GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P01213	Q9H1B7	0	transcriptional regulation	down-regulates quantity by repression	0.263	EAP1 encoded a nuclear protein expressed in neurons involved in the inhibitory and facilitatory control of reproduction. EAP1 transactivated genes required for reproductive function, such as GNRH1, and repressed inhibitory genes, such as preproenkephalin. It contained a RING finger domain of the C3HC4 subclass required for this dual transcriptional activity.These results suggest that EAP1 is a transcriptional regulator that, acting within the neuroendocrine brain, contributes to controlling female reproductive function.	SIGNOR-267156
Q13257	O43683	0	relocalization	up-regulates activity	0.96	Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity	SIGNOR-252018
Q09472	Q13315	0	phosphorylation	up-regulates	0.4	Atm mediates phosphorylation of p300 in response to dna damageexpression of nonphosphorylatable serine to alanine form of p300 (s106a) destabilized both p300 and nbs1 proteins, after dna damage	SIGNOR-165567
P28482	P49585	1	phosphorylation	down-regulates	0.45	Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis.	SIGNOR-134837
Q13535	Q9BW19	1	phosphorylation	up-regulates quantity by stabilization	0.257	ATM and ATR kinases phosphorylate KIFC1-S26 during DNA-damage conditions.KIFC1 was stabilized upon phosphorylation and thus promoted centrosome clustering, CIN, and tumor recurrence both in vivo and in vitro.	SIGNOR-277296
P31749	P67775	0	dephosphorylation	down-regulates activity	0.893	Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes	SIGNOR-252614
Q00535	P12931	1	phosphorylation	up-regulates	0.39	These results present compelling evidence that cdk5/p35 kinase is responsible for the novel phosphorylation of c-src at ser75 in neuronal cells, raising the intriguing possibility that c-src acts as an effector of cdk5/p35 kinase during neuronal development.	SIGNOR-71950
P27361	P51812	1	phosphorylation	up-regulates	0.73	We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway	SIGNOR-81460
Q9H7Z6	Q13315	0	phosphorylation	up-regulates activity	0.469	In this study we present evidence that MOF is phosphorylated at the threonine 392 residue (pT392-MOF) by ATM subsequent to IR induced DNA damage.\|Interestingly, ATM dependent-MOF phosphorylation increases MOF retention on DNA post-irradiation in S/G2-phase cells.	SIGNOR-278350
P30559	O15530	0	phosphorylation	up-regulates activity	0.2	We found that Ser261 in OXTR was phosphorylated by protein kinase D1 (PKD1).\|In HEK293A cells, the PKD1-mediated phosphorylation of OXTR promoted its binding to Gq protein and, in turn, OXTR-mediated phosphorylation of PKD1, indicating a positive feedback loop.	SIGNOR-268577
Q14457	Q16644	0	phosphorylation	up-regulates activity	0.425	Taken together, these data indicate that MK2 and MK3 directly phosphorylate Beclin 1 S90 in vitro, and that MK2 like kinase activity also mediates starvation induced Beclin 1 S90 phosphorylation in cultured cells.	SIGNOR-279342
O75553	Q93034	0	polyubiquitination	down-regulates quantity by destabilization	0.327	SOCS7 promotes Dab1 polyubiquitylation and degradation. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SOCS7, a CRL5 substrate adaptor protein, is also required for neocortical layering. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1.	SIGNOR-272140
Q05397	P00533	0	phosphorylation	up-regulates	0.595	In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases.	SIGNOR-167646
P52954	P37275	1	transcriptional regulation	up-regulates quantity by expression	0.326	Compared with the empty vector, LBX1 induced increased promoter activity of threefold to fourfold and fivefold to sixfold for ZEB1 and Snail1, respectively	SIGNOR-266054
Q8N1W1	P61586	1	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
Q96SN8	O94986	1	relocalization	up-regulates activity	0.755	Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome.	SIGNOR-271721
Q96SD1	P78527	0	phosphorylation	up-regulates	0.699	Artemis is a nuclear phosphoprotein required for genomic integrity whose phosphorylation is increased subsequent to dna damage. Artemis phosphorylation by the dna-dependent protein kinase (dna-pk). However, regardless of its association with dna-pkcs, phosphorylation of artemis at both s516 and s645 was stimulated in response to the double-stranded dna-damaging agent bleomycin	SIGNOR-148327
Q04206	O15111	0	phosphorylation	up-regulates activity	0.847	Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter.	SIGNOR-129931
P17252	P43405	0	phosphorylation	up-regulates activity	0.391	We present evidence that Tyr-662 and Tyr-658 of PKCbetaI and PKCalpha, respectively, are phosphorylated by Syk in the membrane compartment of FcepsilonRI-stimulated mast cells. These phosphorylations require prior PKC autophosphorylation of the adjacent serine residues (Ser-661 and Ser-657, respectively) and generate a binding site for the SH2 domain of the adaptor protein Grb-2.	SIGNOR-246581
Q96P20	Q15139	0	phosphorylation	up-regulates activity	0.332	PKD at the Golgi phosphorylates NLRP3 to release it from mitochondria-associated endoplasmic reticulum membranes, allowing for assembly of the mature inflammasome in the cytosol.\|These data thus suggest that PKD activity at the Golgi is sufficient to activate the NLRP3 inflammasome.	SIGNOR-279428
Q13191	P27986	1	polyubiquitination	down-regulates quantity by destabilization	0.517	Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells.Here it is shown that Cbl-b interacts with and induces ubiquitin conjugation to the p85 regulatory subunit of phosphatidylinositol 3-kinase, an upstream regulator of Vav.	SIGNOR-272583
Q15652	Q16695	1	demethylation	down-regulates activity	0.2	We now determine that JMJD1C is recruited by USF-1 to various lipogenic genes for H3K9 demethylation to enhance chromatin accessibility in the fed state.	SIGNOR-265170
P27361	Q13115	0	dephosphorylation	down-regulates activity	0.709	Dephosphorylation and Inactivation of ERKs\|ERK1 phosphorylated on either threonine (ERK1Y204F) or tyrosine alone (ERK1T202A) was utilized as a substrate for HVH2. Threonine 202 and tyrosine 204 in ERK1 (53) correspond to threonine 183 and tyrosine 185 in ERK2 which are the activation-phosphorylation sites by MEK(14, 15, 16). ERK1, a kinase-deficient mutant, was phosphorylated on both threonine and tyrosine by MEK2 (Fig. 3B). ERK1T202A, having threonine 202 substituted by an alanine, was phosphorylated only on tyrosine while ERK1Y204F, having tyrosine 204 substituted by a phenylalanine, was phosphorylated only on threonine (Fig. 3B). GST-HVH2 dephosphorylated all three ERK1 mutants (Fig. 3A), suggesting that double phosphorylations of adjacent threonine and tyrosine were not a prerequisite for HVH2 recognition. However, HVH2 dephosphorylated ERK1* and ERK1T202A more efficiently than ERK1Y204F (Fig. 3A), indicating that HVH2 preferred phosphotyrosine over phosphothreonine. Interestingly, MEK also phosphorylated tyrosine residues more efficiently than threonine residues of ERK	SIGNOR-248716
Q9Y4C1	Q5TEC6	1	demethylation	up-regulates activity	0.2	Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.	SIGNOR-276843
P28482	Q07869	1	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
