GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
Q7KZF4	Q12772	0	transcriptional regulation	up-regulates quantity by expression	0.342	These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression.	SIGNOR-259136
Q9NQU5	P10275	1	phosphorylation	down-regulates quantity by destabilization	0.2	Furthermore, AR phosphorylation at Ser-578 by PAK6 promotes AR-E3 ligase murine double minute-2 (Mdm2) association, causing AR degradation upon androgen stimuli.	SIGNOR-279247
P05412	Q14774	0	transcriptional regulation	up-regulates quantity by expression	0.2	In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells.	SIGNOR-261623
P61586	Q8N1W1	0	guanine nucleotide exchange factor	up-regulates activity	0.755	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260546
Q15139	P12931	0	phosphorylation	up-regulates	0.411	Critical for the regulation of pkd1 activity in response to oxidative stress are src- and abl-mediated tyrosine phosphorylations that eventually lead to protein kinase cdelta (pkcdelta)-mediated activation of pkd1. our data suggest that pkd1 phosphorylation at tyr95 generates a binding motif for pkcdelta, and that oxidative stress-mediated pkcdelta/pkd interaction results in pkd1 activation loop phosphorylation and activation.	SIGNOR-157716
Q14493	P06899	1	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-265381
Q13315	Q9NRC8	0	deacetylation	down-regulates activity	0.36	Here, we report that sirtuin 7 (SIRT7)-mediated deacetylation is essential for dephosphorylation and deactivation of ATM. We show that SIRT7, a class III histone deacetylase, interacts with and deacetylates ATM in vitro and in vivo. \|Upon DNA damage, ATM is activated via a series of highly organized machineries, including acetylation by the histone acetyltransferase TIP60 at lysine 3016	SIGNOR-275890
P30559	P25098	0	phosphorylation	down-regulates activity	0.2	Recent experiments in COS-7 cells transfected with OTR have demonstrated that a rapid GRK2-mediated phosphorylation of the agonist-occupied OTR is a key first step leading to its desensitization, and that it precedes and is required for β-arrestin-dependent internalization	SIGNOR-270329
P23443	P35568	1	phosphorylation	down-regulates quantity by destabilization	0.788	In this report, we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase in a manner that depends on mammalian target of rapamycin and the p70 S6 kinase activities.Elimination of phosphorylation at S307/S312/S527/S636/S639 renders V5-IRS-1 partially resistant to degradation by Fbw8	SIGNOR-236599
P00519	P37231	1	phosphorylation	up-regulates quantity	0.341	We show that the tyrosine kinase Abelson murine leukemia viral oncogene (cAbl) is an adipogenic key regulator. c-Abl promotes adipogenesis by phosphorylation and subsequent stabilization of PPARγ.	SIGNOR-262297
P35637	Q8WXD5	1	relocalization	up-regulates activity	0.2	Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.\|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 \|Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells	SIGNOR-262106
P42224	O00141	0	phosphorylation	up-regulates activity	0.252	Notably, A\u03b2-activated SGK1 or JAK2 kinase phosphorylates STAT1 and induces its association with Tau(1\u2013368).	SIGNOR-279281
P41240	P12931	1	phosphorylation	down-regulates	0.569	The catalytic activity of the src family of tyrosine kinases is suppressed by phosphorylation on a tyrosine residue located near the c terminus (tyr 527 in c-src), which is catalyzed by c-terminal src kinase (csk).	SIGNOR-179417
P15976	Q03112	0	transcriptional regulation	up-regulates quantity by expression	0.319	We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2	SIGNOR-266061
Q9BUL8	Q12923	0	dephosphorylation	down-regulates activity	0.567	In addition, our yeast two-hybrid analysis revealed that CCM3 also binds to the 270-kDa nonreceptor protein tyrosine phos- phatase FAP-1 in a region predicted to contain the C- terminal phosphatase domain [23]. We have shown that this catalytic domain is capable to dephosphorylate CCM3. By dephosphorylation, FAP-1 might therefore negatively reg- ulate CCM3 activity and downstream signaling.	SIGNOR-248714
O75553	P12931	0	phosphorylation	up-regulates activity	0.42	Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons.	SIGNOR-247080
P16220	Q9H2X6	0	phosphorylation	up-regulates	0.389	Ere we found that homeodomain-interacting protein kinase 2 (hipk2), a dna-damage responsive nuclear kinase, is a new creb kinase for phosphorylation at ser-271 but not ser-133, and activates creb transactivation function	SIGNOR-166338
P29350	P43403	1	dephosphorylation	down-regulates	0.588	We propose that shp1 can dephosphorylate sites in zap-70 and syk that are involved in coupling these kinases to downstream signaling cascades, including erk2 and elements of the il-2 gene.	SIGNOR-70237
P61586	Q52LW3	0	gtpase-activating protein	down-regulates activity	0.552	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260484
Q86YT6	Q9BVV6	1	ubiquitination	down-regulates quantity by destabilization	0.2	Conversely, expression of active, but not inactive, Mib1 likewise drastically reduced the levels of centriolar Talpid3 (XREF_FIG).\|Mib1 promotes the poly-ubiquitylation of Talpid3, Cep131, and PCM1.	SIGNOR-278829
P05114	P68400	0	phosphorylation	down-regulates	0.2	Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools.	SIGNOR-76274
P63000	P12931	0	phosphorylation	up-regulates activity	0.615	In addition, Rac1 is phosphorylated at Y64 by FAK and Src kinases ( xref ); Y64 phosphorylation targets Rac1 to focal adhesions.	SIGNOR-280132
Q12778	P31749	0	phosphorylation	down-regulates activity	0.87	Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export.	SIGNOR-236163
Q9ULL1	P06241	0	phosphorylation	up-regulates activity	0.2	We also show that this activation of PLEKHG1 by FYN requires interaction between these two proteins and FYN-induced tyrosine phosphorylation of PLEKHG1 .\|We also show that this activation of PLEKHG1 by FYN requires interaction between these two proteins and FYN-induced tyrosine phosphorylation of PLEKHG1.	SIGNOR-279988
Q15154	Q9BV73	1	relocalization	up-regulates	0.551	Recruitment of nek2 and c-nap1 to the centrosome is dependent on pcm-1	SIGNOR-133334
Q06187	P40763	1	phosphorylation	down-regulates activity	0.382	Phosphorylation of STAT-3 by BTK may also alter the conformation of STAT-3 in such a way as to make it inaccessible as a substrate of activating kinases such as JAK3.\|The ability of BTK to negatively regulate STAT-3 activity suggests several possible models for a mechanism of BTK action.	SIGNOR-279011
Q02535	Q12857	0	transcriptional regulation	down-regulates quantity	0.2	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268873
Q00613	P45983	0	phosphorylation	down-regulates activity	0.497	JNK is activated by heat shock and phosphorylates HSF-1 on serine 363. JNK Phosphorylation of HSF-1 Leads to Reduction in Its Transcriptional Activity	SIGNOR-250119
