GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P22736	O60858	0	ubiquitination	down-regulates quantity by destabilization	0.2	These results suggest that Trim13 activity mediates Nur77 ubiquitination, leading to its degradation.	SIGNOR-278564
Q92905	Q9NZQ7	1	deubiquitination	up-regulates quantity by stabilization	0.2	The results suggested that TNF-α upregulates expression of CSN5, which interacts and deubiquitinates PD-L1 for protein stabilization.	SIGNOR-274977
P01116	Q8N653	0	ubiquitination	down-regulates activity	0.25	By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine-170. LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane.	SIGNOR-269068
O15530	Q9UBS0	1	phosphorylation	up-regulates activity	0.609	Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70beta1 was indispensable for the kinase activity. In contrast, a p70beta1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70beta1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities.	SIGNOR-250272
P00519	Q06830	1	phosphorylation	down-regulates activity	0.387	Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation.	SIGNOR-276278
Q96BN8	P0CG48	1	cleavage	up-regulates quantity	0.717	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270820
P42574	O43903	1	cleavage	up-regulates	0.451	We now demonstrate that gas2 is a substrate of caspase-3 but not of caspase-6. Proteolytic processing both in vitro and in vivo is dependent on aspartic residue 279.	SIGNOR-72347
P51812	Q99990	1	phosphorylation	down-regulates activity	0.2	Site-directed mutagenesis and immunoprecipitation experiments revealed that RSK2 phosphorylated VGLL1 at S84 in the presence of TGF-β. Mutation of VGLL1 at S84 suppressed VGLL1-TEAD4 binding and the subsequent transcriptional activation of matrix metalloprotease 9 (MMP9).	SIGNOR-273842
P23458	P42226	1	phosphorylation	up-regulates activity	0.765	IL-4-stimulated Stat6 activation is mediated by Jak1 whereas Tyk2 is required for Stat6 activation in IL-13-treated monocytes	SIGNOR-249531
Q9Y4H2	P16220	0	transcriptional regulation	up-regulates quantity by expression	0.342	Taken together, these results indicate that the IRS2 gene is a direct target for CREB action in vivo	SIGNOR-278145
P11802	Q12778	1	phosphorylation	up-regulates activity	0.46	In summary, our study showed that Cdk4 phosphorylates and activates PAX3-FOXO1, thereby promoting its oncogenic function.\|These findings suggest that Cdk4 phosphorylates the Ser 430 residue of PAX3-FOXO1 in vitro .	SIGNOR-278377
Q96J92	Q9UEW8	1	phosphorylation	up-regulates activity	0.507	Vitari et al. (76) and Moriguchi et al. (52) demonstrated that WNK4 bound and phosphorylated PASK at Thr-233 and Ser-373 in mammalian cells.\| this phosphorylation event activates PASK, which in turn phosphorylates and activates NKCC1	SIGNOR-264641
Q15746	Q05682	1	phosphorylation	down-regulates	0.641	Phosphorylation of caldesmon by myosin light chain kinase increases its binding affinity for phosphorylated myosin filaments.	SIGNOR-166049
P11142	Q9UNE7	0	polyubiquitination	down-regulates quantity by destabilization	0.728	BAG-1 stimulates CHIP-induced degradation of the glucocorticoid hormone receptor (GR). A model for the cooperation of CHIP and BAG-1 in coupling Hsc/Hsp70 to the ubiquitin/proteasome system. CHIP associates with Hsc/Hsp70 via its TPR chaperone adaptor (TPR) and, at the same time, recruits E2 ubiquitin-conjugating enzymes of the Ubc4/5 family to the chaperone complex. BAG-1 binds to Hsp70 via its BAG domain (BAG) and utilizes its ubiquitin-like domain (ubl) for proteasomal association	SIGNOR-272588
Q00987	P00519	0	phosphorylation	down-regulates activity	0.716	C-abl binds and phosphorylates mdm2 in vivo and in vitro;phosphorylation of mdm2 by c-abl impairs the inhibition of p53 by mdm2.	SIGNOR-90512
Q00535	Q02078	1	phosphorylation	down-regulates activity	0.506	Cdk5-mediated inhibition of the protective effects of transcription factor mef2 in neurotoxicity-induced apoptosis.We have identified the prosurvival transcription factor mef2 as a direct nuclear target of cdk5. Cdk5 phosphorylates mef2 at a distinct serine in its transactivation domain to inhibit mef2 activity.	SIGNOR-100574
P53396	P42345	0	phosphorylation	up-regulates activity	0.332	Biochemical studies indicated that mTOR directly and specifically phosphorylated ACL on Ser 455 in vitro.	SIGNOR-278962
P04637	O15391	0	transcriptional regulation	up-regulates quantity by expression	0.572	YY2 activated the p53 promoter. However, in contrast to YY1, which represses the activity of c-Fos, YY2 increased the activity of the c-Fos promoter.	SIGNOR-266213
Q9C0B5	P04637	0	transcriptional regulation	up-regulates quantity by expression	0.2	Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y	SIGNOR-261150
O15392	P53350	0	phosphorylation	up-regulates	0.583	Thus, we conclude that plk1-mediated phosphorylation of sur at ser20 is critical for accurate chromosome segregation\|SUR (survivin)	SIGNOR-170460
Q9BRS8	P31749	0	phosphorylation	up-regulates activity	0.353	Akt dependent phosphorylation of LARP6. We provide the first description that LARP6 is phosphorylated at multiple sites and that phosphorylation of S451 is critical to activate the protein in type I collagen biosynthesis.	SIGNOR-277213
P06239	P28482	0	phosphorylation	up-regulates activity	0.583	Phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62.\|phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation.	SIGNOR-249412
Q96KS0	P30566	1	hydroxylation	up-regulates activity	0.2	ADSL is hydroxylated by EglN2 on Proline 24. An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. ADSL regulates cMYC protein level through adenosine levels	SIGNOR-266613
P62714	Q05655	1	dephosphorylation	down-regulates activity	0.3	PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.\|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex	SIGNOR-248595
Q9Y253	Q96PM5	0	monoubiquitination	down-regulates activity	0.581	Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues.we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions.These results suggest that Pirh2 monoubiquitinates PolH at one of the four lysine residues (K682, K686, K694, and K709).	SIGNOR-272733
Q99102	P42224	0	transcriptional regulation	up-regulates quantity by expression	0.393	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-254099
P12931	Q9Y2X7	1	phosphorylation	up-regulates activity	0.542	Tyrosines 246 and 293 are required to hold GIT1 in a closed conformation.Hyperphosphorylation of GIT1-N by Src and pervanadate does not affect its binding in vitro to full length GIT1 proteins. Mutations Y246E and Y293E of GIT1 enhance binding to paxillin.	SIGNOR-276627