P28482	P19419	1	phosphorylation	up-regulates activity	0.563	We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erk1 phosphorylates five c-terminal sites in elk-1 (s324,t336, s383, s389 and s422) with varying degrees of efficiency.	SIGNOR-235455
Q05397	O00401	1	phosphorylation	up-regulates activity	0.69	In addition, FAK can phosphorylate N-WASP and promote actin polymerization, and inhibition of FAK kinase activity suppresses N-WASP activity.	SIGNOR-278977
P62136	P28482	1	dephosphorylation	down-regulates	0.446	P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3)	SIGNOR-103152
P49841	P23246	1	phosphorylation	down-regulates	0.345	Psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. / threonine phosphorylation of psf by gsk3 primarily occurs on residue t687	SIGNOR-168392
P19784	Q00613	1	phosphorylation	up-regulates	0.348	Transcriptional activity and dna binding of heat shock factor-1 involve phosphorylation on threonine 142 by ck2.As hsf1 is activated by heat shock simultaneously with the nuclear translocation of the protein kinase ck2, we have investigated the role of ck2 in hsf1 activatio	SIGNOR-99606
P46937-3	P12931	0	phosphorylation	up-regulates activity	0.632	We found that YAP1, the pivotal effector of the Hippo signaling pathway, is a direct SRC phosphorylation target, and YAP1 phosphorylation at three sites in its transcription activation domain is necessary for SRC-YAP1-mediated transformation.	SIGNOR-274025
P11908	Q9UHD2	0	phosphorylation	up-regulates activity	0.2	Here, we show that ionizing radiation results in TBK1-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase (PRPS)1/2 at T228, thereby enhancing PRPS1/2 catalytic activity and promoting deoxyribonucleotide synthesis.	SIGNOR-277317
P15923	P28482	0	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
Q9HC98	P52948	1	phosphorylation	down-regulates activity	0.315	To elucidate which of the identified sites can be targeted by CDK1/cyclin B1 and Nek6 in vitro (Figure S1D), we performed phosphorylation reactions using recombinant kinases and unlabeled ATP followed by phosphopeptide mapping (Table S1). MS analysis confirmed phosphorylation of S591 and S822 by Nek6 as well as phosphorylation of T529, T536, S595, S606, and T653 by CDK1. Phosphomimetic Mutants of Nup98 Show Defects in NPC Localization	SIGNOR-273893
P15172	P15692	1	transcriptional regulation	up-regulates quantity by expression	0.391	We further demonstrate that the myogenic transcription factor, MyoD, and its heterodimeric binding proteins E12 and E47, up-regulate the expression of endogenous VEGF through direct interaction with the VEGF promoter.	SIGNOR-257598
P28482	P23396	1	phosphorylation	up-regulates	0.2	Erk phosphorylates threonine 42 residue of ribosomal protein s3.	SIGNOR-137955
P35222	P00533	0	phosphorylation	up-regulates activity	0.773	EGFR and TRKA effect on WNT3a mediated Topflash induction was abolished by U0126 or expression of dominant negative LRP6-5A mutant (XREF_FIG), demonstrating that both EGFR and TRKA signal via ERK and LRP6 pathway to upregulate WNT and beta-catenin signaling.\|FGFR2, FGFR3, EGFR and TRKA Phosphorylate beta-catenin at Tyr142.	SIGNOR-278309
P18433	P07948	1	dephosphorylation	down-regulates activity	0.3	We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397\|Lyn expressed in CHO cells has a substantially higher specific activity than Lyn in RBL cells because of high levels of phosphorylation at its active site Tyr-397 (Fig. 1). Enhanced Lyn kinase activity in the CHO cells leads to spontaneous phosphorylation of multiple cellular proteins, including FcϵRI	SIGNOR-248436
Q13043	P98177	1	phosphorylation	up-regulates	0.427	The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1	SIGNOR-178193
P13497	P20908	1	cleavage	up-regulates activity	0.623	BMP-1 Can Efficiently Cleave Pro-α1(V) N-propeptides and Pro-α2(V) C-propeptides and Less Efficiently Cleave Pro-α1(V) C-propeptides in Vitro.NH2-terminal sequencing of an ∼35-kDa band in the BMP-1-treated material (N-α1(V), Fig. 3 B,lanes 2 and 3) showed it to correspond to the NH2-terminal portion of the pro-α1(V) N-propeptide previously shown to be cleaved in pro-α1(V)3 homotrimers by BMP-1 (39), whereas NH2-terminal sequencing of an ∼38-kDa band (C-α1(V)BMP-1, Fig. 3 B,lanes 2 and 3) showed it to correspond to pro-α1(V) C-propeptides cleaved between Asp-1594 and Asp-1595.	SIGNOR-256344
Q8TBZ2	P22681	0	monoubiquitination	up-regulates activity	0.298	We moreover found that AMAP1 is monoubiquitinated, rather than polyubiquitinated, by virtue of Cbl and provide evidence that the ability of AMAP1 to be monoubiquitinated is important for its involvement in invasion.	SIGNOR-272627
Q14703	Q70SY1	1	cleavage	up-regulates	0.561	Bbf2h7 is cleaved by s1p in response to er stress / cleaved fragments of the bbf2h7 n-terminal portion containing the bzip domain translocate into nuclei	SIGNOR-151309
P68431	Q9BYW2	0	trimethylation	up-regulates activity	0.2	Our results suggest that HYPB HMTase may coordinate histone methylation and transcriptional regulation in mammals and open perspective for the further study of the potential roles of HYPB protein in hematopoiesis and pathogenesis of HD.	SIGNOR-269071
Q15569	P23528	1	phosphorylation	down-regulates activity	0.528	Like TESK1, TESK2 phosphorylated cofilin specifically at Ser-3 and induced formation of actin stress fibers and focal adhesionsExpression of cofilin or S3A-cofilin into HeLa cells induced marked decreases in rhodamine-phalloidin staining due to the actin binding and -depolymerizing activity of cofilin	SIGNOR-246723
P12931	Q9NPF5	1	phosphorylation	down-regulates activity	0.2	C-Src phosphorylates DMAP1 at Tyr246 and disrupts Bub3/DMAP1 complex formation.	SIGNOR-279431
P06241	P24666	1	phosphorylation	up-regulates activity	0.382	We identify Tyr-131 as the major phosphorylation site and Tyr-132 as a minor site and the Src family PTKs Lck and Fyn as enzymes capable of phosphorylating these sites in vivo and in vitro. Both Tyr-131 and Tyr-132 are located next to the catalytic pocket of LMPTP, and especially, Tyr-131 seems to be important for the activity of LMPTP. Phosphorylation of Tyr-131 or Tyr-132, particularly the former, caused an increase in the activity of LMPTP.	SIGNOR-251150
P45983	Q9H211	1	phosphorylation	up-regulates quantity by stabilization	0.368	We discovered that human Cdt1, an essential origin licensing protein whose activity must be restricted to G(1) phase, is a substrate of the stress-activated mitogen-activated protein (MAP) kinases p38 and c-Jun N-terminal kinase (JNK). These MAP kinases phosphorylate Cdt1 both during unperturbed G(2) phase and during an acute stress response. Phosphorylation renders Cdt1 resistant to ubiquitin-mediated degradation during S phase and after DNA damage by blocking Cdt1 binding to the Cul4 adaptor, Cdt2.	SIGNOR-276361
P60953	Q96DR7	0	guanine nucleotide exchange factor	up-regulates activity	0.585	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-260545
P06493	Q2NKX8	1	phosphorylation	up-regulates	0.579	Following phosphorylation of pich on the cdk1 site t1063, plk1 is recruited to pich and controls its localization. Starting in prometaphase, pich accumulates at kinetochores and inner centromeres.	SIGNOR-152133