P28062	Q07820	1	null	down-regulates quantity by destabilization	0.2	Surprisingly, siRNA knockdown of PSMB8 (LMP7), an ‘immunoproteasome’ component, reversed IFNγ-induced sensitivity to Fas ligation and prevented Fas/IFNγ-induced degradation of Mcl-1, but did not protect p-Bcl-2 or p-Bcl-XL. Proteasome inhibition markedly increased Mcl-1, p-Bcl-2, and p-Bcl-XL levels after IFNγ treatment	SIGNOR-261974
Q9Y4K3	P42345	1	ubiquitination	up-regulates activity	0.438	Together, these results demonstrate that mTOR polyubiquitination by TRAF6 modulates its activation in response to amino acids and point to a role for K63 ubiquitin modification as a sensor of nutrient status.	SIGNOR-278789
Q9HCU9	Q09472	1	ubiquitination	down-regulates quantity by destabilization	0.363	BRMS1 suppresses lung cancer metastases through an E3 ligase function on histone acetyltransferase p300. BRMS1 induces polyubiquitination of p300, resulting in its proteasome-mediated degradation.	SIGNOR-266408
Q9H2P9	P13639	1	methylation	down-regulates activity	0.747	Analysis of EF2 in the mutant cells revealed a novel form of diphthamide with an additional methyl group that prevented ADP-ribosylation and inactivation of EF2. The abnormal methylation appeared to be catalyzed by DPH5.	SIGNOR-261146
P53778	Q12888	1	phosphorylation	down-regulates activity	0.2	Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.\|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks \|phosphorylation of T1609 is likely to be mediated by p38 MAPK	SIGNOR-264448
Q9H3Y6	Q02790	1	phosphorylation	down-regulates activity	0.267	Together, these data indicate that SRMS inhibits the scaffolding function of its endogenous substrate FKBP51, thus antagonizing FKBP51-dependent inactivation of AKT (S4E Fig).\|We demonstrate that SRMS phosphorylates FKBP51 to inhibit its scaffolding activity and promote its degradation through the ubiquitin-proteasome pathway.	SIGNOR-279764
Q9UMS4	P27694	1	polyubiquitination	up-regulates activity	0.509	PRP19 is a ubiquitin ligase involved in pre-mRNA splicing and the DNA damage response (DDR). PRP19 ubiquitylates RPA and promotes ATRIP recruitment.	SIGNOR-272076
P14921	Q99102	1	transcriptional regulation	up-regulates quantity by expression	0.2	Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level.	SIGNOR-254098
O43312	P48730	0	phosphorylation	down-regulates quantity by destabilization	0.327	Mechanistically, we defined that Casein Kinase Iδ (CKIδ) phosphorylates Ser322 to trigger MTSS1's interaction with β-TRCP for subsequent ubiquitination and degradation.	SIGNOR-276611
O14757	P24941	0	phosphorylation	up-regulates	0.554	Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency	SIGNOR-175083
Q9Y6N7	Q14938	0	transcriptional regulation	up-regulates quantity	0.2	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268907
P37231	P11274	0	phosphorylation	down-regulates activity	0.2	Overexpression of Bcr WT inhibited PPARgamma transcriptional activity (XREF_FIG).\|Point-mutation and in vitro kinase analysis showed that PPAR\u03b3 was phosphorylated by Bcr at serine 82.	SIGNOR-279441
P20936	P12931	0	phosphorylation	down-regulates	0.615	The phosphorylation of p120-gap by p60c-src inhibited its ability to stimulate the ha-ras-gtpase activity	SIGNOR-86008
P56704	Q5T9L3	0	relocalization	up-regulates activity	0.641	WNT secretion requires its binding to the carrier protein wntless (WLS);	SIGNOR-256599
Q9UQ84	O96017	0	phosphorylation	down-regulates activity	0.565	Inhibition of Exo1 activity by the DDR kinase Rad53.\|Unlike Sae2/CtIP activation by CDK, Exo1 phosphorylation by Rad53 limits extended resection of ssDNA at uncapped telomeres and consequently minimizes further activation of the DDR.	SIGNOR-279028
Q14164	Q92844	1	phosphorylation	down-regulates activity	0.743	IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex	SIGNOR-262722
P04637	O15164	0	ubiquitination	down-regulates	0.532	New ring-domain e3-ubiquitin ligase trim24 that targets p53 for degradation	SIGNOR-188726
P40425	P55075	1	transcriptional regulation	down-regulates quantity by repression	0.251	Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription	SIGNOR-265778
Q06124	Q08881	1	dephosphorylation	down-regulates activity	0.324	Using genetic and pharmacological approaches, we discovered that SHP2 dephosphorylates ITK specifically downstream of PD-1 and that this event was associated with PD-1 inhibitory cellular functions.	SIGNOR-277174
P51955	P46937	1	phosphorylation	up-regulates quantity by stabilization	0.2	NEK2 promotes the migration and proliferation of ESCC via stabilization of YAP1 by phosphorylation at Thr-143	SIGNOR-276586
Q16539	Q12888	1	phosphorylation	down-regulates activity	0.28	Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.\|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks \|phosphorylation of T1609 is likely to be mediated by p38 MAPK	SIGNOR-264446
Q9NS91	P12004	1	ubiquitination	up-regulates activity	0.846	Second, these findings suggest the following model (XREF_FIG) : upon replication fork stalling at cisplatin induced DNA lesions, the RAD18 and RAD6 complex ubiquitylates PCNA on Lys164.\|The DNA damage-activated E3 ubiquitin ligase RAD18 promotes repair of interstrand DNA cross-links by ubiquitylating PCNA and recruiting FANCL to chromatin.	SIGNOR-278612
Q96GD0	P23528	1	dephosphorylation	down-regulates activity	0.447	Chronophin, a novel HAD-type serine protein phosphatase, regulates cofilin-dependent actin dynamics\|Cofilin is a key regulator of actin cytoskeletal dynamics whose activity is controlled by phosphorylation of a single serine residue. We report the biochemical isolation of chronophin (CIN), a unique cofilin-activating phosphatase of the haloacid dehalogenase (HAD) superfamily.	SIGNOR-248764
P49910	Q9HAU4	1	transcriptional regulation	down-regulates quantity by repression	0.268	ZNF165 drives the unrestrained activation of transforming growth factor β (TGFβ) signalling by directly inactivating the expression of negative feedback pathway regulators, SMURF2, SMAD7 and PMEPA1.	SIGNOR-266095
O75385	A2RUS2	1	phosphorylation	up-regulates activity	0.435	ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12.	SIGNOR-264731
P67775	P29372	0	polyubiquitination	down-regulates quantity by destabilization	0.2	Here we report that MID1 catalyzes the in vitro ubiquitination of the catalytic subunit of PP2A (PP2Ac) in the absence of alpha4. In the presence of alpha4, the level of PP2Ac ubiquitination is reduced.The high molecular weight smear pattern was not as obvious, suggesting that domains within the C-terminal half of MID1 may contribute to the polyubiquitination of PP2Ac.	SIGNOR-271930