P14921	Q93084	1	transcriptional regulation	up-regulates quantity by expression	0.326	Ets-1 was able to transactivate the SERCA3 promoter in MoBr 204 as cotransfection of an Ets-1 expression vector increased the activity of the −97/+301-Luc construct by 6-fold.	SIGNOR-261601
Q96TA2	O60313	1	cleavage	up-regulates activity	0.455	YME1L cleaves OPA1 at S2 and S3 site to transform into L-OPA1 to induce fusion when cells are faced with increased oxidative phosphorylation, whereas OMA1 cleaves OPA1 at an S1 site to transform into S-OPA1, resulting in the fragmented response to cellular stress, mitochondrial dysfunction, or deletion of YME1L	SIGNOR-274140
O94992	Q9UGL1	1	relocalization	up-regulates activity	0.2	We previously reported that the tumor suppressor HEXIM1 is a mediator of KDM5B recruitment to its target genes, and HEXIM1 is required for the inhibition of nuclear hormone receptor activity by KDM5B.	SIGNOR-273439
Q12904	P45983	0	phosphorylation	down-regulates	0.473	We further demonstrated that serine-140 residue of aimp1 was phosphorylated by jnk and alanine mutation of serine-140 suppressed lps-induced cell surface altogether, these results suggest that aimp1 is phosphorylated by jnk through tlr-myd88 pathway and lose the regulatory activity for er retention of gp96expression of gp96.	SIGNOR-165763
P49841	P16220	1	phosphorylation	up-regulates activity	0.691	GSK-3 can phosphorylate CREB at S129 Transactivation of CREB is significantly reduced (p ≤ 0.05) by 86% for the S129A mutant	SIGNOR-251233
Q99675	P00533	1	polyubiquitination	down-regulates quantity by destabilization	0.2	CGRRF1 ubiquitinates EGFR through K48-linked ubiquitination, which leads to proteasome degradation.	SIGNOR-272220
P23443	Q92934	1	phosphorylation	down-regulates activity	0.295	P70S6K, the downstream target of mTORC1, can phosphorylate and inactivate pro apoptotic BAD by producing a reaction that disrupts BAD 's binding to other pro apoptotic molecules thereby allowing cell survival.\|p70S6K, the downstream target of mTORC1, can phosphorylate and inactivate pro-apoptotic BAD by producing a reaction that disrupts BAD\u2019s binding to other pro-apoptotic molecules thereby allowing cell survival. xref , xref On the other hand, in a recent study, Li et al showed that increased expression of anti-apoptotic BCL2 was induced in myeloid progenitor cells upon activation of p76S6K, thereby promoting cell survival. xref Further studies are needed to better understand the effect of rapamycin and its derivatives on apoptosis in various cancer cells.	SIGNOR-280016
Q8IYD8	Q92547	1	relocalization	up-regulates	0.418	The enzymatic activity of fan cm is then required to remodel and stabilize the fork to allow topbp1 access to activate atr , in a 9-1-1-independent manner.	SIGNOR-164765
Q5JUK2	Q68G74	1	transcriptional regulation	up-regulates quantity by expression	0.486	Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters.	SIGNOR-266076
P04035	Q86TM6	0	polyubiquitination	down-regulates quantity by destabilization	0.562	In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation.Human HRD1 appears to be involved in the basal degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase but not in the degradation that is regulated by sterols.	SIGNOR-272594
Q9NP62	Q14012	0	phosphorylation	up-regulates activity	0.388	We show that Epac1 and Rap1, in response to cAMP, activate CaMKI to phosphorylate Ser47 in GCM1. This phosphorylation facilitates the interaction between GCM1 and the desumoylating enzyme SENP1 and thereby leads to GCM1 desumoylation and activation.	SIGNOR-262680
Q13535	O60934	1	phosphorylation	up-regulates	0.785	We demonstrate that mrn and atr/atr-interacting protein (trip) interact with each other, and the forkhead-associated/breast cancer c-terminal domains (fha/brct) of nbs1 play a significant role in mediating this interaction. Mutations in the fha/brct domains do not prevent atr activation but specifically impair atr-mediated nbs1 phosphorylation at ser-343, which results in a defect in the s-phase checkpoint.	SIGNOR-155214
P98177	O43638	0	transcriptional regulation	down-regulates quantity by repression	0.2	Fkhl18 suppressed the transcriptional activity of FoxO3a and FoxO4.	SIGNOR-261611
P45983	Q8WTR2	0	dephosphorylation	down-regulates	0.421	Skrp1 was highly specific for c-jun n-terminal kinase (jnk) in vitro and effectively suppressed the jnk activation in response to tumor necrosis factor alpha or thapsigargin skrp1 does not bind directly to its target jnk, but co-precipitation of skrp1 with the mapk kinase mkk7, a jnk activator, was found in vitro and in vivo.	SIGNOR-117260
Q9UK17	P09769	0	phosphorylation	up-regulates activity	0.2	These results indicate that Y108 (for Src-family kinases) and Y136 (for EGFR kinase) are involved in the tyrosine phosphorylation of hKv4.3 channels.	SIGNOR-276394
P84022	P12931	0	phosphorylation	up-regulates activity	0.377	Although the role of ERK in mediating phosphorylation of Smad2/3 remains to be investigated, our data indicate that early Smad3 phosphorylation is independent of transient EGFR transactivation and ERK1/2 activation initiated by HB-EGF release, whereas Src mediated chronic EGFR transactivation and ERK1/2 activation involve late Smad3 activation induced by TGF-beta1.\|Inhibition of Src not only decreases Smad3 phosphorylation but also decreases phosphorylation dependent nuclear translocation of Smad2/3, suggesting that Src kinase could modulate Smad3 activity.	SIGNOR-279292
Q9H204	P06241	0	phosphorylation	up-regulates	0.446	To unravel the cellular functions of magicin, we used a yeast two-hybrid system and identified fyn tyrosine kinase as a specific binding partner for magicin. Fyn phosphorylates magicin in vitro.	SIGNOR-148700
O00533	Q01484	1	relocalization	up-regulates quantity	0.409	Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.	SIGNOR-266722
Q92793	P52630	1	acetylation	up-regulates activity	0.557	STAT2 is another important component of ISGF3 complex, and its acetylation was similar to IFNaR2 and IRF9 acetylation in many respects: CBP downregulation largely abolished STAT2 acetylation induction by IFNa (Figure 6A), and CBP was more potent than transferases tested in catalyzing STAT2 acetylation (Figure 6B). [...] Figure 6 (I) STAT2-K390R substitution has reduced activity in ISGF3 complex formation.	SIGNOR-217891
P32004	P17252	0	phosphorylation	down-regulates activity	0.2	CKII phosphorylates T1172 of the L1 CD and phosphorylation of T1172 is responsible for loss of 2C2 signal.	SIGNOR-276283
P00519	Q15746	1	phosphorylation	up-regulates	0.3	Nonmuscle myosin light chain kinase (nmmlck), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity	SIGNOR-167989
