GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
P06213	P43378	dephosphorylation	down-regulates	0.26	Ectopic expression of ptp-meg2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while rnai-mediated reduction of ptp-meg2 transcript levels enhanced insulin action	SIGNOR-146676
P49841	Q13976	phosphorylation	down-regulates activity	0.26	Moreover, PrkG1 inhibits GSK3\u03b2 by binding and directly phosphorylating GSK3\u03b2 at its serine-9 residue (Zhao et al., xref ).\|Moreover, PrkG1 inhibits GSK3beta by binding and directly phosphorylating GSK3beta at its serine 9 residue.	SIGNOR-280094
Q08209	Q969Q1	ubiquitination	down-regulates quantity	0.26	First, downregulation of MuRF1 significantly attenuates degradation of CnA in cardiomyocytes in vitro, indicating that endogenous MuRF1 negatively regulates the stability of CnA in a cell-autonomous manner.\|Furthermore, MuRF1 directly ubiquitinated CnA in vitro.\|These results suggest that MuRF1 directly polyubiquitinates CnA.	SIGNOR-278736
P35398	P28482	phosphorylation	down-regulates	0.26	We identified the extracellular signal-regulated kinase 2 (erk-2) as roralpha4 phosphorylating kinase in vitro. The primary sequence of roralpha4 contains an erk-2 recognition motif (p-l-t(128)-p) within the hinge domain, and mutation of thr-128 to ala prevents roralpha4 phosphorylation by erk. The roralpha4-t128a mutant exhibits an increased dna-binding affinity, an increased transcriptional activity	SIGNOR-154914
Q03113	P32249	binding	up-regulates activity	0.26	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-257202
P08235	P34947	phosphorylation	down-regulates	0.26	We report that GRK5 phosphorylates and inhibits the cardiac MR whereas GRK2 phosphorylates and desensitizes GPER.	SIGNOR-278478
P51813	P23470	dephosphorylation	down-regulates activity	0.26	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254693
Q13156	P54727	binding	up-regulates activity	0.26	GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process\|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).\|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo	SIGNOR-275701
P53667	P23470	dephosphorylation	down-regulates activity	0.26	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254711
Q05655	P31749	phosphorylation	up-regulates activity	0.26	Of note, the amino acid sequence adjacent to Ser204 phosphorylation site matches the minimal AKT substrate motif (RxxpS) suggesting that AKT1 could potentially directly regulate PRKCD through phosphorylation.\|This integrative analysis allowed us to confirm that the enrichment of PRKCD centered network is likely the result of elevated phosphorylation of PRKCD by AKT1.	SIGNOR-280175
Q13501	Q9Y4E8	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
P09630	O15550	transcriptional regulation	up-regulates quantity by expression	0.26	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260028
Q9NR30	Q9NRC8	deacetylation	up-regulates activity	0.26	Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.\|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21.	SIGNOR-275903
P35236	Q05513	phosphorylation	up-regulates activity	0.26	HePTP is phosphorylated by PKC isozymes at Ser-225 in vitro. While all isozymes phosphorylated Ser-225 predominantly and Ser-113 to a lesser extent (Fig. (Fig.5),5), they differed strikingly in how much 32P they incorporated into HePTP during the 30-min assay. PKC θ was the most efficient, while PKC ζ and PKC μ were clearly less potent; PKC δ, ɛ, and η were quite inefficient.	SIGNOR-276047
P40763	Q99558	phosphorylation	up-regulates activity	0.26	Activation of Stat3 by NIK requires NIK kinase activity as showed by kinase assays.\|When we transfected NIK into LNCaP cells, NIK was able to phosphorylate Stat3 at both tyrosine 705 and serine 727 residues ( Fig. 3 A).	SIGNOR-279341
Q99814	P27361	phosphorylation	up-regulates quantity by stabilization	0.26	The activation of ERK1/2 upon hypoxia promoted HIF-2alpha phosphorylation, enhancing its interaction with USP33.Here, we identified USP33 as essential deubiquitinase that stabilizes HIF-2alpha protein in an ERK1/2-dependent manner to promote hypoxia response in cancer cells.	SIGNOR-277584
Q96LC7	P06239	phosphorylation	up-regulates	0.26	These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Y597 and y667 are likely involved in intracellular signaling	SIGNOR-112491
P41181	Q07002	phosphorylation	down-regulates quantity by destabilization	0.26	CDK18 controls AQP2 through phosphorylation at serine 261 and STUB1-mediated ubiquitination. \|We had previously observed that a decrease in the phosphorylation of AQP2 at S261 is associated with a decrease in its poly-ubiquitination and an increase in its abundance	SIGNOR-264562
Q9HAW9	Q99626	transcriptional regulation	up-regulates quantity by expression	0.26	Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter.	SIGNOR-253969
Q15672	P0C2W1	binding	down-regulates quantity by destabilization	0.26	One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively.	SIGNOR-272183
Q01970	P17612	phosphorylation	down-regulates	0.26	These data indicate that pkc and pka act similarly in that they inhibit galpha(q)-stimulated plcbeta(3) as a result of phosphorylation of ser(1105).	SIGNOR-79148
Q86UR1	P04637	transcriptional regulation	up-regulates quantity by expression	0.26	As a transcription factor, p53 induces several pro-apoptotic Bcl-2 members including Bax, Puma, Noxa and Bid, and represses the transcription of certain anti-apoptotic genes, including those encoding Bcl-2, Bcl-xL and survivin 3_and_5.	SIGNOR-209687
O15111	O00141	phosphorylation	up-regulates activity	0.26	SGK1 directly phosphorylates IKKalpha at Thr 23 and indirectly activates IKKalpha at Ser 180.\|SGK1 directly phosphorylates IKKalpha at Thr-23 and indirectly activates IKKalpha at Ser-180.	SIGNOR-278987
Q96E17	Q9UJD0	relocalization	up-regulates activity	0.26	N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle	SIGNOR-264380
P54253	O75582	phosphorylation	up-regulates quantity by stabilization	0.26	In summary, the data from the cell based screen, biochemical studies and genetic interactions strongly suggest that MSK1 phosphorylates ATXN1 and regulates its stability.	SIGNOR-279109
P46531	Q8IUQ4	relocalization	up-regulates	0.26	The overexpression of siah1 causes the re-localization of notch from the cell surface to the cytoplasm and to the nucleus, which is indicative of notch activation	SIGNOR-168460