P04114	P55157	0	lipidation	up-regulates activity	0.793	As ApoB is translated, it is lipidated by microsomal triglyceride transfer protein (MTP). MTP adds triglycerides to the nascent ApoB during its co-translational translocation into the lumen of the endoplasmic reticulum.	SIGNOR-252118
O14974	O14757	0	phosphorylation	down-regulates quantity by destabilization	0.2	MYPT1 is phosphorylated by CDK1, thus recruiting protein phosphatase 1β (PP1cβ) to dephosphorylate and inactivate Plk1. Here we identified that Chk1 directly interacts with MYPT1 and preferentially phosphorylates MYPT1 at Ser20, which is essential for MYPT1-PP1cβ interaction and subsequent Plk1 dephosphorylation.	SIGNOR-277870
P52735	P63000	1	guanine nucleotide exchange factor	up-regulates	0.761	Vav2 activates rac1 / vav2 is an exchange factor for rho family gtpases.	SIGNOR-81645
P17612	Q13698	1	phosphorylation	up-regulates activity	0.346	To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2.	SIGNOR-263112
Q8NA31	P54274	1	relocalization	up-regulates activity	0.2	The shelterin complex has six proteins, containing TRF1, TRF2, POT1, RAP1, TIN2, and TPP1. The shelterin complex is localized to the chromosome end and protects telomeric DNA (Palm and de Lange, 2008). The TTM complex acts as a “linker” and bridges the LINC and shelterin complexes together. The connection between TTM and shelterin complexes is well-known, which is mediated by TERB1 and TRF1	SIGNOR-263315
Q7Z6Z7	O14757	1	ubiquitination	down-regulates quantity by destabilization	0.298	Taken together, these results are consistent with our hypothesis that HUWE1 directly poly-ubiquitinates and targets Chk1 to the proteasome.	SIGNOR-278568
Q9H2X6	O00257	1	phosphorylation	up-regulates activity	0.423	In addition, HIPK2 phosphorylates Pc2 at several sites, including threonine 495.	SIGNOR-278484
P60484	P23528	1	dephosphorylation	up-regulates activity	0.441	Unexpectedly, cofilin-1 activation by PGE 2 was mediated by the protein phosphatase activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10), with which it directly associated.\|Unexpectedly, cofilin-1 dephosphorylation and activation in our model was mediated by the protein phosphatase activity of PTEN.	SIGNOR-276980
P21333	P48454	0	dephosphorylation	down-regulates quantity by destabilization	0.2	Filamin is a phosphoprotein that organizes actin filaments into networks. We report that a purified C-terminal recombinant region of filamin is a suitable substrate for calcineurin \|Mutagenesis analysis showed that a dephosphorylation step occurred in Ser 2152, which was previously shown to provide resistance to calpain cleavage when endogenous PKA is activated. In contrast, phosphorylation of Ser 2152 was recently reported to be necessary for membrane dynamic changes. In this regard, we found that CsA protects filamin in platelets from calpain degradation.	SIGNOR-248507
P35222	P67870	0	phosphorylation	up-regulates activity	0.601	We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin	SIGNOR-251067
P12931	O75365	1	phosphorylation	down-regulates activity	0.358	Our results show that Src kinase activity leads to the tyrosine phosphorylation of PRL-3, primarily on Y53.\|Collectively these results support a model in which Src causes phosphorylation of PRL-3 on Y53 to promote its pro-invasion functions, and suggest for the first time that the metastasis-associated tyrosine phosphatase PRL-3 may itself be regulated by post-translational modification.	SIGNOR-278262
P62714	P37840	1	dephosphorylation	down-regulates activity	0.276	α-Synuclein (α-Syn) is a key protein that accumulates as hyperphosphorylated aggregates in pathologic hallmark features of Parkinson's disease (PD) and other neurodegenerative disorders. Phosphorylation of this protein at serine 129 is believed to promote its aggregation and neurotoxicity, suggesting that this post-translational modification could be a therapeutic target. Here, we demonstrate that phosphoprotein phosphatase 2A (PP2A) dephosphorylates α-Syn at serine 129	SIGNOR-248592
Q96JN8	O95714	0	polyubiquitination	down-regulates quantity by destabilization	0.456	NEURL4 is a substrate of HERC2, and together these results indicate that the NEURL4-HERC2 complex participates in the ubiquitin-dependent regulation of centrosome architecture.	SIGNOR-272921
P60953	Q96PX9	0	guanine nucleotide exchange factor	up-regulates activity	0.285	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-260565
P49757	Q8TBB1	0	ubiquitination	down-regulates	0.74	Lnx functions as a ring type e3 ubiquitin ligase that targets the cell fate determinant numb for ubiquitin-dependent degradation.	SIGNOR-112201
Q03112	P23769	1	transcriptional regulation	up-regulates quantity by expression	0.359	Evi1 directly binds to the promoter region of GATA-2 and thus enhances the GATA-2 transcription.	SIGNOR-266062
P62136	P04150	1	dephosphorylation	up-regulates activity	0.291	The current study assessed whether PP1\u03b1 can stimulate GR function and tested two different hypotheses: First, that PP1\u03b1 regulates GR activity through suppression of MDM2 activity by dephosphorylating it at Ser166, thereby reducing the MDM2-mediated ubiquitination of GR and the subsequent proteasomal degradation of the receptor, as shown for the MR and AR ( xref ; xref ); and second, that PP1\u03b1 directly dephosphorylates the GR at a particular site to relieve functional repression as demonstrated for PP2A and PP5 ( xref ; xref ; xref ).\|The involvement of GR-Ser211 phosphorylation supports the assumption that altered subcellular trafficking is a mechanism less likely contributing to the PP1\u03b1-dependent GR activation.	SIGNOR-277161
Q9UEW8	Q9H4A3	0	phosphorylation	up-regulates	0.446	Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1).	SIGNOR-151671
P27361	Q969V6	1	phosphorylation	down-regulates	0.2	Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization.	SIGNOR-195157
Q13148	P09651	1	post transcriptional regulation	up-regulates	0.406	TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis	SIGNOR-262824
P20645	Q8IWJ2	0	relocalization	up-regulates activity	0.532	Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector	SIGNOR-253086
Q13557	Q14571	1	phosphorylation	down-regulates activity	0.308	Phopho-specific antibodies demonstrate that InsP(3)R2 Ser-150 is phosphorylated in vivo by CaMKIIδ. The results of this study show that serine 150 of the InsP(3)R2 is phosphorylated by CaMKII and results in a decrease in the channel open probability.	SIGNOR-262692
P28482	Q02447	1	phosphorylation	up-regulates	0.305	Here, we show that sp3, which, as sp1, belongs to the gc-rich binding transcription factor family, is also phosphorylated by erk in vitro on serine 73. in the inducible cell lines, expression of wild-type form of sp3 increases vegf production whereas the s73a form has a reduced potential reflecting its lower transcriptional activity.	SIGNOR-157272
Q9H3R0	P04908	1	demethylation	down-regulates activity	0.2	As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation	SIGNOR-263862
O96017	P40337	1	phosphorylation	up-regulates	0.455	We demonstrated that checkpoint kinase-2 (chk2) binds to the beta-domain of pvhl and phosphorylates ser 111 on dna damage. Notably, this modification enhances pvhl-mediated transactivation of p53 by recruiting p300 and tip60 to the chromatin of p53 target gene	SIGNOR-177091