P12235	Q06124	0	dephosphorylation	down-regulates activity	0.271	Specifically, SHP2-mediated dephosphorylation of ANT1 at Tyr 191 is essential for mitochondrial homeostasis and mitigation of NLRP3 inflammasome activation.\|The interaction between SHP2 and ANT1 (Fig.\u00a0 xref ), and the opposite effects of SHP2 and ANT1 shRNAs in the activation of NLRP3 inflammasome (Figs.\u00a0 xref and xref ) raised the possibility that the SHP2 may inhibit ANT1 to suppress NLRP3 inflammasome activation.\|To further determine which tyrosine phosphorylation site of ANT1 is dephosphorylated by SHP2, we created the dephosphorylated mutant of ANT1, in which tyrosine was replaced with phenylalanine (Y to F mutation).	SIGNOR-277124
P35638	Q13131	0	phosphorylation	down-regulates activity	0.265	Here, we report that phosphorylation of CHOP at Ser30 by AMPKα1 triggers CHOP degradation resulting in reduced macrophage apoptosis and subsequent ameliorated plaque vulnerability in vivo.	SIGNOR-259864
P17252	Q15311	1	phosphorylation	up-regulates activity	0.389	In deletion mutant analyses of potential phosphorylation sites in RLIP76, we identified T297 and S509 as targets for phosphorylation by PKCalpha. Phosphorylation at T297 increased doxorubicin (DOX)-transport activity approximately 2-fold for RLIP76 purified from recombinant source	SIGNOR-263164
P42345	O15111	0	phosphorylation	up-regulates activity	0.511	In those studies, we found that IKKalpha interacts with and phosphorylates mTOR in the mTORC1 complex to activate mTORC1, and that Akt signaling drives the IKKalpha-mTORC1 interaction.\|We then studied whether IKKalpha promotes Akt and mTOR activity in other mammalian cancer cell lines.	SIGNOR-279607
Q14012	Q8N5S9	0	phosphorylation	up-regulates activity	0.414	Human calcium-calmodulin dependent protein kinase I: cDNA cloning, domain structure and activation by phosphorylation at threonine-177 by calcium-calmodulin dependent protein kinase I kinase.	SIGNOR-250717
Q04206	Q14164	0	phosphorylation	up-regulates	0.439	Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro.	SIGNOR-129943
Q07889	P27361	0	phosphorylation	down-regulates	0.636	For example, inactivation of sos through phosphorylation by the downstream mapk	SIGNOR-26338
P30305	Q8TDC3	0	phosphorylation	down-regulates	0.506	Hssad1 specifically phosphorylated wee1a, cdc25-c, and -b on ser-642, ser-216, and ser-361 in vitro, respectivelyphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3	SIGNOR-124839
P63000	Q7Z5H3	0	gtpase-activating protein	down-regulates activity	0.529	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260477
P21359	P01112	1	gtpase-activating protein	down-regulates activity	0.813	Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation	SIGNOR-204357
Q92538	P68400	0	phosphorylation	down-regulates quantity by destabilization	0.2	We show that, in mitosis, GBF1 is phosphorylated on Ser292 and Ser297 by casein kinase-2 allowing recognition by the F-box protein βTrCP. GBF1 interaction with βTrCP recruits GBF1 to the SCFβTrCP ubiquitin ligase complex, triggering its degradation.	SIGNOR-277398
Q05655	P11831	1	phosphorylation	down-regulates activity	0.2	Protein kinase C delta blocks immediate-early gene expression in senescent cells by inactivating serum response factor.\|The phosphorylation of T160 of SRF by PKC delta in vitro and in vivo led to loss of SRF DNA binding activity.	SIGNOR-279347
Q04760	P07948	0	phosphorylation	up-regulates activity	0.2	We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).	SIGNOR-276186
P25440	Q9ULU4	1	relocalization	up-regulates activity	0.287	ZMYND8 and BRD2 therefore work together to protect H4Ac domains from HDAC activity.\|Further, when BRD2 was depleted, ZMYND8 accumulation was lost (Fig. 2e), indicating that either BRD2, or the underlying H4Ac, is required for ZMYND8 loading.	SIGNOR-262036
P29597	Q13261	0	null	up-regulates	0.245	Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated	SIGNOR-256253
P68431	Q9NR48	0	trimethylation	up-regulates activity	0.2	We show that human ASH1L specifically methylates histone H3 Lys-36. Our data implicate that there may be a regulatory mechanism of ASH1L histone methyltransferases	SIGNOR-269055
Q16576	Q13131	0	phosphorylation	up-regulates activity	0.2	AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314\| interaction between RBBP7 and HAT1 is required for acetyltransferase activity	SIGNOR-264784
P51955	P62136	0	dephosphorylation	down-regulates	0.374	Nek2 is activated by autophosphorylation, and its dephosphorylation is catalyzed by pp1	SIGNOR-152949
O75122	P53350	0	phosphorylation	up-regulates activity	0.622	Cdk1 and Plk1 mediate a CLASP2 phospho-switch that stabilizes kinetochore-microtubule attachments.\|Finally, we demonstrate that CLASP2 phosphorylation on S1234 and S1255 by Cdk1 and Plk1, respectively, increases with conditions that allow the establishment and stabilization of KT\u2013MT attachments ( xref ).	SIGNOR-278321
P12004	P49459	0	ubiquitination	up-regulates	0.476	Pcna is mono-ubiquitinated through rad6 and rad18, modified by lysine-63-linked multi-ubiquitination--which additionally requires mms2, ubc13 and rad5--and is conjugated to sumo by ubc9. The first of these is monoubiquitination of lysine 164 on one or more of the pcna subunits by the e2-e3 complex of rad6-rad18.	SIGNOR-92737
Q04760	P17948	0	phosphorylation	up-regulates activity	0.2	We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).	SIGNOR-276190
Q13315	Q504Q3	1	phosphorylation	up-regulates activity	0.2	Here, we identify that USP52 directly interacts with and deubiquitinates CtIP, thereby promoting DNA end resection and HR. Mechanistically, USP52 removes the ubiquitination of CtIP to facilitate the phosphorylation and activation of CtIP at Thr-847. In addition, USP52 is phosphorylated by ATM at Ser-1003 after DNA damage, which enhances the catalytic activity of USP52.	SIGNOR-273508
Q7KZI7	P17612	0	phosphorylation	down-regulates activity	0.2	Here, we found the disruption of microtubule and neurite outgrowth induced by MARK2 overexpression was blocked by active PKA. The interaction between PKA and MARK2 was confirmed by coimmunoprecipitation and immunocytochemistry both in vitro and in vivo. PKA was found to inhibit MARK2 kinase activity by phosphorylating a novel site, serine 409.	SIGNOR-276870
P06730	P17252	0	phosphorylation	up-regulates	0.382	Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the translational repressors, 4E-binding proteins.[..] This suggests a two-step model for the phosphorylation (and activation) of eIF4E by growth factors and hormones: first, dissociation of eIF4E .	SIGNOR-248945
Q13444	P06239	0	phosphorylation	up-regulates	0.349	Hck, and to a lesser extent lck, phosphorylated the adam15. Deletion and point mutation analysis of the adam15 cytoplasmic domain confirmed the importance of the proline-rich motifs for grb2 and lck binding and indicated the regulatory nature of tyr(715) and tyr(735). These data demonstrate selective, phosphorylation-dependent interactions of adam15 with src family ptks and grb2, which highlight the potential for integration of adam functions and cellular signaling.	SIGNOR-112931