Q15067	Q9NXA8	catalytic activity	down-regulates activity	0.26	SIRT5‐mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation.	SIGNOR-261210
Q6VAB6	P16298	dephosphorylation	up-regulates activity	0.259	These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.\|the negative regulators 14-3-3	SIGNOR-248381
P49675	P01100	transcriptional regulation	up-regulates quantity by expression	0.259	We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters.	SIGNOR-254878
Q6VAB6	P48454	dephosphorylation	up-regulates activity	0.259	These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.\|the negative regulators 14-3-3	SIGNOR-248527
P49736	P68400	phosphorylation	up-regulates	0.259	In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2	SIGNOR-144004
P10275	P16591	phosphorylation	up-regulates	0.259	Fer is required for il-6 mediated ar activation by phosphorylating ar tyrosine 223 and binding via its sh2 domain.	SIGNOR-194749
P01024	P17676	transcriptional regulation	up-regulates quantity by expression	0.259	CCAAT/enhancer binding protein β directly regulates the expression of the complement component 3 gene in neural cells: implications for the pro-inflammatory effects of this transcription factor	SIGNOR-261927
P41229	Q16665	transcriptional regulation	up-regulates quantity by expression	0.259	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271564
O14733	P21333	binding	up-regulates activity	0.259	We used Filamin-A-deficient cells to show that Filamin A enhances MKK7 activation and is important for synergistic stress-induced JNK activation in vivo. Thus Filamin A is a novel member of the group of scaffold proteins whose function is to link two MAPKKs together and promote JNK activation. The present study provides evidence that Filamin A is one of the ‘binder’ molecules presumed to directly and closely connect MKK4 and MKK7 so that they can mediate this tyrosine/threonine phosphorylation. We showed that Filamin A (as well as Filamin B and C) associate with MKK7 and MKK4, but not with JNK1 itself	SIGNOR-260628
P12931	Q9Y2J4	binding	up-regulates activity	0.259	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-271870
Q9NVD7	P28482	phosphorylation	up-regulates activity	0.259	Actopaxin (alpha-parvin) is a paxillin, integrin-linked kinase, and F-actin binding focal adhesion protein with several serine phosphorylation sites in the amino terminus that contribute to the regulation of cell spreading and migration.\|Actopaxin phosphorylation of Ser4/8 enhances cell migration whereas a nonphosphorylatable (Quint) mutant suppresses migration in U2OS osteosarcoma cells (7).	SIGNOR-265759
P03372	Q00526	phosphorylation	up-regulates activity	0.259	CDK3 was shown to be overexpressed in breast cancer and phosphorylate ERα at Ser104/116 and Ser118. Furthermore, we found that Mir-873 inhibits ER activity and cell growth via targeting CDK3	SIGNOR-273187
P35637	P00533	phosphorylation	up-regulates activity	0.259	Thus, EGFR appears to mediate FUS nuclear translocation by phosphorylating Y6 and Y296 in FUS.	SIGNOR-279168
Q92915	P49841	phosphorylation	up-regulates activity	0.259	Our laboratory has also demonstrated that FGF14 is a key accessory protein that binds to the intracellular Nav1.6 C-terminal tail, and that GSK3β can phosphorylate FGF14 both in vitro and in vivo at S226 [20] in an experimental model of Alzheimer's disease	SIGNOR-275746
P54132	P49841	phosphorylation	down-regulates quantity by destabilization	0.259	We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates.	SIGNOR-276906
Q16665	Q00535	phosphorylation	up-regulates activity	0.259	In conclusion, we obtained compelling evidence that CDK5 directly stabilizes the transcription factor hypoxia inducible factor-1\u03b1 by phosphorylation, and thus promotes the formation of blood vessels.\|Mass spectrometry and site directed mutagenesis revealed a stabilizing phosphorylation of HIF-1\u03b1 at Ser687 by CDK5.	SIGNOR-279020
Q01105-2	P19784	phosphorylation	down-regulates	0.259	Ckii-mediated phosphorylation at ser9 hinders nuclear import of set	SIGNOR-200802
P12830	P49674	phosphorylation	down-regulates activity	0.259	Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts\|CK1 colocalizes with E-cadherin and phosphorylates the cytoplasmic domain of E-cadherin in vitro and in a cell culture system. We show that the major CK1 phosphorylation site of E-cadherin is serine 846	SIGNOR-274047
P46527	O15297	dephosphorylation	down-regulates activity	0.259	Increased expression of wildtype WIP1 reduces stability of p27 Kip1 while increased expression of similar amounts of phosphatase-dead WIP1 has no effect on p27 Kip1 protein stability.\|We demonstrate that wildtype, but not phosphatase-dead WIP1, efficiently dephosphorylates p27 Kip1 Ser140 both in vitro and in cells and that this dephosphorylation is sensitive to the WIP1 specific inhibitor GSK 2830371.	SIGNOR-277109
Q9ULB1	Q9NR48	transcriptional regulation	down-regulates quantity by repression	0.259	Our results reveal that a novel process of activity-dependent transcriptional repression exists in neurons and that Ash1L mediates the long-term repression of nrxn1α, thus implicating an important role for epigenetic modification in brain functioning.	SIGNOR-269056
Q86VB7	P69905	binding	up-regulates activity	0.259	These data suggest that hemoglobin may mediate a stimulatory effect on erythropoiesis through the activation of CD163 on hematopoietic progenitor cells.	SIGNOR-251747
P45985	Q9UL54	binding	up-regulates activity	0.259	Immunoprecipitated psk phosphorylates myelin basic protein and transfected psk stimulates mkk4 and mkk7 and activates the c-jun n-terminal kinase mitogen-activated protein kinase pathway.	SIGNOR-74864
Q9BZL4	P54646	phosphorylation	down-regulates	0.259	Ampk-induced phosphorylation is necessary for ppp1r12c interaction with 14-3-3 and phosphorylation of myosin regulatory light chain. Both ampk activity and ppp1r12c phosphorylation are increased in mitotic cells and are important for mitosis completion. The interaction between ppp1r12c and 14-3-3_ may inactivate the ppp1r12c-containing phosphatase complex in vivo.	SIGNOR-195148
P32243	P14652	transcriptional regulation	up-regulates quantity by expression	0.259	Transactivation of the mouse OTX2 Luc constructs by the human HOXB1, HOXB2, and HOXB3 proteins. \| Likewise, the construct pOTX2LucΔ−710 showed an 8-, 12-, and 6-fold increase in transcriptional activity if co-transfected with pSG-HOXB1, -HOXB2, and -HOXB3, respectively	SIGNOR-261634