P17676	P00519	0	phosphorylation	up-regulates	0.399	The y79 amino acid residue of c/ebpbeta was phosphorylated by c-abl or arg. The phosphorylation of c/ebpbeta resulted in an increased c/ebpbeta stability and a potentiation of c/ebpbeta transcription activation activity in cells	SIGNOR-186423
P05019	P42229	0	transcriptional regulation	up-regulates quantity by expression	0.433	Growth hormone induces insulin-like growth factor-I gene transcription by a synergistic action of STAT5 and HNF-1α	SIGNOR-251743
Q15034	Q04206	1	ubiquitination	down-regulates quantity by destabilization	0.325	Our data so far suggest that HERC3 reduces NF-kappaB transcriptional activity by binding to the proteasome and delivering RelA for degradation.\|We show that HERC3 mediates ubiquitination of RelA on two distinct lysine residues, K195 and K315.	SIGNOR-278546
P18146	P10645	1	transcriptional regulation	up-regulates quantity by expression	0.2	Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation.	SIGNOR-254265
Q96D31	P05771	0	phosphorylation	down-regulates	0.2	We propose that pkc suppresses soce and crac channel function by phosphorylation of orai1 at n-terminal serine residues ser-27 and ser-30.	SIGNOR-166040
P48764	Q6P0Q8	0	phosphorylation	down-regulates activity	0.456	Coexpression of MAST205 inhibits the activity of Na +/H+ exchanger NHE3.\|Consistent with these results, we found that MAST205 phosphorylated NHE3 under in vitro conditions.	SIGNOR-279229
O60260	Q6NUN9	1	polyubiquitination	down-regulates quantity by destabilization	0.2	. Parkin ubiquitinates and regulates the ubiquitin proteasomal degradation of PARIS	SIGNOR-272758
P42771	P35226	0	transcriptional regulation	down-regulates quantity by repression	0.455	In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity,	SIGNOR-253385
Q9Y2H1	Q9Y6E0	0	phosphorylation	up-regulates	0.441	Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity.	SIGNOR-142510
P11387	P00519	0	phosphorylation	up-regulates activity	0.399	This study demonstrates that ABL1-dependent phosphorylation up-regulates topo I activity. The ABL1 SH3 domain bound directly to the N-terminal region of topo I. The results demonstrate that ABL1 phosphorylated topo I at Tyr268 in core subdomain II.	SIGNOR-260775
Q15797	O95819	0	phosphorylation	down-regulates activity	0.2	Msn kinases directly phosphorylate α-helix 1 of Smad. we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for α-helix 1 phosphorylation.	SIGNOR-276335
P27361	P62136	0	dephosphorylation	down-regulates	0.444	P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases	SIGNOR-103155
P06681	P48740	0	cleavage	up-regulates activity	0.537	The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase	SIGNOR-263420
P63279	Q13485	1	sumoylation	up-regulates	0.626	The mh1 domain of smad4 was shown to associate physically with ubc9, the ubiquitin carrier protein (e2) conjugating enzyme in sumoylation. In cultured cells, smad4 is modified by sumo-1 at the endogenous level. The sumoylation sites were identified as two evolutionarily conserved lysine residues, lys-113 and lys-159, in the mh1 domain. We found that the mutations at lys-113 and lys-159 did not alter the ability of smad4 to form a complex with smad2 and fast on the mix.2 promoter. Importantly, sumo-1 overexpression enhanced tgf-beta-induced transcriptional responses. These findings identify sumoylation as a unique mechanism to modulate smad4-dependent cellular responses	SIGNOR-98997
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
P28482	P15923	1	phosphorylation	down-regulates quantity by destabilization	0.36	Notch-induced degradation requires phosphorylation of E47 by p42/p44 MAP kinases. \|Wild_type E47 but not the Mm mutant reacted to the antibodies, suggesting that E47 is at least phosphorylated at the M2 site (Figure 3A)\|anti_phospho_M2 peptide (SSPSpTPVGSPQG)	SIGNOR-249451
P46527	Q86TM6	0	ubiquitination	down-regulates quantity by destabilization	0.2	The E3 ligase activity of Hrd1 is required for p27 kip1 ubiquitination, because co-expression of Hrd1 containing an alanine point mutation at the critical cysteine within the RING E3 ligase region (Hrd1/CA) failed to enhance p27 kip1 ubiquitination (XREF_FIG).\|Therefore, our study identifies Hrd1 as an E3 ligase of p27 kip1 and establishes that Hrd1 mediated p27 kip1 degradation plays an important role in T-cell immunity.	SIGNOR-278786
Q13362	P04637	1	dephosphorylation	up-regulates quantity by stabilization	0.611	Ablation of the B56gamma protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis. To investigate the molecular mechanisms, we have shown that the endogenous B56gamma protein level and association with p53 increase after DNA damage. Finally, we demonstrate that Thr55 dephosphorylation is required for B56gamma3-mediated inhibition of cell proliferation and cell transformation.	SIGNOR-268154
P27361	P19419	1	phosphorylation	up-regulates	0.601	Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency.	SIGNOR-34669
O95471	Q13363	0	transcriptional regulation	down-regulates quantity by repression	0.2	ChIP assays revealed that SNAI1P is recruited on the CLDN7 gene promoter along with the co-repressor CtBP1 and the effector HDAC1.	SIGNOR-254105
Q15418	P49841	1	phosphorylation	down-regulates	0.359	S6k then phosphorylates the same serine residue on gsk3 that is targeted by pkb/akt (fig. 1), thereby inhibiting its activity.	SIGNOR-110917
P10644	Q13976	0	phosphorylation	up-regulates activity	0.234	In this study, we further examined the potential of RIα phosphorylation to regulate physiologically relevant "desensitization" of PKAc activity. First, the serine 101 site of RIα was validated as a target of PKGIα phosphorylation both in vitro and in cells.These findings suggest that RIα phosphorylation may be a novel mechanism to circumvent the requirement of cAMP stimulus to activate type I PKA in cells.	SIGNOR-277383
Q15672	P31751	0	phosphorylation	up-regulates activity	0.398	AKT2 phosphorylates Twist1 at S42 to enhance Twist1 mediated E-cadherin suppression.	SIGNOR-279137
P08254	P10915	1	cleavage	down-regulates quantity by destabilization	0.384	Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix.	SIGNOR-256330
P19474	Q02556	1	ubiquitination	down-regulates quantity	0.638	From these results, we concluded that TRIM21 down-regulated IRF8 and enhanced the secretion of IL-12/23p40 in BD monocytes.\|IRF8 is ubiquitinated by TRIM21, which promotes secretion of IL-12/23p40 after TLR/IFN-\u03b3 stimulation xref .	SIGNOR-278791
Q99640	P45983	0	phosphorylation	up-regulates	0.336	A kinase assay using gst-myt1 revealed that active jnk1 or jnk3, but not jnk2, phosphorylated myt1 in vitro.	SIGNOR-183899
Q6ZVD8	Q13043	1	dephosphorylation	up-regulates activity	0.2	PHLPPs dephosphorylate Mst1 on the T387 inhibitory site, which activate Mst1 and its downstream effectors p38 and JNK to induce apoptosis.	SIGNOR-248730