O14757	Q9UJM3	1	phosphorylation	down-regulates activity	0.326	Our results suggest that Chk1 phosphorylates Mig-6 on Ser 251, resulting in the inhibition of Mig-6, and that Chk1 acts as a positive regulator of EGF signalling. This is a novel function of Chk1.	SIGNOR-276411
O14647	Q13426	1	relocalization	up-regulates quantity	0.2	CHD2 Promotes the Recruitment of Core NHEJ Factors. overexpression of ATPase-dead CHD2 (K515R; Figure S5F), but not wild-type CHD2, also reduced the recruitment of XRCC4 (Figure 5E). Together, these findings suggest that the chromatin remodeling activity of CHD2 promotes the efficient assembly of NHEJ complexes at DSBs.	SIGNOR-264528
O95786	P19784	0	phosphorylation	down-regulates activity	0.2	Phosphorylation of RIG-I by casein kinase II inhibits its antiviral response.Threonine at amino acid (aa) 770 and serine at aa 854 to 855 of RIG-I are phosphorylated by casein kinase II (CK2) in the resting state of the cell and dephosphorylated when cells are infected by RNA virus.	SIGNOR-276285
O43255	Q92667	1	polyubiquitination	down-regulates quantity by destabilization	0.507	Seven In-Absentia Homolog 2 (Siah2), an E3-ubiquitin ligase whose expression is induced in hypoxic conditions, formed a complex and degraded AKAP121.	SIGNOR-272641
P49675	P17676	0	transcriptional regulation	up-regulates quantity by expression	0.365	Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells.	SIGNOR-254046
P06241	P04629	1	phosphorylation	up-regulates activity	0.254	Here, we demonstrate that Fyn can directly phosphorylate the intracellular domain of TrkA and that its kinase activity towards Trk is increased by GPCR stimulation ( Fig. 4 ).	SIGNOR-279410
O60260	Q9NX09	1	ubiquitination	down-regulates quantity by destabilization	0.2	In conclusion, our work in cellular and animal models and in human samples strongly indicates that RTP801 is a substrate of parkin and that RTP801 elevation due to parkin loss of function in both AR-JP and sporadic Parkinson's disease may contribute to neurodegeneration.\|We showed that parkin poly-ubiquitinates RTP801, both in vitro and in vivo.	SIGNOR-278560
Q03014	Q01196	0	transcriptional regulation	up-regulates quantity	0.271	We identified Hhex as a direct target of RUNX1 and FLT3-ITD stimulation and confirmed high HHEX expression in FLT3-ITD AMLs. HHEX could replace RUNX1 in cooperating with FLT3-ITD to induce AML.	SIGNOR-256305
Q96EB6	Q9UPT9	0	deubiquitination	up-regulates quantity by stabilization	0.534	USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells.	SIGNOR-261561
Q16644	Q6JBY9	1	phosphorylation	down-regulates activity	0.482	Human CapZIP was phosphorylated at Ser-179 and Ser-244 by MAPKAP-K2 (mitogen-activated protein kinase-activated protein kinase 2) or MAPKAP-K3 in vitro. In the present paper we have identified CapZIP as a protein that is phosphorylated exceptionally rapidly by several SAPKs in vitro (Figure 4), and which is expressed in muscles and immune cells. Both MAPKAP-K2 and MAPKAP-K3 phosphorylated CapZIP at Ser-179 in vitro. An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.	SIGNOR-263082
Q13363	P12830	1	transcriptional regulation	down-regulates quantity by repression	0.6	Carboxyl-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor with oncogenic potential. We found CtBP1 was recruited to the promoter regions of Brca1 and E-cadherin genes in breast cancer cells.	SIGNOR-259197
P38398	O14965	0	phosphorylation	up-regulates	0.677	Previous studies have shown that the brca1 breast cancer tumor suppressor also localizes to the centrosome and that brca1 inactivation results in loss of the g(2)-m checkpoint. We demonstrate here that aurora-a physically binds to and phosphorylates brca1. We propose that brca1 phosphorylation by aurora-a plays a role in g(2) to m transition of cell cycle	SIGNOR-123065
P12830	P54253	0	transcriptional regulation	up-regulates quantity by expression	0.343	Overexpression of the CtBP2 protein enhanced the repression activity of the E-cadherin promoter in a dose-dependent manner, whereas overexpression of ataxin-1 increased the activity of the E-cadherin promoter in a dose-dependent manner	SIGNOR-261577
P57764	P49662	0	cleavage	up-regulates activity	0.647	Co-expression of GSDMD with caspase-1, 4, 5 or 11 but not apoptotic caspases (caspase-2, 8 and 9) in 293T cells induced the same cleavage of GSDMD\|inflammatory caspases specifically cleave GSDMD after the 272FLTD275 (or 273LLSD276) sequence \|	SIGNOR-256417
Q969V5	O00429	1	sumoylation	up-regulates activity	0.534	Through a detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms.	SIGNOR-274128
Q05397	P31749	0	phosphorylation	up-regulates activity	0.43	In mouse embryonic fibroblasts, AKT1 phosphorylates S695 and T700 on FAK ( xref ) and in human colon cancer cells AKT1 phosphorylates S517, S601, and S695 on FAK ( xref , xref ).\|This suggests that further activation of FAK by AKT1 ( beyond that of Pten loss alone ) is required to promote FA turnover , increase tumor invasion , and ultimately elicit brain metastasis .	SIGNOR-279777
Q07869	P28482	0	phosphorylation	up-regulates activity	0.578	We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution.	SIGNOR-249434
P16591	P35222	1	phosphorylation	down-regulates activity	0.72	Interaction of beta-catenin with alpha-catenin is regulated by the phosphorylation of beta-catenin Tyr-142. This residue can be phosphorylated in vitro by Fer or Fyn tyrosine kinases. Transfection of these kinases to epithelial cells disrupted the association between both catenins.	SIGNOR-251131
Q13683	P15173	0	transcriptional regulation	up-regulates quantity by expression	0.283	Only myogenin and MyoD were able to efficiently trans-activate the alpha7 promoter-CAT construct (Fig. 7). Myogenin trans-activated the promoter by _2-fold whereas MyoD was able to trans-activate by nearly 4-fold, indicating that both of these factors may play a role in alpha7 gene expression during muscle development.	SIGNOR-241521
Q9NWF9	Q9NR97	1	polyubiquitination	down-regulates quantity by destabilization	0.257	E3 ligase RNF216 (ring finger protein 216) targets TLR8 for ubiquitination and degradation.	SIGNOR-272257
Q13557	O15084	1	phosphorylation	down-regulates activity	0.2	We provide evidence for a dual kinase-mediated regulation of the PITK holoenzyme whereby PITK phosphorylation at S1017 is catalyzed by calcium/calmodulin-dependent kinase II-delta (CaMKIIdelta), promoting the subsequent phosphorylation of S1013 by glycogen synthase kinase-3 (GSK3) in vitro.\|the phosphorylation of PITK at these specific residues altered PP1 binding and subsequent PITK-directed dephosphorylation of hnRNP K	SIGNOR-264793