P02511	P05549	transcriptional regulation	up-regulates quantity by expression	0.259	Aberrant expression of CRYAB has been shown to be associated with several neurological diseases and malignant neoplasms. To identify transcriptional regulators of CRYAB expression, we examined its promoter for binding sites of transcription factors and identified four potential AP-2 binding sites in addition to a p53 binding site reported previously\|Taken together, our results indicate that AP-2_ up-regulates the transcription of the CRYAB gene through stabilizing p53	SIGNOR-253636
P21333	Q08209	dephosphorylation	down-regulates	0.259	We report that a purified c-terminal recombinant region of filamin is a suitable substrate for calcineurin in vitro. Furthermore, 1 microm cyclosporin a (csa), a specific calcineurin inhibitor, reduced the dephosphorylation of the recombinant fragment in 293ft cells	SIGNOR-143979
O60341	Q04759	phosphorylation	down-regulates activity	0.259	Inhibiting PKC-theta also increased the H3K4 demethylase activity of LSD1, indicating that active PKC-theta may prevent LSD1 from demethylating H3K4 and subsequently causing gene repression.\|PKC-theta directly phosphorylates LSD1 at serine 111 and regulates its repressive activity and nuclear localization.	SIGNOR-279104
O14920	P62714	dephosphorylation	down-regulates activity	0.259	Permanent activation of the upstream kinase IKK beta results from UVB-induced inhibition of the catalytic subunit of Ser-Thr phosphatase PP2A (PP2Ac), leading to immediate phosphorylation and degradation of newly synthesized I kappaB alpha\|Chronic Ser 177/181 phosphorylation of IKKβ was due to UVB-induced inhibition of the catalytic subunit of the Ser-Thr phosphatase PP2A (PP2Ac)	SIGNOR-248580
P40763	P23470	dephosphorylation	up-regulates activity	0.259	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254729
P63096	P21452	binding	up-regulates activity	0.259	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-256736
Q96CW1	Q5S007	phosphorylation	up-regulates activity	0.259	These data confirmed that LRRK2 phosphorylates AP2M1 at Thr 156 in vitro.	SIGNOR-278183
P15173	O43257	transcriptional regulation	up-regulates quantity by expression	0.259	We show that the srcap subunit named znhit1 or p18hamlet, which is a substrate of p38 mapk, is recruited to the myogenin promoter at the onset of muscle differentiation, in a p38 mapk-dependent manner. We also show that p18hamlet is required for h2a.z accumulation into this genomic region and for subsequent muscle gene transcriptional activation.	SIGNOR-165613
P01019	P24158	cleavage	up-regulates activity	0.259	Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen.	SIGNOR-256314
P25963	Q9HC78	transcriptional regulation	down-regulates quantity by repression	0.259	ChIP and next generation high-throughput DNA sequencing assay showed that ZBTB20 specifically bound to IκBα gene promoter (+1 to +60 region) after TLR activation. ZBTB20 could inhibit IκBα gene transcription, govern IκBα protein expression, and then promote NF-κB activation. Therefore, transcriptional repressor ZBTB20 is needed to promote full activation of TLR signaling and TLR-triggered innate immune response by selectively suppressing the suppressor IκBα gene transcription.	SIGNOR-266868
Q14118	Q12955	relocalization	up-regulates quantity	0.259	We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4.	SIGNOR-266714
P14618	Q00534	phosphorylation	down-regulates activity	0.259	Here, using human cancer cells and patient-derived xenografts in mice, we show that the cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2.	SIGNOR-279158
P35498	Q92914	binding	down-regulates activity	0.259	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253422
P00519	P49759	phosphorylation	down-regulates	0.259	Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3	SIGNOR-181031
Q9UPW6	Q99717	transcriptional regulation	up-regulates quantity	0.259	Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation	SIGNOR-268939
P35247	P49715	transcriptional regulation	up-regulates quantity by expression	0.259	Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells\| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D.	SIGNOR-254042
Q9NRC8	Q96LA8	methylation	down-regulates activity	0.259	Protein arginine methyltransferase 6 (PRMT6) directly interacts with and methylates SIRT7 at R388 in vitro and in vivo R388 methylation suppresses the H3K18 deacetylase activity of SIRT7 without modulating its subcellular localization.	SIGNOR-275888
Q04637	P17252	phosphorylation	up-regulates activity	0.258	Phospho-proteomic and mutational analyses revealed that eIF4G1 is a substrate for PKCα at Ser1186.	SIGNOR-276327
P07900	P05129	phosphorylation	down-regulates	0.258	Threonine residue set, thr(115)/thr(425)/thr(603), of hsp90_ is specifically phosphorylated by pkc_phosphorylation of hsp90_ by pkc_ decreases the binding affinity of hsp90_ towards atp and co-chaperones such as cdc37 (cell-division cycle 37), thereby decreasing its chaperone activity.	SIGNOR-202812
P31644	Q8TAB3	binding	up-regulates quantity by stabilization	0.258	Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.	SIGNOR-267219
P09874	Q00535	phosphorylation	down-regulates activity	0.258	These results would suggest that the phosphorylation of PARP-1 via Cdk5's kinase activity is necessary for its persistence at damage sites.Based on these results and the recruitment data, we hypothesize that the phosphorylation of the PARP-1 protein by Cdk5 on one or more of the serines 782, 785, and 786 results in an attenuation of its ribosylating activity facilitating its persistence at the sites of DNA damage.	SIGNOR-276359
P35226	Q9Y243	phosphorylation	up-regulates activity	0.258	the polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate	SIGNOR-249583
Q9GZV5	P06493	phosphorylation	down-regulates activity	0.258	We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity	SIGNOR-276518
P49841	Q13237	phosphorylation	down-regulates activity	0.258	These data indicate that hypertrophic differentiation of growth plate chondrocytes during skeletal growth is promoted by phosphorylation and inactivation of GSK-3beta by cGKII.	SIGNOR-280095