Q8IXJ6	P35558	1	deacetylation	up-regulates quantity by stabilization	0.426	Conversely, SIRT2 deacetylates and stabilizes PEPCK1.\|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1	SIGNOR-267599
P98170	Q04726	1	ubiquitination	up-regulates activity	0.507	These findings suggest that TLE3 ubiquitylation by XIAP may be required during Wnt pathway activation to facilitate its dissociation from TCF/Lef, allowing subsequent beta-catenin binding and transcriptional activation.	SIGNOR-278528
Q13255	P17252	0	phosphorylation	down-regulates activity	0.385	Furthermore, we demonstrate that the selectivity of PKC action on receptor signaling rests on phosphorylation of a threonine residue located in the G protein-interacting domain of the receptor. Modification at Thr(695) selectively disrupts mGluR1alpha-G(q/11) interaction without affecting signaling through G(s).	SIGNOR-249043
P33176	Q96N16	1	relocalization	up-regulates activity	0.2	Marlin-1 is associated with kinesin-I and suggest that the movement of Marlin-1 is mediated by plus end microtubuledependent molecular motors	SIGNOR-260989
P43378	P10912	1	dephosphorylation	down-regulates activity	0.314	Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR	SIGNOR-248505
P20020	P17612	0	phosphorylation	up-regulates activity	0.451	The ATPase is phosphorylated only at this site by the cAMP-dependent protein kinase, and the phosphorylation is inhibited by calmodulin. The effect of the phosphorylation is to decrease the Km for Ca2+ of the purified ATPase from about 10 microM to about 1.4 microM and to increase the Vmax of ATP hydrolysis about 2-fold.	SIGNOR-262694
Q06124	Q05397	1	dephosphorylation	down-regulates	0.731	Dca concomitantly and significantly increased association of tyrosine phosphatase shp2 with fak. Incubation of immunoprecipitated fak, in vitro, with glutathione-s-transferase-shp2 fusion protein resulted in tyrosine dephosphorylation of fak in a concentration-dependent manner.	SIGNOR-148926
P68400	Q9BRS2	1	phosphorylation	up-regulates quantity by stabilization	0.332	Casein kinase 2 (CK2) phosphorylates RIOK1 at T410, which stabilizes RIOK1 by antagonizing K411 methylation and impeding the recruitment of FBXO6 to RIOK1.	SIGNOR-273630
Q04724	P68400	0	phosphorylation	up-regulates	0.32	These results suggest that ck2 phosphorylation of serine 239 of gro/tle1 is important for its function during neuronal differentiation.	SIGNOR-129026
P17542	Q02750	0	phosphorylation	down-regulates	0.2	We found that hypoxia greatly accelerated tal1 turnover in these cells through mitogen-activated protein kinase (mapk)2-mediated phosphorylation, ubiquitination, and proteasomal degradation.	SIGNOR-116149
Q99661	Q13153	0	phosphorylation	down-regulates	0.385	Here we found that mcak is a cognate substrate of pak1 wherein pak1 phosphorylates mcak on serines 192 and 111 both in vivo and in vitro. Furthermore, we found that pak1 phosphorylation of mcak on serines 192 and 111 preferentially regulates its microtubule depolymerization activity and localization to centrosomes	SIGNOR-199084
P49815	P28482	0	phosphorylation	down-regulates activity	0.681	Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. \|Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation.	SIGNOR-249454
Q16539	P42566	1	phosphorylation	up-regulates	0.345	Tnf-_ induces phosphorylation of eps15 at ser-796eps15 is a substrate for p38_these results suggest an attractive model in which p38 phosphorylates both eps15 and egfr to trigger efficient endocytosis	SIGNOR-203315
P49841	P17612	0	phosphorylation	down-regulates activity	0.557	Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3alpha or ser9 in gsk3beta. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka).	SIGNOR-188577
P28482	Q15796	1	phosphorylation	up-regulates	0.722	We show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity.	SIGNOR-91714
P48729	Q99873	1	phosphorylation	up-regulates activity	0.2	CSNK1a1 directly bound and phosphorylated PRMT1 to control its genomic targeting to PRMT1-sustained proliferation genes as well as PRMT1-suppressed differentiation genes.\|Taken together, these data support a provisional model in which CSNK1a1 directs PRMT1 to genomic targets that promote self-renewal and suppress terminal differentiation.In the context of transcription regulation, PRMT1 has been generally considered as a transcriptional co-activator.	SIGNOR-279733
P49841	P52945	1	phosphorylation	down-regulates quantity	0.2	We show that glucose levels modulate PDX1 protein phosphorylation at a novel C-terminal GSK3 consensus that maps to serines 268 and 272. A decrease in glucose levels triggers increased turnover of the PDX1 protein in a GSK3-dependent manner, such that PDX1 phosphomutants are refractory to the destabilizing effect of low glucose	SIGNOR-255566
Q13546	Q6WCQ1	1	phosphorylation	up-regulates activity	0.2	Under such conditions, RIP1 phosphorylates and activates RIP3, which in turn phosphorylates its downstream substrate MLKL, leading to plasma membrane rupture and necrosis( xref ).	SIGNOR-279755
Q13322	P28482	0	phosphorylation	up-regulates	0.373	We show that grb10 is a direct substrate of the p42/44 mitogen-activated protein kinase (mapk)we identified ser(150), ser(418), and ser(476) of human grb10zeta as mapk-mediated in vitro phosphorylation sites. Replacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation. Taken together, our findings suggest that phosphorylation of the adaptor protein may provide a feedback inhibitory mechanism by which grb10 regulates insulin signaling.	SIGNOR-138163
P43403	P15941	1	phosphorylation	up-regulates activity	0.448	Indeed, the present results demonstrate that ZAP-70 phosphorylates MUC1-CD and that the MUC1-CD Y-20 site functions, at least in part, as a ZAP-70 substrate (Fig. 4C). In this regard, the in vivo phosphorylation data indicate that ZAP-70 may also contribute to phosphorylation of MUC1-CD Y-46.The results further show that ZAP-70 phosphorylation of MUC1-CD stimulates the interaction of MUC1 andBeta-catenin.	SIGNOR-247039
P01106	Q01196	0	transcriptional regulation	down-regulates quantity by repression	0.337	RUNX1 represses MYC expression through direct binding at three downstream enhancer elements	SIGNOR-260093
Q8IZL9	Q9UPZ9	1	phosphorylation	up-regulates	0.2	Recombinant cak1p phosphorylates thr-157 in the tdy motif of recombinant ick and activates its activity in vitro.	SIGNOR-138420
P06493	O95239	1	phosphorylation	up-regulates activity	0.489	Identification of Cdk phosphorylation of Kif4A at T1161 in early mitosis. We show that Cdk phosphorylation of Kif4A licenses its chromosome localization.	SIGNOR-265994
Q9GZV5	Q86U44	0	transcriptional regulation	up-regulates quantity by expression	0.2	Here we find that METTL3 promotes translation of certain mRNAs including epidermal growth factor receptor (EGFR) and the Hippo pathway effector TAZ in human cancer cells.	SIGNOR-265955
Q06124	Q02556	1	dephosphorylation	down-regulates activity	0.353	We found that Bcr-abl-induced, Shp2 dependent dephosphorylation of Icsbp impaired repression of GAS2 by this transcription factor.	SIGNOR-277173
Q14CB8	P61586	1	gtpase-activating protein	down-regulates activity	0.568	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-260471