Q7KZF4

Q12772

0

transcriptional regulation

up-regulates quantity by expression

0.342

These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression.

SIGNOR-259136

Q9NQU5

P10275

1

phosphorylation

down-regulates quantity by destabilization

0.2

Furthermore, AR phosphorylation at Ser-578 by PAK6 promotes AR-E3 ligase murine double minute-2 (Mdm2) association, causing AR degradation upon androgen stimuli.

SIGNOR-279247

P05412

Q14774

0

transcriptional regulation

up-regulates quantity by expression

0.2

In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells.

SIGNOR-261623

P61586

Q8N1W1

0

guanine nucleotide exchange factor

up-regulates activity

0.755

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260546

Q15139

P12931

0

phosphorylation

up-regulates

0.411

Critical for the regulation of pkd1 activity in response to oxidative stress are src- and abl-mediated tyrosine phosphorylations that eventually lead to protein kinase cdelta (pkcdelta)-mediated activation of pkd1. our data suggest that pkd1 phosphorylation at tyr95 generates a binding motif for pkcdelta, and that oxidative stress-mediated pkcdelta/pkd interaction results in pkd1 activation loop phosphorylation and activation.

SIGNOR-157716

Q14493

P06899

1

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-265381

Q13315

Q9NRC8

0

deacetylation

down-regulates activity

0.36

Here, we report that sirtuin 7 (SIRT7)-mediated deacetylation is essential for dephosphorylation and deactivation of ATM. We show that SIRT7, a class III histone deacetylase, interacts with and deacetylates ATM in vitro and in vivo. |Upon DNA damage, ATM is activated via a series of highly organized machineries, including acetylation by the histone acetyltransferase TIP60 at lysine 3016

SIGNOR-275890

P30559

P25098

0

phosphorylation

down-regulates activity

0.2

Recent experiments in COS-7 cells transfected with OTR have demonstrated that a rapid GRK2-mediated phosphorylation of the agonist-occupied OTR is a key first step leading to its desensitization, and that it precedes and is required for β-arrestin-dependent internalization

SIGNOR-270329

P23443

P35568

1

phosphorylation

down-regulates quantity by destabilization

0.788

In this report, we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase in a manner that depends on mammalian target of rapamycin and the p70 S6 kinase activities.Elimination of phosphorylation at S307/S312/S527/S636/S639 renders V5-IRS-1 partially resistant to degradation by Fbw8

SIGNOR-236599

P00519

P37231

1

phosphorylation

up-regulates quantity

0.341

We show that the tyrosine kinase Abelson murine leukemia viral oncogene (cAbl) is an adipogenic key regulator. c-Abl promotes adipogenesis by phosphorylation and subsequent stabilization of PPARγ.

SIGNOR-262297

P35637

Q8WXD5

1

relocalization

up-regulates activity

0.2

Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 |Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells

SIGNOR-262106

P42224

O00141

0

phosphorylation

up-regulates activity

0.252

Notably, A\u03b2-activated SGK1 or JAK2 kinase phosphorylates STAT1 and induces its association with Tau(1\u2013368).

SIGNOR-279281

P41240

P12931

1

phosphorylation

down-regulates

0.569

The catalytic activity of the src family of tyrosine kinases is suppressed by phosphorylation on a tyrosine residue located near the c terminus (tyr 527 in c-src), which is catalyzed by c-terminal src kinase (csk).

SIGNOR-179417

P15976

Q03112

0

transcriptional regulation

up-regulates quantity by expression

0.319

We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2

SIGNOR-266061

Q9BUL8

Q12923

0

dephosphorylation

down-regulates activity

0.567

In addition, our yeast two-hybrid analysis revealed that CCM3 also binds to the 270-kDa nonreceptor protein tyrosine phos- phatase FAP-1 in a region predicted to contain the C- terminal phosphatase domain [23]. We have shown that this catalytic domain is capable to dephosphorylate CCM3. By dephosphorylation, FAP-1 might therefore negatively reg- ulate CCM3 activity and downstream signaling.

SIGNOR-248714

O75553

P12931

0

phosphorylation

up-regulates activity

0.42

Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons.

SIGNOR-247080

P16220

Q9H2X6

0

phosphorylation

up-regulates

0.389

Ere we found that homeodomain-interacting protein kinase 2 (hipk2), a dna-damage responsive nuclear kinase, is a new creb kinase for phosphorylation at ser-271 but not ser-133, and activates creb transactivation function

SIGNOR-166338

P29350

P43403

1

dephosphorylation

down-regulates

0.588

We propose that shp1 can dephosphorylate sites in zap-70 and syk that are involved in coupling these kinases to downstream signaling cascades, including erk2 and elements of the il-2 gene.

SIGNOR-70237

P61586

Q52LW3

0

gtpase-activating protein

down-regulates activity

0.552

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260484

Q86YT6

Q9BVV6

1

ubiquitination

down-regulates quantity by destabilization

0.2

Conversely, expression of active, but not inactive, Mib1 likewise drastically reduced the levels of centriolar Talpid3 (XREF_FIG).|Mib1 promotes the poly-ubiquitylation of Talpid3, Cep131, and PCM1.

SIGNOR-278829

P05114

P68400

0

phosphorylation

down-regulates

0.2

Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools.

SIGNOR-76274

P63000

P12931

0

phosphorylation

up-regulates activity

0.615

In addition, Rac1 is phosphorylated at Y64 by FAK and Src kinases ( xref ); Y64 phosphorylation targets Rac1 to focal adhesions.

SIGNOR-280132

Q12778

P31749

0

phosphorylation

down-regulates activity

0.87

Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export.

SIGNOR-236163

Q9ULL1

P06241

0

phosphorylation

up-regulates activity

0.2

We also show that this activation of PLEKHG1 by FYN requires interaction between these two proteins and FYN-induced tyrosine phosphorylation of PLEKHG1 .|We also show that this activation of PLEKHG1 by FYN requires interaction between these two proteins and FYN-induced tyrosine phosphorylation of PLEKHG1.

SIGNOR-279988

Q15154

Q9BV73

1

relocalization

up-regulates

0.551

Recruitment of nek2 and c-nap1 to the centrosome is dependent on pcm-1

SIGNOR-133334

Q06187

P40763

1

phosphorylation

down-regulates activity

0.382

Phosphorylation of STAT-3 by BTK may also alter the conformation of STAT-3 in such a way as to make it inaccessible as a substrate of activating kinases such as JAK3.|The ability of BTK to negatively regulate STAT-3 activity suggests several possible models for a mechanism of BTK action.