P10636-2	P05771	phosphorylation	down-regulates activity	0.258	We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs.	SIGNOR-275442
Q9UPG8	Q8WUI4	deacetylation	down-regulates	0.258	Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7.	SIGNOR-140953
P46940	P17252	phosphorylation	up-regulates	0.258	Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth.	SIGNOR-128714
O75874	Q12778	transcriptional regulation	up-regulates quantity by expression	0.258	We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH.	SIGNOR-260101
P54646	P12931	phosphorylation	down-regulates activity	0.258	We show here that Src signaling leads to direct phosphorylation of the AMPK-α subunit on a novel site, tyrosine 179, resulting in suppression of AMPK-T172 phosphorylation and autophagy upon integrin-mediated cell adhesion.	SIGNOR-277573
P31645	P12931	phosphorylation	up-regulates quantity by stabilization	0.258	We found that 1) SERT exists in a tyrosine-phosphorylated form, 2) inhibition of tyrosine kinase(s) reduces SERT expression levels by facilitating SERT protein degradation, 3) Src-kinase activity up-regulates SERT protein expression with a concomitant increase in 5-HT uptake and tyrosine phosphorylation, and 4) mutation of Tyr47 or Tyr142 abolishes src-induced increases in transport function and phosphorylation of SERT.	SIGNOR-276386
O00763	Q96RU7	binding	down-regulates quantity by destabilization	0.258	TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1. Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D).	SIGNOR-271601
P51003	P06493	phosphorylation	up-regulates activity	0.258	Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity.	SIGNOR-268338
P13807	Q9Y463	phosphorylation	down-regulates activity	0.258	DYRK Family Protein Kinases Phosphorylate and Inactivate Glycogen Synthase. both protein kinases phosphorylate site 3a but no other sites that affect glycogen synthase activity.	SIGNOR-260633
P27986	P01137	binding	up-regulates activity	0.258	While association of the TGF_RI receptor with p85 requires TGF-_ stimulation.	SIGNOR-217960
Q6PGQ7	P49841	phosphorylation	up-regulates	0.258	It suggests that gsk3_ activity is required for hbora-mediated mitotic entry through ser274 and ser278 phosphorylation	SIGNOR-201519
Q9UQL6	Q96GD4	phosphorylation	down-regulates	0.258	We define the precise site of aurb-mediated phosphorylation as a conserved serine within the nuclear localization signals of hdac4, hdac5, and hdac9 at ser265, ser278, and ser242, respectivelyduring mitosis, aurb-mediated phosphorylation may localize class iia hdacs to a phosphorylation gradient at the spindle midzone, permitting temporal and spatial regulatory mechanisms altering hdac protein interactions	SIGNOR-198650
Q9UGL1	P06493	phosphorylation	down-regulates activity	0.258	Phosphorylation of the histone demethylase KDM5B and regulation of the phenotype of triple negative breast cancer\|Here, we demonstrate that KDM5B is phosphorylated at Ser1456 by the cyclin-dependent kinase 1 (CDK1). Phosphorylation of KDM5B at Ser1456 attenuated the occupancy of KDM5B on the promoters of pluripotency genes.	SIGNOR-273435
P05067	P11802	phosphorylation	down-regulates quantity by destabilization	0.258	These include a significant increase in APP phosphorylation at Thr 668 by cdk2, cdk4, and cdk5, which increases its beta-amyloid production and APP proteolysis by the activated caspases during cell cycle ( xref ; xref ; xref ; xref ).	SIGNOR-280214
P38936	Q9Y463	phosphorylation	up-regulates activity	0.258	Mirk exerts its anti-apoptotic effects during muscle differentiation at least in part through effects on the cell cycle inhibitor and pro-survival molecule p21cip1. Overexpression and rna interference experiments demonstrated that mirk phosphorylates p21 within its nuclear localization domain at ser-153 causing a portion of the typically nuclear p21 to localize in the cytoplasm.Translocation to the cytoplasm enables p21 to block apoptosis through inhibitory interaction with pro-apoptotic molecules.	SIGNOR-235635
O43623	P0C2W1	binding	down-regulates quantity by destabilization	0.258	One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively.	SIGNOR-272182
Q12778	Q96J02	ubiquitination	down-regulates quantity by destabilization	0.258	Mechanistically, Itch ubiquitinates Foxo1 for proteasomal degradation.	SIGNOR-278698
Q9UI33	Q92915	binding	down-regulates activity	0.258	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253437
Q9Y2G1	Q02750	phosphorylation	down-regulates activity	0.258	Mek1 phosphorylation of Ndt80 therefore provides an elegant way for cells to know when it is safe to enter the first meiotic division.\|These observations suggest that phosphorylation of the DBD by Mek1 prevents Ndt80 from binding to MSEs and explains how Mek1 phosphorylation can inhibit Ndt80 activity.	SIGNOR-279416
Q13233	P00519	phosphorylation	up-regulates activity	0.258	Moreover, c-Abl activates MEKK-1 in vitro and in response to DNA damage.\|The results demonstrate that the nuclear c-Abl binds to MEKK-1 and that c-Abl phosphorylates MEKK-1 in vitro and in vivo.	SIGNOR-279672
Q9BQE3	Q14980	binding	up-regulates	0.258	Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.	SIGNOR-116677
Q14164	P00533	phosphorylation	up-regulates activity	0.257	To understand the mechanism by which IKBKE is activated by mutant EGFR, we first investigated if activating mutation of EGFR is able to form a complex with IKBKE.\|While wild-type and mutant EGFR directly interacted with IKBKE, only mutant EGFR phosphorylated IKBKE on residues Y153 and Y179.	SIGNOR-278222
P40337	Q96PY6	phosphorylation	down-regulates quantity by destabilization	0.257	Nek1 phosphorylates Von Hippel-Lindau tumor suppressor to promote its proteasomal degradation and ciliary destabilization. Mutation of pVHL at S-168 increases protein stability.	SIGNOR-276434
Q9NP59	Q16236	transcriptional regulation	up-regulates quantity by expression	0.257	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. SLC40A1 is a target gene of NFE2L2, with a putative ARE identified approximately -7 kb upstream of the SLC40A1 core promoter.	SIGNOR-279863
Q9HAW8	Q99626	transcriptional regulation	up-regulates quantity by expression	0.257	Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter.	SIGNOR-253968
Q01860	Q9Y243	phosphorylation	up-regulates quantity by stabilization	0.257	Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG.	SIGNOR-242107