P01213

Q9H1B7

0

transcriptional regulation

down-regulates quantity by repression

0.263

EAP1 encoded a nuclear protein expressed in neurons involved in the inhibitory and facilitatory control of reproduction. EAP1 transactivated genes required for reproductive function, such as GNRH1, and repressed inhibitory genes, such as preproenkephalin. It contained a RING finger domain of the C3HC4 subclass required for this dual transcriptional activity.These results suggest that EAP1 is a transcriptional regulator that, acting within the neuroendocrine brain, contributes to controlling female reproductive function.

SIGNOR-267156

Q13257

O43683

0

relocalization

up-regulates activity

0.96

Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity

SIGNOR-252018

Q09472

Q13315

0

phosphorylation

up-regulates

0.4

Atm mediates phosphorylation of p300 in response to dna damageexpression of nonphosphorylatable serine to alanine form of p300 (s106a) destabilized both p300 and nbs1 proteins, after dna damage

SIGNOR-165567

P28482

P49585

1

phosphorylation

down-regulates

0.45

Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis.

SIGNOR-134837

Q13535

Q9BW19

1

phosphorylation

up-regulates quantity by stabilization

0.257

ATM and ATR kinases phosphorylate KIFC1-S26 during DNA-damage conditions.KIFC1 was stabilized upon phosphorylation and thus promoted centrosome clustering, CIN, and tumor recurrence both in vivo and in vitro.

SIGNOR-277296

P31749

P67775

0

dephosphorylation

down-regulates activity

0.893

Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes

SIGNOR-252614

Q00535

P12931

1

phosphorylation

up-regulates

0.39

These results present compelling evidence that cdk5/p35 kinase is responsible for the novel phosphorylation of c-src at ser75 in neuronal cells, raising the intriguing possibility that c-src acts as an effector of cdk5/p35 kinase during neuronal development.

SIGNOR-71950

P27361

P51812

1

phosphorylation

up-regulates

0.73

We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway

SIGNOR-81460

Q9H7Z6

Q13315

0

phosphorylation

up-regulates activity

0.469

In this study we present evidence that MOF is phosphorylated at the threonine 392 residue (pT392-MOF) by ATM subsequent to IR induced DNA damage.|Interestingly, ATM dependent-MOF phosphorylation increases MOF retention on DNA post-irradiation in S/G2-phase cells.

SIGNOR-278350

P30559

O15530

0

phosphorylation

up-regulates activity

0.2

We found that Ser261 in OXTR was phosphorylated by protein kinase D1 (PKD1).|In HEK293A cells, the PKD1-mediated phosphorylation of OXTR promoted its binding to Gq protein and, in turn, OXTR-mediated phosphorylation of PKD1, indicating a positive feedback loop.

SIGNOR-268577

Q14457

Q16644

0

phosphorylation

up-regulates activity

0.425

Taken together, these data indicate that MK2 and MK3 directly phosphorylate Beclin 1 S90 in vitro, and that MK2 like kinase activity also mediates starvation induced Beclin 1 S90 phosphorylation in cultured cells.

SIGNOR-279342

O75553

Q93034

0

polyubiquitination

down-regulates quantity by destabilization

0.327

SOCS7 promotes Dab1 polyubiquitylation and degradation. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SOCS7, a CRL5 substrate adaptor protein, is also required for neocortical layering. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1.

SIGNOR-272140

Q05397

P00533

0

phosphorylation

up-regulates

0.595

In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases.

SIGNOR-167646

P52954

P37275

1

transcriptional regulation

up-regulates quantity by expression

0.326

Compared with the empty vector, LBX1 induced increased promoter activity of threefold to fourfold and fivefold to sixfold for ZEB1 and Snail1, respectively

SIGNOR-266054

Q8N1W1

P61586

1

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

Q96SN8

O94986

1

relocalization

up-regulates activity

0.755

Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome.

SIGNOR-271721

Q96SD1

P78527

0

phosphorylation

up-regulates

0.699

Artemis is a nuclear phosphoprotein required for genomic integrity whose phosphorylation is increased subsequent to dna damage. Artemis phosphorylation by the dna-dependent protein kinase (dna-pk). However, regardless of its association with dna-pkcs, phosphorylation of artemis at both s516 and s645 was stimulated in response to the double-stranded dna-damaging agent bleomycin

SIGNOR-148327

Q04206

O15111

0

phosphorylation

up-regulates activity

0.847

Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter.

SIGNOR-129931

P17252

P43405

0

phosphorylation

up-regulates activity

0.391

We present evidence that Tyr-662 and Tyr-658 of PKCbetaI and PKCalpha, respectively, are phosphorylated by Syk in the membrane compartment of FcepsilonRI-stimulated mast cells. These phosphorylations require prior PKC autophosphorylation of the adjacent serine residues (Ser-661 and Ser-657, respectively) and generate a binding site for the SH2 domain of the adaptor protein Grb-2.

SIGNOR-246581

Q96P20

Q15139

0

phosphorylation

up-regulates activity

0.332

PKD at the Golgi phosphorylates NLRP3 to release it from mitochondria-associated endoplasmic reticulum membranes, allowing for assembly of the mature inflammasome in the cytosol.|These data thus suggest that PKD activity at the Golgi is sufficient to activate the NLRP3 inflammasome.

SIGNOR-279428

Q13191

P27986

1

polyubiquitination

down-regulates quantity by destabilization

0.517

Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells.Here it is shown that Cbl-b interacts with and induces ubiquitin conjugation to the p85 regulatory subunit of phosphatidylinositol 3-kinase, an upstream regulator of Vav.

SIGNOR-272583

Q15652

Q16695

1

demethylation

down-regulates activity

0.2

We now determine that JMJD1C is recruited by USF-1 to various lipogenic genes for H3K9 demethylation to enhance chromatin accessibility in the fed state.

SIGNOR-265170

P27361

Q13115

0

dephosphorylation

down-regulates activity

0.709

Dephosphorylation and Inactivation of ERKs|ERK1 phosphorylated on either threonine (ERK1*Y204F) or tyrosine alone (ERK1*T202A) was utilized as a substrate for HVH2. Threonine 202 and tyrosine 204 in ERK1 (53) correspond to threonine 183 and tyrosine 185 in ERK2 which are the activation-phosphorylation sites by MEK(14, 15, 16). ERK1*, a kinase-deficient mutant, was phosphorylated on both threonine and tyrosine by MEK2 (Fig. 3B). ERK1*T202A, having threonine 202 substituted by an alanine, was phosphorylated only on tyrosine while ERK1*Y204F, having tyrosine 204 substituted by a phenylalanine, was phosphorylated only on threonine (Fig. 3B). GST-HVH2 dephosphorylated all three ERK1* mutants (Fig. 3A), suggesting that double phosphorylations of adjacent threonine and tyrosine were not a prerequisite for HVH2 recognition. However, HVH2 dephosphorylated ERK1* and ERK1*T202A more efficiently than ERK1*Y204F (Fig. 3A), indicating that HVH2 preferred phosphotyrosine over phosphothreonine. Interestingly, MEK also phosphorylated tyrosine residues more efficiently than threonine residues of ERK

SIGNOR-248716

Q9Y4C1

Q5TEC6

1

demethylation

up-regulates activity

0.2

Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.