Q15418	P03372	1	phosphorylation	up-regulates	0.494	Serine 167 is the major phosphorylation site on the human estrogen receptor. Phosphorylation is mediated by casein kinase ii.	SIGNOR-34113
O43679	Q9NVW2	0	polyubiquitination	down-regulates quantity by destabilization	0.452	Here we identify RLIM as a ubiquitin protein ligase that is able to target CLIM cofactors for degradation through the 26S proteasome pathway.	SIGNOR-272616
Q9UQM7	P16949	1	phosphorylation	down-regulates	0.403	Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. In vitro, ser16 of recombinant human stathmin was phosphorylated also by purified cam kinase ii, and in vivo, cam kinase ii activity was indeed stimulated in cd2-triggered jurkat cells. Altogether, our results favor an association of cam kinase ii activity with costimulatory signals of t lymphocyte activation and phosphorylation of stathmin on ser16.	SIGNOR-149640
P78344	P06493	0	phosphorylation	up-regulates activity	0.339	To test whether CDK1 phosphorylates T508, Flag-DAP5 was purified from dox-induced HEK293 cells and incubated with active recombinant JNK2 or CDK1 in the presence of ATP (Fig. 3G). DAP5(T508) was phosphorylated only upon incubation with CDK1 (Fig. 3G).	SIGNOR-266387
Q9GZV5	P48730	0	phosphorylation	down-regulates	0.366	LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP)	SIGNOR-234438
P45985	P54762	0	relocalization	up-regulates activity	0.2	The phosphorylated CNK1 interacts with ephrinB1. The binding of ephrinB1 to CNK1 connects RhoA and p115RhoGEF with ephrinB1-associated MKK4, promoting JNK activation and cell migration.	SIGNOR-275922
P67775	O43524	1	dephosphorylation	up-regulates	0.402	Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a.	SIGNOR-163680
Q92556	P08631	0	phosphorylation	up-regulates	0.606	We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts.	SIGNOR-138154
Q96KK5	Q86Y13	0	monoubiquitination	up-regulates activity	0.2	2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271760
Q92973	P35637	1	relocalization	up-regulates activity	0.642	The C-terminal nuclear localization sequence of FUsed in Sarcoma (FUS-NLS) is critical for its nuclear import mediated by transportin (Trn1).	SIGNOR-262101
Q8NHZ8	Q9NRM7	0	phosphorylation	up-regulates activity	0.46	LATS1 and LATS2 phosphorylate CDC26 to modulate assembly of the tetratricopeptide repeat subcomplex of APC/C\|Overall, these results suggest that LATS1/2 are novel kinases involved in APC/C phosphorylation and indicate a direct regulatory link between LATS1/2 and APC/C	SIGNOR-275474
P42229	P60484	0	dephosphorylation	down-regulates	0.439	The forced expression of pten in the eol-1r cells dephosphorylated akt, erk and stat5 /eol-1r cells showed epigenetic silencing of the phosphatase and tensin homolog deleted on chromosome ten (pten) gene. Exposure of eol-1r cells to imatinib failed to dephosphorylate akt, erk and stat5, although pdgfr? Was effectively inactivated. The forced expression of pten negatively regulated these signal pathways and sensitized eol-1r cells to imatinib.	SIGNOR-166481
Q8N699	P01106	0	transcriptional regulation	up-regulates quantity by expression	0.298	MT-MC1 is a widely expressed nuclear protein whose overexpression, unlike that of c-Myc targets reported previously, recapitulates multiple c-Myc phenotypes. These include promotion of apoptosis, alteration of morphology, enhancement of anchorage-independent growth, tumorigenic conversion, promotion of genomic instability, and inhibition of hematopoietic differentiation. The MT-MC1 promoter is a direct c-Myc target; it contains two consensus E-box elements, both of which bind c-Myc.	SIGNOR-261736
P68400	P60484	1	phosphorylation	down-regulates activity	0.68	The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity	SIGNOR-89830
Q9NR50	P20042	1	guanine nucleotide exchange factor	up-regulates activity	0.848	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.	SIGNOR-269131
O75116	Q09472	1	phosphorylation	up-regulates activity	0.297	Nuclear Rho kinase, ROCK2, targets p300 acetyltransferase.\|p300 acetyltransferase activity is dependent on its phosphorylation status in cells, and p300 phosphorylation by ROCK2 results in an increase in its acetyltransferase activity in vitro.	SIGNOR-279482
P23467	P35968	1	dephosphorylation	down-regulates activity	0.454	VE-PTP/VEGFR2 complex formation resumes with time, leading to dephosphorylation and deactivation of VEGFR2 (right). B) In VE-PTP-deficient cells, such as after siRNA treatment, VEGFR2 activation (middle) is exaggerated, leading to increased phosphorylation at the Y951 and Y1175 phosphorylation sites	SIGNOR-248441
O95644	P60568	1	transcriptional regulation	up-regulates quantity by expression	0.565	Together, our results demonstrate that dnNFAT inhibits the production of IL-2. Thus, the NFAT transcription factor contributes to the regulation of IL-2 gene expression and therefore plays a critical role in the initiation of immune responses.	SIGNOR-275405
O00443	P08069	0	phosphorylation	up-regulates	0.275	Analysis of the ability of the full-length igfr and its mutant receptors described above to associate with phosphatidylinositol 3 kinase indicated that the association required ptk activity and tyrosine [?] Phosphorylation of the receptors and correlated well with their transforming activities	SIGNOR-32076
Q13002	P12931	0	phosphorylation	up-regulates activity	0.372	GluK2 binds to Src, and the tyrosine residue at position 590 (Y590) on GluK2 is a major site of phosphorylation by Src kinases. GluK2 phosphorylation at Y590 is responsible for increases in whole-cell currents and calcium influx in response to transient kainate stimulation.	SIGNOR-276850
P27361	P41235	1	phosphorylation	down-regulates activity	0.494	Activation of the ERK1/2 signalling pathway, inducing proliferation and survival, inhibits the expression of HNF4\u03b1.\|Here we have demonstrated that ERK1 is able to phosphorylate HNF4\u03b1 at several serine and threonine residues.	SIGNOR-279070
P19474	P09471	0	null	down-regulates	0.2	Mechanistically, GNAO1 recruited TRIM21 and facilitated TRIM21-mediated ubiquitination.	SIGNOR-278888
O60674	P51692	1	phosphorylation	up-regulates	0.865	Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein	SIGNOR-56894
Q03405	O95644	0	transcriptional regulation	up-regulates quantity by expression	0.2	Inducible podocyte-specific expression of constitutively active NFATc1 increased podocyte uPAR expression by binding to the Plaur gene promoter (encoding uPAR) in chromatin immunoprecipitation assays.	SIGNOR-253336
P53350	P51587	1	phosphorylation	down-regulates activity	0.539	M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1	SIGNOR-102486