P06213

P43378

0

dephosphorylation

down-regulates

0.26

Ectopic expression of ptp-meg2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while rnai-mediated reduction of ptp-meg2 transcript levels enhanced insulin action

SIGNOR-146676

P49841

Q13976

0

phosphorylation

down-regulates activity

0.26

Moreover, PrkG1 inhibits GSK3\u03b2 by binding and directly phosphorylating GSK3\u03b2 at its serine-9 residue (Zhao et al., xref ).|Moreover, PrkG1 inhibits GSK3beta by binding and directly phosphorylating GSK3beta at its serine 9 residue.

SIGNOR-280094

Q08209

Q969Q1

0

ubiquitination

down-regulates quantity

0.26

First, downregulation of MuRF1 significantly attenuates degradation of CnA in cardiomyocytes in vitro, indicating that endogenous MuRF1 negatively regulates the stability of CnA in a cell-autonomous manner.|Furthermore, MuRF1 directly ubiquitinated CnA in vitro.|These results suggest that MuRF1 directly polyubiquitinates CnA.

SIGNOR-278736

P35398

P28482

0

phosphorylation

down-regulates

0.26

We identified the extracellular signal-regulated kinase 2 (erk-2) as roralpha4 phosphorylating kinase in vitro. The primary sequence of roralpha4 contains an erk-2 recognition motif (p-l-t(128)-p) within the hinge domain, and mutation of thr-128 to ala prevents roralpha4 phosphorylation by erk. The roralpha4-t128a mutant exhibits an increased dna-binding affinity, an increased transcriptional activity

SIGNOR-154914

Q03113

P32249

0

binding

up-regulates activity

0.26

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-257202

P08235

P34947

0

phosphorylation

down-regulates

0.26

We report that GRK5 phosphorylates and inhibits the cardiac MR whereas GRK2 phosphorylates and desensitizes GPER.

SIGNOR-278478

P51813

P23470

0

dephosphorylation

down-regulates activity

0.26

PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.

SIGNOR-254693

Q13156

P54727

0

binding

up-regulates activity

0.26

GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo

SIGNOR-275701

P53667

P23470

0

dephosphorylation

down-regulates activity

0.26

PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.

SIGNOR-254711

Q05655

P31749

0

phosphorylation

up-regulates activity

0.26

Of note, the amino acid sequence adjacent to Ser204 phosphorylation site matches the minimal AKT substrate motif (RxxpS) suggesting that AKT1 could potentially directly regulate PRKCD through phosphorylation.|This integrative analysis allowed us to confirm that the enrichment of PRKCD centered network is likely the result of elevated phosphorylation of PRKCD by AKT1.

SIGNOR-280175

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

P09630

O15550

0

transcriptional regulation

up-regulates quantity by expression

0.26

Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.

SIGNOR-260028

Q9NR30

Q9NRC8

0

deacetylation

up-regulates activity

0.26

Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21.

SIGNOR-275903

P35236

Q05513

0

phosphorylation

up-regulates activity

0.26

HePTP is phosphorylated by PKC isozymes at Ser-225 in vitro. While all isozymes phosphorylated Ser-225 predominantly and Ser-113 to a lesser extent (Fig. (Fig.5),5), they differed strikingly in how much 32P they incorporated into HePTP during the 30-min assay. PKC θ was the most efficient, while PKC ζ and PKC μ were clearly less potent; PKC δ, ɛ, and η were quite inefficient.

SIGNOR-276047

P40763

Q99558

0

phosphorylation

up-regulates activity

0.26

Activation of Stat3 by NIK requires NIK kinase activity as showed by kinase assays.|When we transfected NIK into LNCaP cells, NIK was able to phosphorylate Stat3 at both tyrosine 705 and serine 727 residues ( Fig. 3 A).

SIGNOR-279341

Q99814

P27361

0

phosphorylation

up-regulates quantity by stabilization

0.26

The activation of ERK1/2 upon hypoxia promoted HIF-2alpha phosphorylation, enhancing its interaction with USP33.Here, we identified USP33 as essential deubiquitinase that stabilizes HIF-2alpha protein in an ERK1/2-dependent manner to promote hypoxia response in cancer cells.

SIGNOR-277584

Q96LC7

P06239

0

phosphorylation

up-regulates

0.26

These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Y597 and y667 are likely involved in intracellular signaling

SIGNOR-112491

P41181

Q07002

0

phosphorylation

down-regulates quantity by destabilization

0.26

CDK18 controls AQP2 through phosphorylation at serine 261 and STUB1-mediated ubiquitination. |We had previously observed that a decrease in the phosphorylation of AQP2 at S261 is associated with a decrease in its poly-ubiquitination and an increase in its abundance

SIGNOR-264562

Q9HAW9

Q99626

0

transcriptional regulation

up-regulates quantity by expression

0.26

Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter.

SIGNOR-253969

Q15672

P0C2W1

0

binding

down-regulates quantity by destabilization

0.26

One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively.

SIGNOR-272183

Q01970

P17612

0

phosphorylation

down-regulates

0.26

These data indicate that pkc and pka act similarly in that they inhibit galpha(q)-stimulated plcbeta(3) as a result of phosphorylation of ser(1105).

SIGNOR-79148

Q86UR1

P04637

0

transcriptional regulation

up-regulates quantity by expression

0.26

As a transcription factor, p53 induces several pro-apoptotic Bcl-2 members including Bax, Puma, Noxa and Bid, and represses the transcription of certain anti-apoptotic genes, including those encoding Bcl-2, Bcl-xL and survivin 3_and_5.

SIGNOR-209687

O15111

O00141

0

phosphorylation

up-regulates activity

0.26

SGK1 directly phosphorylates IKKalpha at Thr 23 and indirectly activates IKKalpha at Ser 180.|SGK1 directly phosphorylates IKKalpha at Thr-23 and indirectly activates IKKalpha at Ser-180.

SIGNOR-278987

Q96E17

Q9UJD0

0

relocalization

up-regulates activity

0.26

N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle

SIGNOR-264380

P54253

O75582

0

phosphorylation

up-regulates quantity by stabilization

0.26

In summary, the data from the cell based screen, biochemical studies and genetic interactions strongly suggest that MSK1 phosphorylates ATXN1 and regulates its stability.

SIGNOR-279109

P46531

Q8IUQ4

0

relocalization

up-regulates

0.26

The overexpression of siah1 causes the re-localization of notch from the cell surface to the cytoplasm and to the nucleus, which is indicative of notch activation

SIGNOR-168460

Q15067

Q9NXA8

0

catalytic activity

down-regulates activity

0.26

SIRT5‐mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation.