SIGNOR-276843

P28482

Q07869

1

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

P28482

P19419

1

phosphorylation

up-regulates activity

0.563

We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erk1 phosphorylates five c-terminal sites in elk-1 (s324,t336, s383, s389 and s422) with varying degrees of efficiency.

SIGNOR-235455

Q05397

O00401

1

phosphorylation

up-regulates activity

0.69

In addition, FAK can phosphorylate N-WASP and promote actin polymerization, and inhibition of FAK kinase activity suppresses N-WASP activity.

SIGNOR-278977

P62136

P28482

1

dephosphorylation

down-regulates

0.446

P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3)

SIGNOR-103152

P49841

P23246

1

phosphorylation

down-regulates

0.345

Psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. / threonine phosphorylation of psf by gsk3 primarily occurs on residue t687

SIGNOR-168392

P19784

Q00613

1

phosphorylation

up-regulates

0.348

Transcriptional activity and dna binding of heat shock factor-1 involve phosphorylation on threonine 142 by ck2.As hsf1 is activated by heat shock simultaneously with the nuclear translocation of the protein kinase ck2, we have investigated the role of ck2 in hsf1 activatio

SIGNOR-99606

P46937-3

P12931

0

phosphorylation

up-regulates activity

0.632

We found that YAP1, the pivotal effector of the Hippo signaling pathway, is a direct SRC phosphorylation target, and YAP1 phosphorylation at three sites in its transcription activation domain is necessary for SRC-YAP1-mediated transformation.

SIGNOR-274025

P11908

Q9UHD2

0

phosphorylation

up-regulates activity

0.2

Here, we show that ionizing radiation results in TBK1-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase (PRPS)1/2 at T228, thereby enhancing PRPS1/2 catalytic activity and promoting deoxyribonucleotide synthesis.

SIGNOR-277317

P15923

P28482

0

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

Q9HC98

P52948

1

phosphorylation

down-regulates activity

0.315

To elucidate which of the identified sites can be targeted by CDK1/cyclin B1 and Nek6 in vitro (Figure S1D), we performed phosphorylation reactions using recombinant kinases and unlabeled ATP followed by phosphopeptide mapping (Table S1). MS analysis confirmed phosphorylation of S591 and S822 by Nek6 as well as phosphorylation of T529, T536, S595, S606, and T653 by CDK1. Phosphomimetic Mutants of Nup98 Show Defects in NPC Localization

SIGNOR-273893

P15172

P15692

1

transcriptional regulation

up-regulates quantity by expression

0.391

We further demonstrate that the myogenic transcription factor, MyoD, and its heterodimeric binding proteins E12 and E47, up-regulate the expression of endogenous VEGF through direct interaction with the VEGF promoter.

SIGNOR-257598

P28482

P23396

1

phosphorylation

up-regulates

0.2

Erk phosphorylates threonine 42 residue of ribosomal protein s3.

SIGNOR-137955

P35222

P00533

0

phosphorylation

up-regulates activity

0.773

EGFR and TRKA effect on WNT3a mediated Topflash induction was abolished by U0126 or expression of dominant negative LRP6-5A mutant (XREF_FIG), demonstrating that both EGFR and TRKA signal via ERK and LRP6 pathway to upregulate WNT and beta-catenin signaling.|FGFR2, FGFR3, EGFR and TRKA Phosphorylate beta-catenin at Tyr142.

SIGNOR-278309

P18433

P07948

1

dephosphorylation

down-regulates activity

0.3

We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397|Lyn expressed in CHO cells has a substantially higher specific activity than Lyn in RBL cells because of high levels of phosphorylation at its active site Tyr-397 (Fig. 1). Enhanced Lyn kinase activity in the CHO cells leads to spontaneous phosphorylation of multiple cellular proteins, including FcϵRI

SIGNOR-248436

Q13043

P98177

1

phosphorylation

up-regulates

0.427

The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1

SIGNOR-178193

P13497

P20908

1

cleavage

up-regulates activity

0.623

BMP-1 Can Efficiently Cleave Pro-α1(V) N-propeptides and Pro-α2(V) C-propeptides and Less Efficiently Cleave Pro-α1(V) C-propeptides in Vitro.NH2-terminal sequencing of an ∼35-kDa band in the BMP-1-treated material (N-α1(V), Fig. 3 B,lanes 2 and 3) showed it to correspond to the NH2-terminal portion of the pro-α1(V) N-propeptide previously shown to be cleaved in pro-α1(V)3 homotrimers by BMP-1 (39), whereas NH2-terminal sequencing of an ∼38-kDa band (C-α1(V)BMP-1, Fig. 3 B,lanes 2 and 3) showed it to correspond to pro-α1(V) C-propeptides cleaved between Asp-1594 and Asp-1595.

SIGNOR-256344

Q8TBZ2

P22681

0

monoubiquitination

up-regulates activity

0.298

We moreover found that AMAP1 is monoubiquitinated, rather than polyubiquitinated, by virtue of Cbl and provide evidence that the ability of AMAP1 to be monoubiquitinated is important for its involvement in invasion.

SIGNOR-272627

Q14703

Q70SY1

1

cleavage

up-regulates

0.561

Bbf2h7 is cleaved by s1p in response to er stress / cleaved fragments of the bbf2h7 n-terminal portion containing the bzip domain translocate into nuclei

SIGNOR-151309

P68431

Q9BYW2

0

trimethylation

up-regulates activity

0.2

Our results suggest that HYPB HMTase may coordinate histone methylation and transcriptional regulation in mammals and open perspective for the further study of the potential roles of HYPB protein in hematopoiesis and pathogenesis of HD.

SIGNOR-269071

Q15569

P23528

1

phosphorylation

down-regulates activity

0.528

Like TESK1, TESK2 phosphorylated cofilin specifically at Ser-3 and induced formation of actin stress fibers and focal adhesionsExpression of cofilin or S3A-cofilin into HeLa cells induced marked decreases in rhodamine-phalloidin staining due to the actin binding and -depolymerizing activity of cofilin

SIGNOR-246723

P12931

Q9NPF5

1

phosphorylation

down-regulates activity

0.2

C-Src phosphorylates DMAP1 at Tyr246 and disrupts Bub3/DMAP1 complex formation.

SIGNOR-279431

P06241

P24666

1

phosphorylation

up-regulates activity

0.382

We identify Tyr-131 as the major phosphorylation site and Tyr-132 as a minor site and the Src family PTKs Lck and Fyn as enzymes capable of phosphorylating these sites in vivo and in vitro. Both Tyr-131 and Tyr-132 are located next to the catalytic pocket of LMPTP, and especially, Tyr-131 seems to be important for the activity of LMPTP. Phosphorylation of Tyr-131 or Tyr-132, particularly the former, caused an increase in the activity of LMPTP.