P22736

O60858

0

ubiquitination

down-regulates quantity by destabilization

0.2

These results suggest that Trim13 activity mediates Nur77 ubiquitination, leading to its degradation.

SIGNOR-278564

Q92905

Q9NZQ7

1

deubiquitination

up-regulates quantity by stabilization

0.2

The results suggested that TNF-α upregulates expression of CSN5, which interacts and deubiquitinates PD-L1 for protein stabilization.

SIGNOR-274977

P01116

Q8N653

0

ubiquitination

down-regulates activity

0.25

By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine-170. LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane.

SIGNOR-269068

O15530

Q9UBS0

1

phosphorylation

up-regulates activity

0.609

Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70beta1 was indispensable for the kinase activity. In contrast, a p70beta1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70beta1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities.

SIGNOR-250272

P00519

Q06830

1

phosphorylation

down-regulates activity

0.387

Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation.

SIGNOR-276278

Q96BN8

P0CG48

1

cleavage

up-regulates quantity

0.717

Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.

SIGNOR-270820

P42574

O43903

1

cleavage

up-regulates

0.451

We now demonstrate that gas2 is a substrate of caspase-3 but not of caspase-6. Proteolytic processing both in vitro and in vivo is dependent on aspartic residue 279.

SIGNOR-72347

P51812

Q99990

1

phosphorylation

down-regulates activity

0.2

Site-directed mutagenesis and immunoprecipitation experiments revealed that RSK2 phosphorylated VGLL1 at S84 in the presence of TGF-β. Mutation of VGLL1 at S84 suppressed VGLL1-TEAD4 binding and the subsequent transcriptional activation of matrix metalloprotease 9 (MMP9).

SIGNOR-273842

P23458

P42226

1

phosphorylation

up-regulates activity

0.765

IL-4-stimulated Stat6 activation is mediated by Jak1 whereas Tyk2 is required for Stat6 activation in IL-13-treated monocytes

SIGNOR-249531

Q9Y4H2

P16220

0

transcriptional regulation

up-regulates quantity by expression

0.342

Taken together, these results indicate that the IRS2 gene is a direct target for CREB action in vivo

SIGNOR-278145

P11802

Q12778

1

phosphorylation

up-regulates activity

0.46

In summary, our study showed that Cdk4 phosphorylates and activates PAX3-FOXO1, thereby promoting its oncogenic function.|These findings suggest that Cdk4 phosphorylates the Ser 430 residue of PAX3-FOXO1 in vitro .

SIGNOR-278377

Q96J92

Q9UEW8

1

phosphorylation

up-regulates activity

0.507

Vitari et al. (76) and Moriguchi et al. (52) demonstrated that WNK4 bound and phosphorylated PASK at Thr-233 and Ser-373 in mammalian cells.| this phosphorylation event activates PASK, which in turn phosphorylates and activates NKCC1

SIGNOR-264641

Q15746

Q05682

1

phosphorylation

down-regulates

0.641

Phosphorylation of caldesmon by myosin light chain kinase increases its binding affinity for phosphorylated myosin filaments.

SIGNOR-166049

P11142

Q9UNE7

0

polyubiquitination

down-regulates quantity by destabilization

0.728

BAG-1 stimulates CHIP-induced degradation of the glucocorticoid hormone receptor (GR). A model for the cooperation of CHIP and BAG-1 in coupling Hsc/Hsp70 to the ubiquitin/proteasome system. CHIP associates with Hsc/Hsp70 via its TPR chaperone adaptor (TPR) and, at the same time, recruits E2 ubiquitin-conjugating enzymes of the Ubc4/5 family to the chaperone complex. BAG-1 binds to Hsp70 via its BAG domain (BAG) and utilizes its ubiquitin-like domain (ubl) for proteasomal association

SIGNOR-272588

Q00987

P00519

0

phosphorylation

down-regulates activity

0.716

C-abl binds and phosphorylates mdm2 in vivo and in vitro;phosphorylation of mdm2 by c-abl impairs the inhibition of p53 by mdm2.

SIGNOR-90512

Q00535

Q02078

1

phosphorylation

down-regulates activity

0.506

Cdk5-mediated inhibition of the protective effects of transcription factor mef2 in neurotoxicity-induced apoptosis.We have identified the prosurvival transcription factor mef2 as a direct nuclear target of cdk5. Cdk5 phosphorylates mef2 at a distinct serine in its transactivation domain to inhibit mef2 activity.

SIGNOR-100574

P53396

P42345

0

phosphorylation

up-regulates activity

0.332

Biochemical studies indicated that mTOR directly and specifically phosphorylated ACL on Ser 455 in vitro.

SIGNOR-278962

P04637

O15391

0

transcriptional regulation

up-regulates quantity by expression

0.572

YY2 activated the p53 promoter. However, in contrast to YY1, which represses the activity of c-Fos, YY2 increased the activity of the c-Fos promoter.

SIGNOR-266213

Q9C0B5

P04637

0

transcriptional regulation

up-regulates quantity by expression

0.2

Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y

SIGNOR-261150

O15392

P53350

0

phosphorylation

up-regulates

0.583

Thus, we conclude that plk1-mediated phosphorylation of sur at ser20 is critical for accurate chromosome segregation|SUR (survivin)

SIGNOR-170460

Q9BRS8

P31749

0

phosphorylation

up-regulates activity

0.353

Akt dependent phosphorylation of LARP6. We provide the first description that LARP6 is phosphorylated at multiple sites and that phosphorylation of S451 is critical to activate the protein in type I collagen biosynthesis.

SIGNOR-277213

P06239

P28482

0

phosphorylation

up-regulates activity

0.583

Phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62.|phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation.

SIGNOR-249412

Q96KS0

P30566

1

hydroxylation

up-regulates activity

0.2

ADSL is hydroxylated by EglN2 on Proline 24. An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. ADSL regulates cMYC protein level through adenosine levels

SIGNOR-266613

P62714

Q05655

1

dephosphorylation

down-regulates activity

0.3

PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex

SIGNOR-248595

Q9Y253

Q96PM5

0

monoubiquitination

down-regulates activity

0.581

Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues.we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions.These results suggest that Pirh2 monoubiquitinates PolH at one of the four lysine residues (K682, K686, K694, and K709).

SIGNOR-272733

Q99102

P42224

0

transcriptional regulation

up-regulates quantity by expression

0.393

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-254099

P12931

Q9Y2X7

1

phosphorylation

up-regulates activity

0.542

Tyrosines 246 and 293 are required to hold GIT1 in a closed conformation.Hyperphosphorylation of GIT1-N by Src and pervanadate does not affect its binding in vitro to full length GIT1 proteins. Mutations Y246E and Y293E of GIT1 enhance binding to paxillin.

SIGNOR-276627

P14921

Q93084

1

transcriptional regulation

up-regulates quantity by expression

0.326

Ets-1 was able to transactivate the SERCA3 promoter in MoBr 204 as cotransfection of an Ets-1 expression vector increased the activity of the −97/+301-Luc construct by 6-fold.