SIGNOR-261210

Q6VAB6

P16298

0

dephosphorylation

up-regulates activity

0.259

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

SIGNOR-248381

P49675

P01100

0

transcriptional regulation

up-regulates quantity by expression

0.259

We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters.

SIGNOR-254878

Q6VAB6

P48454

0

dephosphorylation

up-regulates activity

0.259

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

SIGNOR-248527

P49736

P68400

0

phosphorylation

up-regulates

0.259

In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2

SIGNOR-144004

P10275

P16591

0

phosphorylation

up-regulates

0.259

Fer is required for il-6 mediated ar activation by phosphorylating ar tyrosine 223 and binding via its sh2 domain.

SIGNOR-194749

P01024

P17676

0

transcriptional regulation

up-regulates quantity by expression

0.259

CCAAT/enhancer binding protein β directly regulates the expression of the complement component 3 gene in neural cells: implications for the pro-inflammatory effects of this transcription factor

SIGNOR-261927

P41229

Q16665

0

transcriptional regulation

up-regulates quantity by expression

0.259

To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.

SIGNOR-271564

O14733

P21333

0

binding

up-regulates activity

0.259

We used Filamin-A-deficient cells to show that Filamin A enhances MKK7 activation and is important for synergistic stress-induced JNK activation in vivo. Thus Filamin A is a novel member of the group of scaffold proteins whose function is to link two MAPKKs together and promote JNK activation. The present study provides evidence that Filamin A is one of the ‘binder’ molecules presumed to directly and closely connect MKK4 and MKK7 so that they can mediate this tyrosine/threonine phosphorylation. We showed that Filamin A (as well as Filamin B and C) associate with MKK7 and MKK4, but not with JNK1 itself

SIGNOR-260628

P12931

Q9Y2J4

0

binding

up-regulates activity

0.259

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-271870

Q9NVD7

P28482

0

phosphorylation

up-regulates activity

0.259

Actopaxin (alpha-parvin) is a paxillin, integrin-linked kinase, and F-actin binding focal adhesion protein with several serine phosphorylation sites in the amino terminus that contribute to the regulation of cell spreading and migration.|Actopaxin phosphorylation of Ser4/8 enhances cell migration whereas a nonphosphorylatable (Quint) mutant suppresses migration in U2OS osteosarcoma cells (7).

SIGNOR-265759

P03372

Q00526

0

phosphorylation

up-regulates activity

0.259

CDK3 was shown to be overexpressed in breast cancer and phosphorylate ERα at Ser104/116 and Ser118. Furthermore, we found that Mir-873 inhibits ER activity and cell growth via targeting CDK3

SIGNOR-273187

P35637

P00533

0

phosphorylation

up-regulates activity

0.259

Thus, EGFR appears to mediate FUS nuclear translocation by phosphorylating Y6 and Y296 in FUS.

SIGNOR-279168

Q92915

P49841

0

phosphorylation

up-regulates activity

0.259

Our laboratory has also demonstrated that FGF14 is a key accessory protein that binds to the intracellular Nav1.6 C-terminal tail, and that GSK3β can phosphorylate FGF14 both in vitro and in vivo at S226 [20] in an experimental model of Alzheimer's disease

SIGNOR-275746

P54132

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.259

We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates.

SIGNOR-276906

Q16665

Q00535

0

phosphorylation

up-regulates activity

0.259

In conclusion, we obtained compelling evidence that CDK5 directly stabilizes the transcription factor hypoxia inducible factor-1\u03b1 by phosphorylation, and thus promotes the formation of blood vessels.|Mass spectrometry and site directed mutagenesis revealed a stabilizing phosphorylation of HIF-1\u03b1 at Ser687 by CDK5.

SIGNOR-279020

Q01105-2

P19784

0

phosphorylation

down-regulates

0.259

Ckii-mediated phosphorylation at ser9 hinders nuclear import of set

SIGNOR-200802

P12830

P49674

0

phosphorylation

down-regulates activity

0.259

Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts|CK1 colocalizes with E-cadherin and phosphorylates the cytoplasmic domain of E-cadherin in vitro and in a cell culture system. We show that the major CK1 phosphorylation site of E-cadherin is serine 846

SIGNOR-274047

P46527

O15297

0

dephosphorylation

down-regulates activity

0.259

Increased expression of wildtype WIP1 reduces stability of p27 Kip1 while increased expression of similar amounts of phosphatase-dead WIP1 has no effect on p27 Kip1 protein stability.|We demonstrate that wildtype, but not phosphatase-dead WIP1, efficiently dephosphorylates p27 Kip1 Ser140 both in vitro and in cells and that this dephosphorylation is sensitive to the WIP1 specific inhibitor GSK 2830371.

SIGNOR-277109

Q9ULB1

Q9NR48

0

transcriptional regulation

down-regulates quantity by repression

0.259

Our results reveal that a novel process of activity-dependent transcriptional repression exists in neurons and that Ash1L mediates the long-term repression of nrxn1α, thus implicating an important role for epigenetic modification in brain functioning.

SIGNOR-269056

Q86VB7

P69905

0

binding

up-regulates activity

0.259

These data suggest that hemoglobin may mediate a stimulatory effect on erythropoiesis through the activation of CD163 on hematopoietic progenitor cells.

SIGNOR-251747

P45985

Q9UL54

0

binding

up-regulates activity

0.259

Immunoprecipitated psk phosphorylates myelin basic protein and transfected psk stimulates mkk4 and mkk7 and activates the c-jun n-terminal kinase mitogen-activated protein kinase pathway.

SIGNOR-74864

Q9BZL4

P54646

0

phosphorylation

down-regulates

0.259

Ampk-induced phosphorylation is necessary for ppp1r12c interaction with 14-3-3 and phosphorylation of myosin regulatory light chain. Both ampk activity and ppp1r12c phosphorylation are increased in mitotic cells and are important for mitosis completion. The interaction between ppp1r12c and 14-3-3_ may inactivate the ppp1r12c-containing phosphatase complex in vivo.