SIGNOR-251150

P45983

Q9H211

1

phosphorylation

up-regulates quantity by stabilization

0.368

We discovered that human Cdt1, an essential origin licensing protein whose activity must be restricted to G(1) phase, is a substrate of the stress-activated mitogen-activated protein (MAP) kinases p38 and c-Jun N-terminal kinase (JNK). These MAP kinases phosphorylate Cdt1 both during unperturbed G(2) phase and during an acute stress response. Phosphorylation renders Cdt1 resistant to ubiquitin-mediated degradation during S phase and after DNA damage by blocking Cdt1 binding to the Cul4 adaptor, Cdt2.

SIGNOR-276361

P60953

Q96DR7

0

guanine nucleotide exchange factor

up-regulates activity

0.585

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-260545

P06493

Q2NKX8

1

phosphorylation

up-regulates

0.579

Following phosphorylation of pich on the cdk1 site t1063, plk1 is recruited to pich and controls its localization. Starting in prometaphase, pich accumulates at kinetochores and inner centromeres.

SIGNOR-152133

P04114

P55157

0

lipidation

up-regulates activity

0.793

As ApoB is translated, it is lipidated by microsomal triglyceride transfer protein (MTP). MTP adds triglycerides to the nascent ApoB during its co-translational translocation into the lumen of the endoplasmic reticulum.

SIGNOR-252118

O14974

O14757

0

phosphorylation

down-regulates quantity by destabilization

0.2

MYPT1 is phosphorylated by CDK1, thus recruiting protein phosphatase 1β (PP1cβ) to dephosphorylate and inactivate Plk1. Here we identified that Chk1 directly interacts with MYPT1 and preferentially phosphorylates MYPT1 at Ser20, which is essential for MYPT1-PP1cβ interaction and subsequent Plk1 dephosphorylation.

SIGNOR-277870

P52735

P63000

1

guanine nucleotide exchange factor

up-regulates

0.761

Vav2 activates rac1 / vav2 is an exchange factor for rho family gtpases.

SIGNOR-81645

P17612

Q13698

1

phosphorylation

up-regulates activity

0.346

To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2.

SIGNOR-263112

Q8NA31

P54274

1

relocalization

up-regulates activity

0.2

The shelterin complex has six proteins, containing TRF1, TRF2, POT1, RAP1, TIN2, and TPP1. The shelterin complex is localized to the chromosome end and protects telomeric DNA (Palm and de Lange, 2008). The TTM complex acts as a “linker” and bridges the LINC and shelterin complexes together. The connection between TTM and shelterin complexes is well-known, which is mediated by TERB1 and TRF1

SIGNOR-263315

Q7Z6Z7

O14757

1

ubiquitination

down-regulates quantity by destabilization

0.298

Taken together, these results are consistent with our hypothesis that HUWE1 directly poly-ubiquitinates and targets Chk1 to the proteasome.

SIGNOR-278568

Q9H2X6

O00257

1

phosphorylation

up-regulates activity

0.423

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

SIGNOR-278484

P60484

P23528

1

dephosphorylation

up-regulates activity

0.441

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

SIGNOR-276980

P21333

P48454

0

dephosphorylation

down-regulates quantity by destabilization

0.2

Filamin is a phosphoprotein that organizes actin filaments into networks. We report that a purified C-terminal recombinant region of filamin is a suitable substrate for calcineurin |Mutagenesis analysis showed that a dephosphorylation step occurred in Ser 2152, which was previously shown to provide resistance to calpain cleavage when endogenous PKA is activated. In contrast, phosphorylation of Ser 2152 was recently reported to be necessary for membrane dynamic changes. In this regard, we found that CsA protects filamin in platelets from calpain degradation.

SIGNOR-248507

P35222

P67870

0

phosphorylation

up-regulates activity

0.601

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

SIGNOR-251067

P12931

O75365

1

phosphorylation

down-regulates activity

0.358

Our results show that Src kinase activity leads to the tyrosine phosphorylation of PRL-3, primarily on Y53.|Collectively these results support a model in which Src causes phosphorylation of PRL-3 on Y53 to promote its pro-invasion functions, and suggest for the first time that the metastasis-associated tyrosine phosphatase PRL-3 may itself be regulated by post-translational modification.

SIGNOR-278262

P62714

P37840

1

dephosphorylation

down-regulates activity

0.276

α-Synuclein (α-Syn) is a key protein that accumulates as hyperphosphorylated aggregates in pathologic hallmark features of Parkinson's disease (PD) and other neurodegenerative disorders. Phosphorylation of this protein at serine 129 is believed to promote its aggregation and neurotoxicity, suggesting that this post-translational modification could be a therapeutic target. Here, we demonstrate that phosphoprotein phosphatase 2A (PP2A) dephosphorylates α-Syn at serine 129

SIGNOR-248592

Q96JN8

O95714

0

polyubiquitination

down-regulates quantity by destabilization

0.456

NEURL4 is a substrate of HERC2, and together these results indicate that the NEURL4-HERC2 complex participates in the ubiquitin-dependent regulation of centrosome architecture.

SIGNOR-272921

P60953

Q96PX9

0

guanine nucleotide exchange factor

up-regulates activity

0.285

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-260565

P49757

Q8TBB1

0

ubiquitination

down-regulates

0.74

Lnx functions as a ring type e3 ubiquitin ligase that targets the cell fate determinant numb for ubiquitin-dependent degradation.

SIGNOR-112201

Q03112

P23769

1

transcriptional regulation

up-regulates quantity by expression

0.359

Evi1 directly binds to the promoter region of GATA-2 and thus enhances the GATA-2 transcription.

SIGNOR-266062

P62136

P04150

1

dephosphorylation

up-regulates activity

0.291

The current study assessed whether PP1\u03b1 can stimulate GR function and tested two different hypotheses: First, that PP1\u03b1 regulates GR activity through suppression of MDM2 activity by dephosphorylating it at Ser166, thereby reducing the MDM2-mediated ubiquitination of GR and the subsequent proteasomal degradation of the receptor, as shown for the MR and AR ( xref ; xref ); and second, that PP1\u03b1 directly dephosphorylates the GR at a particular site to relieve functional repression as demonstrated for PP2A and PP5 ( xref ; xref ; xref ).|The involvement of GR-Ser211 phosphorylation supports the assumption that altered subcellular trafficking is a mechanism less likely contributing to the PP1\u03b1-dependent GR activation.

SIGNOR-277161

Q9UEW8

Q9H4A3

0

phosphorylation

up-regulates

0.446

Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1).

SIGNOR-151671

P27361

Q969V6

1

phosphorylation

down-regulates

0.2

Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization.

SIGNOR-195157

Q13148

P09651

1

post transcriptional regulation

up-regulates

0.406

TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis

SIGNOR-262824

P20645

Q8IWJ2

0

relocalization

up-regulates activity

0.532

Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector

SIGNOR-253086

Q13557

Q14571

1

phosphorylation

down-regulates activity

0.308

Phopho-specific antibodies demonstrate that InsP(3)R2 Ser-150 is phosphorylated in vivo by CaMKIIδ. The results of this study show that serine 150 of the InsP(3)R2 is phosphorylated by CaMKII and results in a decrease in the channel open probability.

SIGNOR-262692

P28482

Q02447

1

phosphorylation

up-regulates

0.305

Here, we show that sp3, which, as sp1, belongs to the gc-rich binding transcription factor family, is also phosphorylated by erk in vitro on serine 73. in the inducible cell lines, expression of wild-type form of sp3 increases vegf production whereas the s73a form has a reduced potential reflecting its lower transcriptional activity.