SIGNOR-261601

Q96TA2

O60313

1

cleavage

up-regulates activity

0.455

YME1L cleaves OPA1 at S2 and S3 site to transform into L-OPA1 to induce fusion when cells are faced with increased oxidative phosphorylation, whereas OMA1 cleaves OPA1 at an S1 site to transform into S-OPA1, resulting in the fragmented response to cellular stress, mitochondrial dysfunction, or deletion of YME1L

SIGNOR-274140

O94992

Q9UGL1

1

relocalization

up-regulates activity

0.2

We previously reported that the tumor suppressor HEXIM1 is a mediator of KDM5B recruitment to its target genes, and HEXIM1 is required for the inhibition of nuclear hormone receptor activity by KDM5B.

SIGNOR-273439

Q12904

P45983

0

phosphorylation

down-regulates

0.473

We further demonstrated that serine-140 residue of aimp1 was phosphorylated by jnk and alanine mutation of serine-140 suppressed lps-induced cell surface altogether, these results suggest that aimp1 is phosphorylated by jnk through tlr-myd88 pathway and lose the regulatory activity for er retention of gp96expression of gp96.

SIGNOR-165763

P49841

P16220

1

phosphorylation

up-regulates activity

0.691

GSK-3 can phosphorylate CREB at S129 Transactivation of CREB is significantly reduced (p ≤ 0.05) by 86% for the S129A mutant

SIGNOR-251233

Q99675

P00533

1

polyubiquitination

down-regulates quantity by destabilization

0.2

CGRRF1 ubiquitinates EGFR through K48-linked ubiquitination, which leads to proteasome degradation.

SIGNOR-272220

P23443

Q92934

1

phosphorylation

down-regulates activity

0.295

P70S6K, the downstream target of mTORC1, can phosphorylate and inactivate pro apoptotic BAD by producing a reaction that disrupts BAD 's binding to other pro apoptotic molecules thereby allowing cell survival.|p70S6K, the downstream target of mTORC1, can phosphorylate and inactivate pro-apoptotic BAD by producing a reaction that disrupts BAD\u2019s binding to other pro-apoptotic molecules thereby allowing cell survival. xref , xref On the other hand, in a recent study, Li et al showed that increased expression of anti-apoptotic BCL2 was induced in myeloid progenitor cells upon activation of p76S6K, thereby promoting cell survival. xref Further studies are needed to better understand the effect of rapamycin and its derivatives on apoptosis in various cancer cells.

SIGNOR-280016

Q8IYD8

Q92547

1

relocalization

up-regulates

0.418

The enzymatic activity of fan cm is then required to remodel and stabilize the fork to allow topbp1 access to activate atr , in a 9-1-1-independent manner.

SIGNOR-164765

Q5JUK2

Q68G74

1

transcriptional regulation

up-regulates quantity by expression

0.486

Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters.

SIGNOR-266076

P04035

Q86TM6

0

polyubiquitination

down-regulates quantity by destabilization

0.562

In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation.Human HRD1 appears to be involved in the basal degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase but not in the degradation that is regulated by sterols.

SIGNOR-272594

Q9NP62

Q14012

0

phosphorylation

up-regulates activity

0.388

We show that Epac1 and Rap1, in response to cAMP, activate CaMKI to phosphorylate Ser47 in GCM1. This phosphorylation facilitates the interaction between GCM1 and the desumoylating enzyme SENP1 and thereby leads to GCM1 desumoylation and activation.

SIGNOR-262680

Q13535

O60934

1

phosphorylation

up-regulates

0.785

We demonstrate that mrn and atr/atr-interacting protein (trip) interact with each other, and the forkhead-associated/breast cancer c-terminal domains (fha/brct) of nbs1 play a significant role in mediating this interaction. Mutations in the fha/brct domains do not prevent atr activation but specifically impair atr-mediated nbs1 phosphorylation at ser-343, which results in a defect in the s-phase checkpoint.

SIGNOR-155214

P98177

O43638

0

transcriptional regulation

down-regulates quantity by repression

0.2

Fkhl18 suppressed the transcriptional activity of FoxO3a and FoxO4.

SIGNOR-261611

P45983

Q8WTR2

0

dephosphorylation

down-regulates

0.421

Skrp1 was highly specific for c-jun n-terminal kinase (jnk) in vitro and effectively suppressed the jnk activation in response to tumor necrosis factor alpha or thapsigargin skrp1 does not bind directly to its target jnk, but co-precipitation of skrp1 with the mapk kinase mkk7, a jnk activator, was found in vitro and in vivo.

SIGNOR-117260

Q9UK17

P09769

0

phosphorylation

up-regulates activity

0.2

These results indicate that Y108 (for Src-family kinases) and Y136 (for EGFR kinase) are involved in the tyrosine phosphorylation of hKv4.3 channels.

SIGNOR-276394

P84022

P12931

0

phosphorylation

up-regulates activity

0.377

Although the role of ERK in mediating phosphorylation of Smad2/3 remains to be investigated, our data indicate that early Smad3 phosphorylation is independent of transient EGFR transactivation and ERK1/2 activation initiated by HB-EGF release, whereas Src mediated chronic EGFR transactivation and ERK1/2 activation involve late Smad3 activation induced by TGF-beta1.|Inhibition of Src not only decreases Smad3 phosphorylation but also decreases phosphorylation dependent nuclear translocation of Smad2/3, suggesting that Src kinase could modulate Smad3 activity.

SIGNOR-279292

Q9H204

P06241

0

phosphorylation

up-regulates

0.446

To unravel the cellular functions of magicin, we used a yeast two-hybrid system and identified fyn tyrosine kinase as a specific binding partner for magicin. Fyn phosphorylates magicin in vitro.

SIGNOR-148700

O00533

Q01484

1

relocalization

up-regulates quantity

0.409

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

SIGNOR-266722

Q92793

P52630

1

acetylation

up-regulates activity

0.557

STAT2 is another important component of ISGF3 complex, and its acetylation was similar to IFNaR2 and IRF9 acetylation in many respects: CBP downregulation largely abolished STAT2 acetylation induction by IFNa (Figure 6A), and CBP was more potent than transferases tested in catalyzing STAT2 acetylation (Figure 6B). [...] Figure 6 (I) STAT2-K390R substitution has reduced activity in ISGF3 complex formation.

SIGNOR-217891

P32004

P17252

0

phosphorylation

down-regulates activity

0.2

CKII phosphorylates T1172 of the L1 CD and phosphorylation of T1172 is responsible for loss of 2C2 signal.