SIGNOR-195148

P32243

P14652

0

transcriptional regulation

up-regulates quantity by expression

0.259

Transactivation of the mouse OTX2 Luc constructs by the human HOXB1, HOXB2, and HOXB3 proteins. | Likewise, the construct pOTX2LucΔ−710 showed an 8-, 12-, and 6-fold increase in transcriptional activity if co-transfected with pSG-HOXB1, -HOXB2, and -HOXB3, respectively

SIGNOR-261634

P02511

P05549

0

transcriptional regulation

up-regulates quantity by expression

0.259

Aberrant expression of CRYAB has been shown to be associated with several neurological diseases and malignant neoplasms. To identify transcriptional regulators of CRYAB expression, we examined its promoter for binding sites of transcription factors and identified four potential AP-2 binding sites in addition to a p53 binding site reported previously|Taken together, our results indicate that AP-2_ up-regulates the transcription of the CRYAB gene through stabilizing p53

SIGNOR-253636

P21333

Q08209

0

dephosphorylation

down-regulates

0.259

We report that a purified c-terminal recombinant region of filamin is a suitable substrate for calcineurin in vitro. Furthermore, 1 microm cyclosporin a (csa), a specific calcineurin inhibitor, reduced the dephosphorylation of the recombinant fragment in 293ft cells

SIGNOR-143979

O60341

Q04759

0

phosphorylation

down-regulates activity

0.259

Inhibiting PKC-theta also increased the H3K4 demethylase activity of LSD1, indicating that active PKC-theta may prevent LSD1 from demethylating H3K4 and subsequently causing gene repression.|PKC-theta directly phosphorylates LSD1 at serine 111 and regulates its repressive activity and nuclear localization.

SIGNOR-279104

O14920

P62714

0

dephosphorylation

down-regulates activity

0.259

Permanent activation of the upstream kinase IKK beta results from UVB-induced inhibition of the catalytic subunit of Ser-Thr phosphatase PP2A (PP2Ac), leading to immediate phosphorylation and degradation of newly synthesized I kappaB alpha|Chronic Ser 177/181 phosphorylation of IKKβ was due to UVB-induced inhibition of the catalytic subunit of the Ser-Thr phosphatase PP2A (PP2Ac)

SIGNOR-248580

P40763

P23470

0

dephosphorylation

up-regulates activity

0.259

PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.

SIGNOR-254729

P63096

P21452

0

binding

up-regulates activity

0.259

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-256736

Q96CW1

Q5S007

0

phosphorylation

up-regulates activity

0.259

These data confirmed that LRRK2 phosphorylates AP2M1 at Thr 156 in vitro.

SIGNOR-278183

P15173

O43257

0

transcriptional regulation

up-regulates quantity by expression

0.259

We show that the srcap subunit named znhit1 or p18hamlet, which is a substrate of p38 mapk, is recruited to the myogenin promoter at the onset of muscle differentiation, in a p38 mapk-dependent manner. We also show that p18hamlet is required for h2a.z accumulation into this genomic region and for subsequent muscle gene transcriptional activation.

SIGNOR-165613

P01019

P24158

0

cleavage

up-regulates activity

0.259

Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen.

SIGNOR-256314

P25963

Q9HC78

0

transcriptional regulation

down-regulates quantity by repression

0.259

ChIP and next generation high-throughput DNA sequencing assay showed that ZBTB20 specifically bound to IκBα gene promoter (+1 to +60 region) after TLR activation. ZBTB20 could inhibit IκBα gene transcription, govern IκBα protein expression, and then promote NF-κB activation. Therefore, transcriptional repressor ZBTB20 is needed to promote full activation of TLR signaling and TLR-triggered innate immune response by selectively suppressing the suppressor IκBα gene transcription.

SIGNOR-266868

Q14118

Q12955

0

relocalization

up-regulates quantity

0.259

We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4.

SIGNOR-266714

P14618

Q00534

0

phosphorylation

down-regulates activity

0.259

Here, using human cancer cells and patient-derived xenografts in mice, we show that the cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2.

SIGNOR-279158

P35498

Q92914

0

binding

down-regulates activity

0.259

Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.

SIGNOR-253422

P00519

P49759

0

phosphorylation

down-regulates

0.259

Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3

SIGNOR-181031

Q9UPW6

Q99717

0

transcriptional regulation

up-regulates quantity

0.259

Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation

SIGNOR-268939

P35247

P49715

0

transcriptional regulation

up-regulates quantity by expression

0.259

Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D.

SIGNOR-254042

Q9NRC8

Q96LA8

0

methylation

down-regulates activity

0.259

Protein arginine methyltransferase 6 (PRMT6) directly interacts with and methylates SIRT7 at R388 in vitro and in vivo R388 methylation suppresses the H3K18 deacetylase activity of SIRT7 without modulating its subcellular localization.

SIGNOR-275888

Q04637

P17252

0

phosphorylation

up-regulates activity

0.258

Phospho-proteomic and mutational analyses revealed that eIF4G1 is a substrate for PKCα at Ser1186.

SIGNOR-276327

P07900

P05129

0

phosphorylation

down-regulates

0.258

Threonine residue set, thr(115)/thr(425)/thr(603), of hsp90_ is specifically phosphorylated by pkc_phosphorylation of hsp90_ by pkc_ decreases the binding affinity of hsp90_ towards atp and co-chaperones such as cdc37 (cell-division cycle 37), thereby decreasing its chaperone activity.

SIGNOR-202812

P31644

Q8TAB3

0

binding

up-regulates quantity by stabilization

0.258

Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.

SIGNOR-267219

P09874

Q00535

0

phosphorylation

down-regulates activity

0.258

These results would suggest that the phosphorylation of PARP-1 via Cdk5's kinase activity is necessary for its persistence at damage sites.Based on these results and the recruitment data, we hypothesize that the phosphorylation of the PARP-1 protein by Cdk5 on one or more of the serines 782, 785, and 786 results in an attenuation of its ribosylating activity facilitating its persistence at the sites of DNA damage.

SIGNOR-276359

P35226

Q9Y243

0

phosphorylation

up-regulates activity

0.258

the polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate

SIGNOR-249583

Q9GZV5

P06493

0

phosphorylation

down-regulates activity

0.258

We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity

SIGNOR-276518

P49841

Q13237

0

phosphorylation

down-regulates activity

0.258

These data indicate that hypertrophic differentiation of growth plate chondrocytes during skeletal growth is promoted by phosphorylation and inactivation of GSK-3beta by cGKII.

SIGNOR-280095

P10636-2

P05771

0

phosphorylation

down-regulates activity

0.258

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

SIGNOR-275442

Q9UPG8

Q8WUI4

0

deacetylation

down-regulates

0.258

Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7.