SIGNOR-279011

Q02535

Q12857

0

transcriptional regulation

down-regulates quantity

0.2

By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development

SIGNOR-268873

Q00613

P45983

0

phosphorylation

down-regulates activity

0.497

JNK is activated by heat shock and phosphorylates HSF-1 on serine 363. JNK Phosphorylation of HSF-1 Leads to Reduction in Its Transcriptional Activity

SIGNOR-250119

P28062

Q07820

1

null

down-regulates quantity by destabilization

0.2

Surprisingly, siRNA knockdown of PSMB8 (LMP7), an ‘immunoproteasome’ component, reversed IFNγ-induced sensitivity to Fas ligation and prevented Fas/IFNγ-induced degradation of Mcl-1, but did not protect p-Bcl-2 or p-Bcl-XL. Proteasome inhibition markedly increased Mcl-1, p-Bcl-2, and p-Bcl-XL levels after IFNγ treatment

SIGNOR-261974

Q9Y4K3

P42345

1

ubiquitination

up-regulates activity

0.438

Together, these results demonstrate that mTOR polyubiquitination by TRAF6 modulates its activation in response to amino acids and point to a role for K63 ubiquitin modification as a sensor of nutrient status.

SIGNOR-278789

Q9HCU9

Q09472

1

ubiquitination

down-regulates quantity by destabilization

0.363

BRMS1 suppresses lung cancer metastases through an E3 ligase function on histone acetyltransferase p300. BRMS1 induces polyubiquitination of p300, resulting in its proteasome-mediated degradation.

SIGNOR-266408

Q9H2P9

P13639

1

methylation

down-regulates activity

0.747

Analysis of EF2 in the mutant cells revealed a novel form of diphthamide with an additional methyl group that prevented ADP-ribosylation and inactivation of EF2. The abnormal methylation appeared to be catalyzed by DPH5.

SIGNOR-261146

P53778

Q12888

1

phosphorylation

down-regulates activity

0.2

Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK

SIGNOR-264448

Q9H3Y6

Q02790

1

phosphorylation

down-regulates activity

0.267

Together, these data indicate that SRMS inhibits the scaffolding function of its endogenous substrate FKBP51, thus antagonizing FKBP51-dependent inactivation of AKT (S4E Fig).|We demonstrate that SRMS phosphorylates FKBP51 to inhibit its scaffolding activity and promote its degradation through the ubiquitin-proteasome pathway.

SIGNOR-279764

Q9UMS4

P27694

1

polyubiquitination

up-regulates activity

0.509

PRP19 is a ubiquitin ligase involved in pre-mRNA splicing and the DNA damage response (DDR). PRP19 ubiquitylates RPA and promotes ATRIP recruitment.

SIGNOR-272076

P14921

Q99102

1

transcriptional regulation

up-regulates quantity by expression

0.2

Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level.

SIGNOR-254098

O43312

P48730

0

phosphorylation

down-regulates quantity by destabilization

0.327

Mechanistically, we defined that Casein Kinase Iδ (CKIδ) phosphorylates Ser322 to trigger MTSS1's interaction with β-TRCP for subsequent ubiquitination and degradation.

SIGNOR-276611

O14757

P24941

0

phosphorylation

up-regulates

0.554

Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency

SIGNOR-175083

Q9Y6N7

Q14938

0

transcriptional regulation

up-regulates quantity

0.2

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

SIGNOR-268907

P37231

P11274

0

phosphorylation

down-regulates activity

0.2

Overexpression of Bcr WT inhibited PPARgamma transcriptional activity (XREF_FIG).|Point-mutation and in vitro kinase analysis showed that PPAR\u03b3 was phosphorylated by Bcr at serine 82.

SIGNOR-279441

P20936

P12931

0

phosphorylation

down-regulates

0.615

The phosphorylation of p120-gap by p60c-src inhibited its ability to stimulate the ha-ras-gtpase activity

SIGNOR-86008

P56704

Q5T9L3

0

relocalization

up-regulates activity

0.641

WNT secretion requires its binding to the carrier protein wntless (WLS);

SIGNOR-256599

Q9UQ84

O96017

0

phosphorylation

down-regulates activity

0.565

Inhibition of Exo1 activity by the DDR kinase Rad53.|Unlike Sae2/CtIP activation by CDK, Exo1 phosphorylation by Rad53 limits extended resection of ssDNA at uncapped telomeres and consequently minimizes further activation of the DDR.

SIGNOR-279028

Q14164

Q92844

1

phosphorylation

down-regulates activity

0.743

IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex

SIGNOR-262722

P04637

O15164

0

ubiquitination

down-regulates

0.532

New ring-domain e3-ubiquitin ligase trim24 that targets p53 for degradation

SIGNOR-188726

P40425

P55075

1

transcriptional regulation

down-regulates quantity by repression

0.251

Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription

SIGNOR-265778

Q06124

Q08881

1

dephosphorylation

down-regulates activity

0.324

Using genetic and pharmacological approaches, we discovered that SHP2 dephosphorylates ITK specifically downstream of PD-1 and that this event was associated with PD-1 inhibitory cellular functions.

SIGNOR-277174

P51955

P46937

1

phosphorylation

up-regulates quantity by stabilization

0.2

NEK2 promotes the migration and proliferation of ESCC via stabilization of YAP1 by phosphorylation at Thr-143

SIGNOR-276586

Q16539

Q12888

1

phosphorylation

down-regulates activity

0.28

Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK

SIGNOR-264446

Q9NS91

P12004

1

ubiquitination

up-regulates activity

0.846

Second, these findings suggest the following model (XREF_FIG) : upon replication fork stalling at cisplatin induced DNA lesions, the RAD18 and RAD6 complex ubiquitylates PCNA on Lys164.|The DNA damage-activated E3 ubiquitin ligase RAD18 promotes repair of interstrand DNA cross-links by ubiquitylating PCNA and recruiting FANCL to chromatin.

SIGNOR-278612

Q96GD0

P23528

1

dephosphorylation

down-regulates activity

0.447

Chronophin, a novel HAD-type serine protein phosphatase, regulates cofilin-dependent actin dynamics|Cofilin is a key regulator of actin cytoskeletal dynamics whose activity is controlled by phosphorylation of a single serine residue. We report the biochemical isolation of chronophin (CIN), a unique cofilin-activating phosphatase of the haloacid dehalogenase (HAD) superfamily.

SIGNOR-248764

P49910

Q9HAU4

1

transcriptional regulation

down-regulates quantity by repression

0.268

ZNF165 drives the unrestrained activation of transforming growth factor β (TGFβ) signalling by directly inactivating the expression of negative feedback pathway regulators, SMURF2, SMAD7 and PMEPA1.

SIGNOR-266095

O75385

A2RUS2

1

phosphorylation

up-regulates activity

0.435

ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12.

SIGNOR-264731

P67775

P29372

0

polyubiquitination

down-regulates quantity by destabilization

0.2

Here we report that MID1 catalyzes the in vitro ubiquitination of the catalytic subunit of PP2A (PP2Ac) in the absence of alpha4. In the presence of alpha4, the level of PP2Ac ubiquitination is reduced.The high molecular weight smear pattern was not as obvious, suggesting that domains within the C-terminal half of MID1 may contribute to the polyubiquitination of PP2Ac.

