Pex6 and Pex6–Pex1 interactions.

SIGNOR-253615

Q02750

Q16584

0

phosphorylation

up-regulates activity

0.335

Here we report that MLK3 can phosphorylate and activate MEK-1 directly in vitro and also can induce MEK phosphorylation on its activation sites in vivo in COS-7 cells.

SIGNOR-280019

P20810

P07384

2

binding

down-regulates activity

0.915

In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain

SIGNOR-251582

P11802

Q14814

2

binding

down-regulates

0.28

In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms.

SIGNOR-176524

Q9UGL1

P78317

0

sumoylation

down-regulates quantity by destabilization

0.3

Hendriks and coworkers showed that, in response to alkylation damage by methyl methanesulfonate (MMS), SUMOylated JARID1B (KDM5B) is ubiquitylated by the SUMOtargeted ubiquitin ligase RNF4 and degraded by the proteasome, whereas JARID1C (KDM5C) is SUMOylated and recruited to the chromatin to demethylate histone H3K4 (Hendriks et al., 2015).

SIGNOR-271575

P08151

P28482

0

phosphorylation

up-regulates activity

0.323

We conclude that multisite phosphorylation of GLI1 by ERK2 or other MAP kinases weakens GLI1-SUFU binding, thereby facilitating GLI1 activation and contributing to both physiological and pathological crosstalk.

SIGNOR-277601

P08908

Q00535

0

phosphorylation

down-regulates quantity by destabilization

0.27

Cyclin-dependent kinase 5 promotes proteasomal degradation of the 5-HT 1A receptor via phosphorylation|5-HT1AR was phosphorylated by the Cdk5-p35 complex at Thr314 in the third cytoplasmic loop.

SIGNOR-264406

P0DTD1-PRO_0000449619

P23396

2

binding

down-regulates activity

0.2

Nsp1 Locks the 40S in a Conformation Incompatible with mRNA Loading and Disrupts Initiation Factor Binding. Molecular interactions between C-Nsp1 and 40S ribosome components, including uS3, h18, and uS5.

SIGNOR-262507

P37173

P10600

2

binding

up-regulates

0.866

T?RII Is known to bind the isoforms tgf??1 And tgf??3. Binding of these ligands causes recruitment of the type i receptor (t?RI) into a signalling receptor complex followed by activation of t?RI Through transphosphorylation

SIGNOR-104798

P31749

O60858

0

polyubiquitination

down-regulates quantity by destabilization

0.353

Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT. We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro.

SIGNOR-271852

Q8WXX7

Q8TCU6

2

binding

up-regulates activity

0.252

Mutations in the Autism susceptibility candidate 2 gene (AUTS2), whose protein is believed to act in neuronal cell nuclei, have been associated with multiple psychiatric illnesses, including autism spectrum disorders, intellectual disability, and schizophrenia. Here we show that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development. AUTS2 activates Rac1 to induce lamellipodia but downregulates Cdc42 to suppress filopodia. Our loss-of-function and rescue experiments show that a cytoplasmic AUTS2-Rac1 pathway is involved in cortical neuronal migration and neuritogenesis in the developing brain. These results suggest that FL-AUTS2 can activate Rac1 via interaction with P-Rex1 and the Elmo2/Dock180 complex to regulate actin dynamics in N1E-115 cells.

SIGNOR-266817

Q13588

P00519

2

binding

up-regulates

0.267

We show that the grb2-related adapter protein, gads, also associates with bcr-abl, specifically through y177 and demonstrate that bcr-abl-driven lymphoid disease requires gads

SIGNOR-200871

Q01094

P45983

0

phosphorylation

down-regulates activity

0.277

JNK1 phosphorylates E2F1 in vitro, and co-transfection of JNK1 reduces the DNA binding activity of E2F1

SIGNOR-279218

P67775

P63151

2

binding

down-regulates activity

0.912

Since B_ suppresses the association of the catalytic C and regulatory A subunits of protein phosphatase 2A [94], the B_ interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity

SIGNOR-217875

Q96A08

Q14493

0

translation regulation

up-regulates quantity by expression

0.2

Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.

SIGNOR-265393

P29597

P08575

0

dephosphorylation

down-regulates activity

0.407

CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells

SIGNOR-248357

Q9H461

P04628

2

binding

up-regulates

0.725

Wnt signaling is mediated by the frizzled (fz) family of seven-pass transmembrane receptors that bind wnt via the conserved amino-terminal cysteine-rich domain (crd)

SIGNOR-109250

P60900

P17861

2

binding

down-regulates quantity by destabilization

0.303

We saw preferential binding of XBP-1u to subunits _5, _6 and _7.2. We demonstrate that XBP-1u undergoes efficient degradation in vitro by 20S proteasomes in the absence of ubiquitination.

SIGNOR-239039

P0CG48

Q9BXM7

0

phosphorylation

up-regulates activity

0.604

Ubiquitin is phosphorylated by PINK1 to activate parkin|PINK1 phosphorylated ubiquitin at Ser65 both in vitro and in cells

SIGNOR-249691

Q86Y13

Q6FI13

1

monoubiquitination

up-regulates activity

0.2

2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.

SIGNOR-271755

Q9BXW9

P51587

2

binding

up-regulates activity

0.812

Fanconi anemia complementation group FANCD2 protein serine 331 phosphorylation is important for fanconi anemia pathway function and BRCA2 interaction

SIGNOR-263238

O15027

P28482

0

phosphorylation

up-regulates activity

0.352

Recombinant active ERK2 also phosphorylated Sec16 (XREF_FIG).

SIGNOR-280022

Q9Y5G0

Q9Y5H9

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-265692

P23588

P31749

0

phosphorylation

up-regulates

0.393

Using an in vitro kinase assay, we found that pkb can directly phosphorylate eif4b on serine 422 (ser422). This was prevented by pretreatment of cells with the phosphatidylinositol 3-kinase (pi3k) inhibitor ly294002 or pharmacological inhibition of pkb. Phosphorylation regultes the activation of eukaryotic translation initiation factor 4b.

SIGNOR-252520

Q13315

Q9UQ84

1

phosphorylation

up-regulates

0.83

The phosphorylation of exo1 by atm appears to regulate the activity of exo1 following resection, allowing optimal rad51 loading and the completion of hr repair.

SIGNOR-162304

P24864

P24941

2

binding

up-regulates

0.955

Our results suggest that ad-induced cyclin e activates cdk2 that targets the transcriptional repressor prb/cyclin e activates the cdk2 kinase necessary for the actual initiation of dna replication

SIGNOR-201506

P28482

Q8IUX7

1

phosphorylation

up-regulates activity

0.2

We show that DNA binding by AEBP1 requires both the N- and C-terminal domains of AEBP1, and MAPK interaction with AEBP1 (through its N terminus) results in enhanced DNA binding. A threonine at position 623 within the C-terminal domain of AEBP1 plays an important role in DNA binding by AEBP1, because the mutation results in decreased DNA binding by AEBP1, which leads to a decrease in the transcriptional repression ability of AEBP1. We also show that in vitro phosphorylation of AEBP1 by MAPK is greatly reduced upon mutation of T623. These results suggest that MAPK regulates the transcriptional activity of AEBP1 by a novel dual mechanism, in which MAPK interaction enhances and subsequent phosphorylation decreases the DNA-binding ability of AEBP1.

SIGNOR-262897

Q9NR19

P11279

1

transcriptional regulation

up-regulates quantity by expression

0.2

Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants

SIGNOR-276556