SIGNOR-140953

P46940

P17252

0

phosphorylation

up-regulates

0.258

Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth.

SIGNOR-128714

O75874

Q12778

0

transcriptional regulation

up-regulates quantity by expression

0.258

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

SIGNOR-260101

P54646

P12931

0

phosphorylation

down-regulates activity

0.258

We show here that Src signaling leads to direct phosphorylation of the AMPK-α subunit on a novel site, tyrosine 179, resulting in suppression of AMPK-T172 phosphorylation and autophagy upon integrin-mediated cell adhesion.

SIGNOR-277573

P31645

P12931

0

phosphorylation

up-regulates quantity by stabilization

0.258

We found that 1) SERT exists in a tyrosine-phosphorylated form, 2) inhibition of tyrosine kinase(s) reduces SERT expression levels by facilitating SERT protein degradation, 3) Src-kinase activity up-regulates SERT protein expression with a concomitant increase in 5-HT uptake and tyrosine phosphorylation, and 4) mutation of Tyr47 or Tyr142 abolishes src-induced increases in transport function and phosphorylation of SERT.

SIGNOR-276386

O00763

Q96RU7

0

binding

down-regulates quantity by destabilization

0.258

TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1. Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D).

SIGNOR-271601

P51003

P06493

0

phosphorylation

up-regulates activity

0.258

Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity.

SIGNOR-268338

P13807

Q9Y463

0

phosphorylation

down-regulates activity

0.258

DYRK Family Protein Kinases Phosphorylate and Inactivate Glycogen Synthase. both protein kinases phosphorylate site 3a but no other sites that affect glycogen synthase activity.

SIGNOR-260633

P27986

P01137

0

binding

up-regulates activity

0.258

While association of the TGF_RI receptor with p85 requires TGF-_ stimulation.

SIGNOR-217960

Q6PGQ7

P49841

0

phosphorylation

up-regulates

0.258

It suggests that gsk3_ activity is required for hbora-mediated mitotic entry through ser274 and ser278 phosphorylation

SIGNOR-201519

Q9UQL6

Q96GD4

0

phosphorylation

down-regulates

0.258

We define the precise site of aurb-mediated phosphorylation as a conserved serine within the nuclear localization signals of hdac4, hdac5, and hdac9 at ser265, ser278, and ser242, respectivelyduring mitosis, aurb-mediated phosphorylation may localize class iia hdacs to a phosphorylation gradient at the spindle midzone, permitting temporal and spatial regulatory mechanisms altering hdac protein interactions

SIGNOR-198650

Q9UGL1

P06493

0

phosphorylation

down-regulates activity

0.258

Phosphorylation of the histone demethylase KDM5B and regulation of the phenotype of triple negative breast cancer|Here, we demonstrate that KDM5B is phosphorylated at Ser1456 by the cyclin-dependent kinase 1 (CDK1). Phosphorylation of KDM5B at Ser1456 attenuated the occupancy of KDM5B on the promoters of pluripotency genes.

SIGNOR-273435

P05067

P11802

0

phosphorylation

down-regulates quantity by destabilization

0.258

These include a significant increase in APP phosphorylation at Thr 668 by cdk2, cdk4, and cdk5, which increases its beta-amyloid production and APP proteolysis by the activated caspases during cell cycle ( xref ; xref ; xref ; xref ).

SIGNOR-280214

P38936

Q9Y463

0

phosphorylation

up-regulates activity

0.258

Mirk exerts its anti-apoptotic effects during muscle differentiation at least in part through effects on the cell cycle inhibitor and pro-survival molecule p21cip1. Overexpression and rna interference experiments demonstrated that mirk phosphorylates p21 within its nuclear localization domain at ser-153 causing a portion of the typically nuclear p21 to localize in the cytoplasm.Translocation to the cytoplasm enables p21 to block apoptosis through inhibitory interaction with pro-apoptotic molecules.

SIGNOR-235635

O43623

P0C2W1

0

binding

down-regulates quantity by destabilization

0.258

One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively.

SIGNOR-272182

Q12778

Q96J02

0

ubiquitination

down-regulates quantity by destabilization

0.258

Mechanistically, Itch ubiquitinates Foxo1 for proteasomal degradation.

SIGNOR-278698

Q9UI33

Q92915

0

binding

down-regulates activity

0.258

Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.

SIGNOR-253437

Q9Y2G1

Q02750

0

phosphorylation

down-regulates activity

0.258

Mek1 phosphorylation of Ndt80 therefore provides an elegant way for cells to know when it is safe to enter the first meiotic division.|These observations suggest that phosphorylation of the DBD by Mek1 prevents Ndt80 from binding to MSEs and explains how Mek1 phosphorylation can inhibit Ndt80 activity.

SIGNOR-279416

Q13233

P00519

0

phosphorylation

up-regulates activity

0.258

Moreover, c-Abl activates MEKK-1 in vitro and in response to DNA damage.|The results demonstrate that the nuclear c-Abl binds to MEKK-1 and that c-Abl phosphorylates MEKK-1 in vitro and in vivo.

SIGNOR-279672

Q9BQE3

Q14980

0

binding

up-regulates

0.258

Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.

SIGNOR-116677

Q14164

P00533

0

phosphorylation

up-regulates activity

0.257

To understand the mechanism by which IKBKE is activated by mutant EGFR, we first investigated if activating mutation of EGFR is able to form a complex with IKBKE.|While wild-type and mutant EGFR directly interacted with IKBKE, only mutant EGFR phosphorylated IKBKE on residues Y153 and Y179.

SIGNOR-278222

P40337

Q96PY6

0

phosphorylation

down-regulates quantity by destabilization

0.257

Nek1 phosphorylates Von Hippel-Lindau tumor suppressor to promote its proteasomal degradation and ciliary destabilization. Mutation of pVHL at S-168 increases protein stability.

SIGNOR-276434

Q9NP59

Q16236

0

transcriptional regulation

up-regulates quantity by expression

0.257

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. SLC40A1 is a target gene of NFE2L2, with a putative ARE identified approximately -7 kb upstream of the SLC40A1 core promoter.

SIGNOR-279863

Q9HAW8

Q99626

0

transcriptional regulation

up-regulates quantity by expression

0.257

Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter.

SIGNOR-253968

Q01860

Q9Y243

0

phosphorylation

up-regulates quantity by stabilization

0.257

Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG.

SIGNOR-242107