SIGNOR-271930

P12235

Q06124

0

dephosphorylation

down-regulates activity

0.271

Specifically, SHP2-mediated dephosphorylation of ANT1 at Tyr 191 is essential for mitochondrial homeostasis and mitigation of NLRP3 inflammasome activation.|The interaction between SHP2 and ANT1 (Fig.\u00a0 xref ), and the opposite effects of SHP2 and ANT1 shRNAs in the activation of NLRP3 inflammasome (Figs.\u00a0 xref and xref ) raised the possibility that the SHP2 may inhibit ANT1 to suppress NLRP3 inflammasome activation.|To further determine which tyrosine phosphorylation site of ANT1 is dephosphorylated by SHP2, we created the dephosphorylated mutant of ANT1, in which tyrosine was replaced with phenylalanine (Y to F mutation).

SIGNOR-277124

P35638

Q13131

0

phosphorylation

down-regulates activity

0.265

Here, we report that phosphorylation of CHOP at Ser30 by AMPKα1 triggers CHOP degradation resulting in reduced macrophage apoptosis and subsequent ameliorated plaque vulnerability in vivo.

SIGNOR-259864

P17252

Q15311

1

phosphorylation

up-regulates activity

0.389

In deletion mutant analyses of potential phosphorylation sites in RLIP76, we identified T297 and S509 as targets for phosphorylation by PKCalpha. Phosphorylation at T297 increased doxorubicin (DOX)-transport activity approximately 2-fold for RLIP76 purified from recombinant source

SIGNOR-263164

P42345

O15111

0

phosphorylation

up-regulates activity

0.511

In those studies, we found that IKKalpha interacts with and phosphorylates mTOR in the mTORC1 complex to activate mTORC1, and that Akt signaling drives the IKKalpha-mTORC1 interaction.|We then studied whether IKKalpha promotes Akt and mTOR activity in other mammalian cancer cell lines.

SIGNOR-279607

Q14012

Q8N5S9

0

phosphorylation

up-regulates activity

0.414

Human calcium-calmodulin dependent protein kinase I: cDNA cloning, domain structure and activation by phosphorylation at threonine-177 by calcium-calmodulin dependent protein kinase I kinase.

SIGNOR-250717

Q04206

Q14164

0

phosphorylation

up-regulates

0.439

Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro.

SIGNOR-129943

Q07889

P27361

0

phosphorylation

down-regulates

0.636

For example, inactivation of sos through phosphorylation by the downstream mapk

SIGNOR-26338

P30305

Q8TDC3

0

phosphorylation

down-regulates

0.506

Hssad1 specifically phosphorylated wee1a, cdc25-c, and -b on ser-642, ser-216, and ser-361 in vitro, respectivelyphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3

SIGNOR-124839

P63000

Q7Z5H3

0

gtpase-activating protein

down-regulates activity

0.529

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260477

P21359

P01112

1

gtpase-activating protein

down-regulates activity

0.813

Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation

SIGNOR-204357

Q92538

P68400

0

phosphorylation

down-regulates quantity by destabilization

0.2

We show that, in mitosis, GBF1 is phosphorylated on Ser292 and Ser297 by casein kinase-2 allowing recognition by the F-box protein βTrCP. GBF1 interaction with βTrCP recruits GBF1 to the SCFβTrCP ubiquitin ligase complex, triggering its degradation.

SIGNOR-277398

Q05655

P11831

1

phosphorylation

down-regulates activity

0.2

Protein kinase C delta blocks immediate-early gene expression in senescent cells by inactivating serum response factor.|The phosphorylation of T160 of SRF by PKC delta in vitro and in vivo led to loss of SRF DNA binding activity.

SIGNOR-279347

Q04760

P07948

0

phosphorylation

up-regulates activity

0.2

We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).

SIGNOR-276186

P25440

Q9ULU4

1

relocalization

up-regulates activity

0.287

ZMYND8 and BRD2 therefore work together to protect H4Ac domains from HDAC activity.|Further, when BRD2 was depleted, ZMYND8 accumulation was lost (Fig. 2e), indicating that either BRD2, or the underlying H4Ac, is required for ZMYND8 loading.

SIGNOR-262036

P29597

Q13261

0

null

up-regulates

0.245

Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated

SIGNOR-256253

P68431

Q9NR48

0

trimethylation

up-regulates activity

0.2

We show that human ASH1L specifically methylates histone H3 Lys-36. Our data implicate that there may be a regulatory mechanism of ASH1L histone methyltransferases

SIGNOR-269055

Q16576

Q13131

0

phosphorylation

up-regulates activity

0.2

AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314| interaction between RBBP7 and HAT1 is required for acetyltransferase activity

SIGNOR-264784

P51955

P62136

0

dephosphorylation

down-regulates

0.374

Nek2 is activated by autophosphorylation, and its dephosphorylation is catalyzed by pp1

SIGNOR-152949

O75122

P53350

0

phosphorylation

up-regulates activity

0.622

Cdk1 and Plk1 mediate a CLASP2 phospho-switch that stabilizes kinetochore-microtubule attachments.|Finally, we demonstrate that CLASP2 phosphorylation on S1234 and S1255 by Cdk1 and Plk1, respectively, increases with conditions that allow the establishment and stabilization of KT\u2013MT attachments ( xref ).

SIGNOR-278321

P12004

P49459

0

ubiquitination

up-regulates

0.476

Pcna is mono-ubiquitinated through rad6 and rad18, modified by lysine-63-linked multi-ubiquitination--which additionally requires mms2, ubc13 and rad5--and is conjugated to sumo by ubc9. The first of these is monoubiquitination of lysine 164 on one or more of the pcna subunits by the e2-e3 complex of rad6-rad18.

SIGNOR-92737

Q04760

P17948

0

phosphorylation

up-regulates activity

0.2

We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).

SIGNOR-276190

Q13315

Q504Q3

1

phosphorylation

up-regulates activity

0.2

Here, we identify that USP52 directly interacts with and deubiquitinates CtIP, thereby promoting DNA end resection and HR. Mechanistically, USP52 removes the ubiquitination of CtIP to facilitate the phosphorylation and activation of CtIP at Thr-847. In addition, USP52 is phosphorylated by ATM at Ser-1003 after DNA damage, which enhances the catalytic activity of USP52.

SIGNOR-273508

Q7KZI7

P17612

0

phosphorylation

down-regulates activity

0.2

Here, we found the disruption of microtubule and neurite outgrowth induced by MARK2 overexpression was blocked by active PKA. The interaction between PKA and MARK2 was confirmed by coimmunoprecipitation and immunocytochemistry both in vitro and in vivo. PKA was found to inhibit MARK2 kinase activity by phosphorylating a novel site, serine 409.

SIGNOR-276870

P06730

P17252

0

phosphorylation

up-regulates

0.382

Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the translational repressors, 4E-binding proteins.[..] This suggests a two-step model for the phosphorylation (and activation) of eIF4E by growth factors and hormones: first, dissociation of eIF4E .