SIGNOR-276283

P00519

Q15746

1

phosphorylation

up-regulates

0.3

Nonmuscle myosin light chain kinase (nmmlck), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity

SIGNOR-167989

P17676

P00519

0

phosphorylation

up-regulates

0.399

The y79 amino acid residue of c/ebpbeta was phosphorylated by c-abl or arg. The phosphorylation of c/ebpbeta resulted in an increased c/ebpbeta stability and a potentiation of c/ebpbeta transcription activation activity in cells

SIGNOR-186423

P05019

P42229

0

transcriptional regulation

up-regulates quantity by expression

0.433

Growth hormone induces insulin-like growth factor-I gene transcription by a synergistic action of STAT5 and HNF-1α

SIGNOR-251743

Q15034

Q04206

1

ubiquitination

down-regulates quantity by destabilization

0.325

Our data so far suggest that HERC3 reduces NF-kappaB transcriptional activity by binding to the proteasome and delivering RelA for degradation.|We show that HERC3 mediates ubiquitination of RelA on two distinct lysine residues, K195 and K315.

SIGNOR-278546

P18146

P10645

1

transcriptional regulation

up-regulates quantity by expression

0.2

Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation.

SIGNOR-254265

Q96D31

P05771

0

phosphorylation

down-regulates

0.2

We propose that pkc suppresses soce and crac channel function by phosphorylation of orai1 at n-terminal serine residues ser-27 and ser-30.

SIGNOR-166040

P48764

Q6P0Q8

0

phosphorylation

down-regulates activity

0.456

Coexpression of MAST205 inhibits the activity of Na +/H+ exchanger NHE3.|Consistent with these results, we found that MAST205 phosphorylated NHE3 under in vitro conditions.

SIGNOR-279229

O60260

Q6NUN9

1

polyubiquitination

down-regulates quantity by destabilization

0.2

. Parkin ubiquitinates and regulates the ubiquitin proteasomal degradation of PARIS

SIGNOR-272758

P42771

P35226

0

transcriptional regulation

down-regulates quantity by repression

0.455

In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity,

SIGNOR-253385

Q9Y2H1

Q9Y6E0

0

phosphorylation

up-regulates

0.441

Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity.

SIGNOR-142510

P11387

P00519

0

phosphorylation

up-regulates activity

0.399

This study demonstrates that ABL1-dependent phosphorylation up-regulates topo I activity. The ABL1 SH3 domain bound directly to the N-terminal region of topo I. The results demonstrate that ABL1 phosphorylated topo I at Tyr268 in core subdomain II.

SIGNOR-260775

Q15797

O95819

0

phosphorylation

down-regulates activity

0.2

Msn kinases directly phosphorylate α-helix 1 of Smad. we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for α-helix 1 phosphorylation.

SIGNOR-276335

P27361

P62136

0

dephosphorylation

down-regulates

0.444

P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases

SIGNOR-103155

P06681

P48740

0

cleavage

up-regulates activity

0.537

The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase

SIGNOR-263420

P63279

Q13485

1

sumoylation

up-regulates

0.626

The mh1 domain of smad4 was shown to associate physically with ubc9, the ubiquitin carrier protein (e2) conjugating enzyme in sumoylation. In cultured cells, smad4 is modified by sumo-1 at the endogenous level. The sumoylation sites were identified as two evolutionarily conserved lysine residues, lys-113 and lys-159, in the mh1 domain. We found that the mutations at lys-113 and lys-159 did not alter the ability of smad4 to form a complex with smad2 and fast on the mix.2 promoter. Importantly, sumo-1 overexpression enhanced tgf-beta-induced transcriptional responses. These findings identify sumoylation as a unique mechanism to modulate smad4-dependent cellular responses

SIGNOR-98997

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

P28482

P15923

1

phosphorylation

down-regulates quantity by destabilization

0.36

Notch-induced degradation requires phosphorylation of E47 by p42/p44 MAP kinases. |Wild_type E47 but not the Mm mutant reacted to the antibodies, suggesting that E47 is at least phosphorylated at the M2 site (Figure 3A)|anti_phospho_M2 peptide (SSPSpTPVGSPQG)

SIGNOR-249451

P46527

Q86TM6

0

ubiquitination

down-regulates quantity by destabilization

0.2

The E3 ligase activity of Hrd1 is required for p27 kip1 ubiquitination, because co-expression of Hrd1 containing an alanine point mutation at the critical cysteine within the RING E3 ligase region (Hrd1/CA) failed to enhance p27 kip1 ubiquitination (XREF_FIG).|Therefore, our study identifies Hrd1 as an E3 ligase of p27 kip1 and establishes that Hrd1 mediated p27 kip1 degradation plays an important role in T-cell immunity.

SIGNOR-278786

Q13362

P04637

1

dephosphorylation

up-regulates quantity by stabilization

0.611

Ablation of the B56gamma protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis. To investigate the molecular mechanisms, we have shown that the endogenous B56gamma protein level and association with p53 increase after DNA damage. Finally, we demonstrate that Thr55 dephosphorylation is required for B56gamma3-mediated inhibition of cell proliferation and cell transformation.

SIGNOR-268154

P27361

P19419

1

phosphorylation

up-regulates

0.601

Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency.

SIGNOR-34669

O95471

Q13363

0

transcriptional regulation

down-regulates quantity by repression

0.2

ChIP assays revealed that SNAI1P is recruited on the CLDN7 gene promoter along with the co-repressor CtBP1 and the effector HDAC1.

SIGNOR-254105

Q15418

P49841

1

phosphorylation

down-regulates

0.359

S6k then phosphorylates the same serine residue on gsk3 that is targeted by pkb/akt (fig. 1), thereby inhibiting its activity.

SIGNOR-110917

P10644

Q13976

0

phosphorylation

up-regulates activity

0.234

In this study, we further examined the potential of RIα phosphorylation to regulate physiologically relevant "desensitization" of PKAc activity. First, the serine 101 site of RIα was validated as a target of PKGIα phosphorylation both in vitro and in cells.These findings suggest that RIα phosphorylation may be a novel mechanism to circumvent the requirement of cAMP stimulus to activate type I PKA in cells.

SIGNOR-277383

Q15672

P31751

0

phosphorylation

up-regulates activity

0.398

AKT2 phosphorylates Twist1 at S42 to enhance Twist1 mediated E-cadherin suppression.

SIGNOR-279137

P08254

P10915

1

cleavage

down-regulates quantity by destabilization

0.384

Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix.

SIGNOR-256330

P19474

Q02556

1

ubiquitination

down-regulates quantity

0.638

From these results, we concluded that TRIM21 down-regulated IRF8 and enhanced the secretion of IL-12/23p40 in BD monocytes.|IRF8 is ubiquitinated by TRIM21, which promotes secretion of IL-12/23p40 after TLR/IFN-\u03b3 stimulation xref .

SIGNOR-278791

Q99640

P45983

0

phosphorylation

up-regulates

0.336

A kinase assay using gst-myt1 revealed that active jnk1 or jnk3, but not jnk2, phosphorylated myt1 in vitro.

SIGNOR-183899

Q6ZVD8

Q13043

1

dephosphorylation

up-regulates activity

0.2

PHLPPs dephosphorylate Mst1 on the T387 inhibitory site, which activate Mst1 and its downstream effectors p38 and JNK to induce apoptosis.

SIGNOR-248730

Q15418

P03372

1

phosphorylation

up-regulates

0.494

Serine 167 is the major phosphorylation site on the human estrogen receptor. Phosphorylation is mediated by casein kinase ii.

SIGNOR-34113

O43679

Q9NVW2

0

polyubiquitination

down-regulates quantity by destabilization

0.452

Here we identify RLIM as a ubiquitin protein ligase that is able to target CLIM cofactors for degradation through the 26S proteasome pathway.

SIGNOR-272616

Q9UQM7

P16949

1

phosphorylation

down-regulates

0.403

Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. In vitro, ser16 of recombinant human stathmin was phosphorylated also by purified cam kinase ii, and in vivo, cam kinase ii activity was indeed stimulated in cd2-triggered jurkat cells. Altogether, our results favor an association of cam kinase ii activity with costimulatory signals of t lymphocyte activation and phosphorylation of stathmin on ser16.

SIGNOR-149640

P78344

P06493

0

phosphorylation

up-regulates activity

0.339

To test whether CDK1 phosphorylates T508, Flag-DAP5 was purified from dox-induced HEK293 cells and incubated with active recombinant JNK2 or CDK1 in the presence of ATP (Fig. 3G). DAP5(T508) was phosphorylated only upon incubation with CDK1 (Fig. 3G).

SIGNOR-266387

Q9GZV5

P48730

0

phosphorylation

down-regulates

0.366

LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP)

SIGNOR-234438

P45985

P54762

0

relocalization

up-regulates activity

0.2

The phosphorylated CNK1 interacts with ephrinB1. The binding of ephrinB1 to CNK1 connects RhoA and p115RhoGEF with ephrinB1-associated MKK4, promoting JNK activation and cell migration.

SIGNOR-275922

P67775

O43524

1

dephosphorylation

up-regulates

0.402

Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a.

SIGNOR-163680

Q92556

P08631

0

phosphorylation

up-regulates

0.606

We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts.

SIGNOR-138154

Q96KK5

Q86Y13

0

monoubiquitination

up-regulates activity

0.2

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

SIGNOR-271760

Q92973

P35637

1

relocalization

up-regulates activity

0.642

The C-terminal nuclear localization sequence of FUsed in Sarcoma (FUS-NLS) is critical for its nuclear import mediated by transportin (Trn1).

SIGNOR-262101

Q8NHZ8

Q9NRM7

0

phosphorylation

up-regulates activity

0.46

LATS1 and LATS2 phosphorylate CDC26 to modulate assembly of the tetratricopeptide repeat subcomplex of APC/C|Overall, these results suggest that LATS1/2 are novel kinases involved in APC/C phosphorylation and indicate a direct regulatory link between LATS1/2 and APC/C

SIGNOR-275474

P42229

P60484

0

dephosphorylation

down-regulates

0.439

The forced expression of pten in the eol-1r cells dephosphorylated akt, erk and stat5 /eol-1r cells showed epigenetic silencing of the phosphatase and tensin homolog deleted on chromosome ten (pten) gene. Exposure of eol-1r cells to imatinib failed to dephosphorylate akt, erk and stat5, although pdgfr? Was effectively inactivated. The forced expression of pten negatively regulated these signal pathways and sensitized eol-1r cells to imatinib.

SIGNOR-166481

Q8N699

P01106

0

transcriptional regulation

up-regulates quantity by expression

0.298

MT-MC1 is a widely expressed nuclear protein whose overexpression, unlike that of c-Myc targets reported previously, recapitulates multiple c-Myc phenotypes. These include promotion of apoptosis, alteration of morphology, enhancement of anchorage-independent growth, tumorigenic conversion, promotion of genomic instability, and inhibition of hematopoietic differentiation. The MT-MC1 promoter is a direct c-Myc target; it contains two consensus E-box elements, both of which bind c-Myc.

SIGNOR-261736

P68400

P60484

1

phosphorylation

down-regulates activity

0.68

The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity

SIGNOR-89830

Q9NR50

P20042

1

guanine nucleotide exchange factor

up-regulates activity

0.848

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

SIGNOR-269131

O75116

Q09472

1

phosphorylation

up-regulates activity

0.297

Nuclear Rho kinase, ROCK2, targets p300 acetyltransferase.|p300 acetyltransferase activity is dependent on its phosphorylation status in cells, and p300 phosphorylation by ROCK2 results in an increase in its acetyltransferase activity in vitro.

SIGNOR-279482

P23467

P35968

1

dephosphorylation

down-regulates activity

0.454

VE-PTP/VEGFR2 complex formation resumes with time, leading to dephosphorylation and deactivation of VEGFR2 (right). B) In VE-PTP-deficient cells, such as after siRNA treatment, VEGFR2 activation (middle) is exaggerated, leading to increased phosphorylation at the Y951 and Y1175 phosphorylation sites

SIGNOR-248441

O95644

P60568

1

transcriptional regulation

up-regulates quantity by expression

0.565

Together, our results demonstrate that dnNFAT inhibits the production of IL-2. Thus, the NFAT transcription factor contributes to the regulation of IL-2 gene expression and therefore plays a critical role in the initiation of immune responses.

SIGNOR-275405

O00443

P08069

0

phosphorylation

up-regulates

0.275

Analysis of the ability of the full-length igfr and its mutant receptors described above to associate with phosphatidylinositol 3 kinase indicated that the association required ptk activity and tyrosine [?] Phosphorylation of the receptors and correlated well with their transforming activities

SIGNOR-32076

Q13002

P12931

0

phosphorylation

up-regulates activity

0.372

GluK2 binds to Src, and the tyrosine residue at position 590 (Y590) on GluK2 is a major site of phosphorylation by Src kinases. GluK2 phosphorylation at Y590 is responsible for increases in whole-cell currents and calcium influx in response to transient kainate stimulation.

SIGNOR-276850

P27361

P41235

1

phosphorylation

down-regulates activity

0.494

Activation of the ERK1/2 signalling pathway, inducing proliferation and survival, inhibits the expression of HNF4\u03b1.|Here we have demonstrated that ERK1 is able to phosphorylate HNF4\u03b1 at several serine and threonine residues.

SIGNOR-279070

P19474

P09471

0

null

down-regulates

0.2

Mechanistically, GNAO1 recruited TRIM21 and facilitated TRIM21-mediated ubiquitination.

SIGNOR-278888

O60674

P51692

1

phosphorylation

up-regulates

0.865

Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein

SIGNOR-56894

Q03405

O95644

0

transcriptional regulation

up-regulates quantity by expression

0.2

Inducible podocyte-specific expression of constitutively active NFATc1 increased podocyte uPAR expression by binding to the Plaur gene promoter (encoding uPAR) in chromatin immunoprecipitation assays.

SIGNOR-253336

P53350

P51587

1

phosphorylation

down-regulates activity

0.539

M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1

SIGNOR-102486