SIGNOR-248945

Q13444

P06239

0

phosphorylation

up-regulates

0.349

Hck, and to a lesser extent lck, phosphorylated the adam15. Deletion and point mutation analysis of the adam15 cytoplasmic domain confirmed the importance of the proline-rich motifs for grb2 and lck binding and indicated the regulatory nature of tyr(715) and tyr(735). These data demonstrate selective, phosphorylation-dependent interactions of adam15 with src family ptks and grb2, which highlight the potential for integration of adam functions and cellular signaling.

SIGNOR-112931

O14757

Q9UJM3

1

phosphorylation

down-regulates activity

0.326

Our results suggest that Chk1 phosphorylates Mig-6 on Ser 251, resulting in the inhibition of Mig-6, and that Chk1 acts as a positive regulator of EGF signalling. This is a novel function of Chk1.

SIGNOR-276411

O14647

Q13426

1

relocalization

up-regulates quantity

0.2

CHD2 Promotes the Recruitment of Core NHEJ Factors. overexpression of ATPase-dead CHD2 (K515R; Figure S5F), but not wild-type CHD2, also reduced the recruitment of XRCC4 (Figure 5E). Together, these findings suggest that the chromatin remodeling activity of CHD2 promotes the efficient assembly of NHEJ complexes at DSBs.

SIGNOR-264528

O95786

P19784

0

phosphorylation

down-regulates activity

0.2

Phosphorylation of RIG-I by casein kinase II inhibits its antiviral response.Threonine at amino acid (aa) 770 and serine at aa 854 to 855 of RIG-I are phosphorylated by casein kinase II (CK2) in the resting state of the cell and dephosphorylated when cells are infected by RNA virus.

SIGNOR-276285

O43255

Q92667

1

polyubiquitination

down-regulates quantity by destabilization

0.507

Seven In-Absentia Homolog 2 (Siah2), an E3-ubiquitin ligase whose expression is induced in hypoxic conditions, formed a complex and degraded AKAP121.

SIGNOR-272641

P49675

P17676

0

transcriptional regulation

up-regulates quantity by expression

0.365

Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells.

SIGNOR-254046

P06241

P04629

1

phosphorylation

up-regulates activity

0.254

Here, we demonstrate that Fyn can directly phosphorylate the intracellular domain of TrkA and that its kinase activity towards Trk is increased by GPCR stimulation ( Fig. 4 ).

SIGNOR-279410

O60260

Q9NX09

1

ubiquitination

down-regulates quantity by destabilization

0.2

In conclusion, our work in cellular and animal models and in human samples strongly indicates that RTP801 is a substrate of parkin and that RTP801 elevation due to parkin loss of function in both AR-JP and sporadic Parkinson's disease may contribute to neurodegeneration.|We showed that parkin poly-ubiquitinates RTP801, both in vitro and in vivo.

SIGNOR-278560

Q03014

Q01196

0

transcriptional regulation

up-regulates quantity

0.271

We identified Hhex as a direct target of RUNX1 and FLT3-ITD stimulation and confirmed high HHEX expression in FLT3-ITD AMLs. HHEX could replace RUNX1 in cooperating with FLT3-ITD to induce AML.

SIGNOR-256305

Q96EB6

Q9UPT9

0

deubiquitination

up-regulates quantity by stabilization

0.534

USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells.

SIGNOR-261561

Q16644

Q6JBY9

1

phosphorylation

down-regulates activity

0.482

Human CapZIP was phosphorylated at Ser-179 and Ser-244 by MAPKAP-K2 (mitogen-activated protein kinase-activated protein kinase 2) or MAPKAP-K3 in vitro. In the present paper we have identified CapZIP as a protein that is phosphorylated exceptionally rapidly by several SAPKs in vitro (Figure 4), and which is expressed in muscles and immune cells. Both MAPKAP-K2 and MAPKAP-K3 phosphorylated CapZIP at Ser-179 in vitro. An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.

SIGNOR-263082

Q13363

P12830

1

transcriptional regulation

down-regulates quantity by repression

0.6

Carboxyl-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor with oncogenic potential. We found CtBP1 was recruited to the promoter regions of Brca1 and E-cadherin genes in breast cancer cells.

SIGNOR-259197

P38398

O14965

0

phosphorylation

up-regulates

0.677

Previous studies have shown that the brca1 breast cancer tumor suppressor also localizes to the centrosome and that brca1 inactivation results in loss of the g(2)-m checkpoint. We demonstrate here that aurora-a physically binds to and phosphorylates brca1. We propose that brca1 phosphorylation by aurora-a plays a role in g(2) to m transition of cell cycle

SIGNOR-123065

P12830

P54253

0

transcriptional regulation

up-regulates quantity by expression

0.343

Overexpression of the CtBP2 protein enhanced the repression activity of the E-cadherin promoter in a dose-dependent manner, whereas overexpression of ataxin-1 increased the activity of the E-cadherin promoter in a dose-dependent manner

SIGNOR-261577

P57764

P49662

0

cleavage

up-regulates activity

0.647

Co-expression of GSDMD with caspase-1, 4, 5 or 11 but not apoptotic caspases (caspase-2, 8 and 9) in 293T cells induced the same cleavage of GSDMD|inflammatory caspases specifically cleave GSDMD after the 272FLTD275 (or 273LLSD276) sequence |

SIGNOR-256417

Q969V5

O00429

1

sumoylation

up-regulates activity

0.534

Through a detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms.

SIGNOR-274128

Q05397

P31749

0

phosphorylation

up-regulates activity

0.43

In mouse embryonic fibroblasts, AKT1 phosphorylates S695 and T700 on FAK ( xref ) and in human colon cancer cells AKT1 phosphorylates S517, S601, and S695 on FAK ( xref , xref ).|This suggests that further activation of FAK by AKT1 ( beyond that of Pten loss alone ) is required to promote FA turnover , increase tumor invasion , and ultimately elicit brain metastasis .

SIGNOR-279777

Q07869

P28482

0

phosphorylation

up-regulates activity

0.578

We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution.

SIGNOR-249434

P16591

P35222

1

phosphorylation

down-regulates activity

0.72

Interaction of beta-catenin with alpha-catenin is regulated by the phosphorylation of beta-catenin Tyr-142. This residue can be phosphorylated in vitro by Fer or Fyn tyrosine kinases. Transfection of these kinases to epithelial cells disrupted the association between both catenins.

SIGNOR-251131

Q13683

P15173

0

transcriptional regulation

up-regulates quantity by expression

0.283

Only myogenin and MyoD were able to efficiently trans-activate the alpha7 promoter-CAT construct (Fig. 7). Myogenin trans-activated the promoter by _2-fold whereas MyoD was able to trans-activate by nearly 4-fold, indicating that both of these factors may play a role in alpha7 gene expression during muscle development.

SIGNOR-241521

Q9NWF9

Q9NR97

1

polyubiquitination

down-regulates quantity by destabilization

0.257

E3 ligase RNF216 (ring finger protein 216) targets TLR8 for ubiquitination and degradation.

SIGNOR-272257

Q13557

O15084

1

phosphorylation

down-regulates activity

0.2

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

SIGNOR-264793