SIGNOR-157272

Q9H3R0

P04908

1

demethylation

down-regulates activity

0.2

As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation

SIGNOR-263862

O96017

P40337

1

phosphorylation

up-regulates

0.455

We demonstrated that checkpoint kinase-2 (chk2) binds to the beta-domain of pvhl and phosphorylates ser 111 on dna damage. Notably, this modification enhances pvhl-mediated transactivation of p53 by recruiting p300 and tip60 to the chromatin of p53 target gene

SIGNOR-177091

Q8IXJ6

P35558

1

deacetylation

up-regulates quantity by stabilization

0.426

Conversely, SIRT2 deacetylates and stabilizes PEPCK1.|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1

SIGNOR-267599

P98170

Q04726

1

ubiquitination

up-regulates activity

0.507

These findings suggest that TLE3 ubiquitylation by XIAP may be required during Wnt pathway activation to facilitate its dissociation from TCF/Lef, allowing subsequent beta-catenin binding and transcriptional activation.

SIGNOR-278528

Q13255

P17252

0

phosphorylation

down-regulates activity

0.385

Furthermore, we demonstrate that the selectivity of PKC action on receptor signaling rests on phosphorylation of a threonine residue located in the G protein-interacting domain of the receptor. Modification at Thr(695) selectively disrupts mGluR1alpha-G(q/11) interaction without affecting signaling through G(s).

SIGNOR-249043

P33176

Q96N16

1

relocalization

up-regulates activity

0.2

Marlin-1 is associated with kinesin-I and suggest that the movement of Marlin-1 is mediated by plus end microtubuledependent molecular motors

SIGNOR-260989

P43378

P10912

1

dephosphorylation

down-regulates activity

0.314

Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR

SIGNOR-248505

P20020

P17612

0

phosphorylation

up-regulates activity

0.451

The ATPase is phosphorylated only at this site by the cAMP-dependent protein kinase, and the phosphorylation is inhibited by calmodulin. The effect of the phosphorylation is to decrease the Km for Ca2+ of the purified ATPase from about 10 microM to about 1.4 microM and to increase the Vmax of ATP hydrolysis about 2-fold.

SIGNOR-262694

Q06124

Q05397

1

dephosphorylation

down-regulates

0.731

Dca concomitantly and significantly increased association of tyrosine phosphatase shp2 with fak. Incubation of immunoprecipitated fak, in vitro, with glutathione-s-transferase-shp2 fusion protein resulted in tyrosine dephosphorylation of fak in a concentration-dependent manner.

SIGNOR-148926

P68400

Q9BRS2

1

phosphorylation

up-regulates quantity by stabilization

0.332

Casein kinase 2 (CK2) phosphorylates RIOK1 at T410, which stabilizes RIOK1 by antagonizing K411 methylation and impeding the recruitment of FBXO6 to RIOK1.

SIGNOR-273630

Q04724

P68400

0

phosphorylation

up-regulates

0.32

These results suggest that ck2 phosphorylation of serine 239 of gro/tle1 is important for its function during neuronal differentiation.

SIGNOR-129026

P17542

Q02750

0

phosphorylation

down-regulates

0.2

We found that hypoxia greatly accelerated tal1 turnover in these cells through mitogen-activated protein kinase (mapk)2-mediated phosphorylation, ubiquitination, and proteasomal degradation.

SIGNOR-116149

Q99661

Q13153

0

phosphorylation

down-regulates

0.385

Here we found that mcak is a cognate substrate of pak1 wherein pak1 phosphorylates mcak on serines 192 and 111 both in vivo and in vitro. Furthermore, we found that pak1 phosphorylation of mcak on serines 192 and 111 preferentially regulates its microtubule depolymerization activity and localization to centrosomes

SIGNOR-199084

P49815

P28482

0

phosphorylation

down-regulates activity

0.681

Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation.

SIGNOR-249454

Q16539

P42566

1

phosphorylation

up-regulates

0.345

Tnf-_ induces phosphorylation of eps15 at ser-796eps15 is a substrate for p38_these results suggest an attractive model in which p38 phosphorylates both eps15 and egfr to trigger efficient endocytosis

SIGNOR-203315

P49841

P17612

0

phosphorylation

down-regulates activity

0.557

Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3alpha or ser9 in gsk3beta. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka).

SIGNOR-188577

P28482

Q15796

1

phosphorylation

up-regulates

0.722

We show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity.

SIGNOR-91714

P48729

Q99873

1

phosphorylation

up-regulates activity

0.2

CSNK1a1 directly bound and phosphorylated PRMT1 to control its genomic targeting to PRMT1-sustained proliferation genes as well as PRMT1-suppressed differentiation genes.|Taken together, these data support a provisional model in which CSNK1a1 directs PRMT1 to genomic targets that promote self-renewal and suppress terminal differentiation.In the context of transcription regulation, PRMT1 has been generally considered as a transcriptional co-activator.

SIGNOR-279733

P49841

P52945

1

phosphorylation

down-regulates quantity

0.2

We show that glucose levels modulate PDX1 protein phosphorylation at a novel C-terminal GSK3 consensus that maps to serines 268 and 272. A decrease in glucose levels triggers increased turnover of the PDX1 protein in a GSK3-dependent manner, such that PDX1 phosphomutants are refractory to the destabilizing effect of low glucose

SIGNOR-255566

Q13546

Q6WCQ1

1

phosphorylation

up-regulates activity

0.2

Under such conditions, RIP1 phosphorylates and activates RIP3, which in turn phosphorylates its downstream substrate MLKL, leading to plasma membrane rupture and necrosis( xref ).

SIGNOR-279755

Q13322

P28482

0

phosphorylation

up-regulates

0.373

We show that grb10 is a direct substrate of the p42/44 mitogen-activated protein kinase (mapk)we identified ser(150), ser(418), and ser(476) of human grb10zeta as mapk-mediated in vitro phosphorylation sites. Replacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation. Taken together, our findings suggest that phosphorylation of the adaptor protein may provide a feedback inhibitory mechanism by which grb10 regulates insulin signaling.

SIGNOR-138163

P43403

P15941

1

phosphorylation

up-regulates activity

0.448

Indeed, the present results demonstrate that ZAP-70 phosphorylates MUC1-CD and that the MUC1-CD Y-20 site functions, at least in part, as a ZAP-70 substrate (Fig. 4C). In this regard, the in vivo phosphorylation data indicate that ZAP-70 may also contribute to phosphorylation of MUC1-CD Y-46.The results further show that ZAP-70 phosphorylation of MUC1-CD stimulates the interaction of MUC1 andBeta-catenin.

SIGNOR-247039

P01106

Q01196

0

transcriptional regulation

down-regulates quantity by repression

0.337

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

SIGNOR-260093

Q8IZL9

Q9UPZ9

1

phosphorylation

up-regulates

0.2

Recombinant cak1p phosphorylates thr-157 in the tdy motif of recombinant ick and activates its activity in vitro.

SIGNOR-138420

P06493

O95239

1

phosphorylation

up-regulates activity

0.489

Identification of Cdk phosphorylation of Kif4A at T1161 in early mitosis. We show that Cdk phosphorylation of Kif4A licenses its chromosome localization.

SIGNOR-265994

Q9GZV5

Q86U44

0

transcriptional regulation

up-regulates quantity by expression

0.2

Here we find that METTL3 promotes translation of certain mRNAs including epidermal growth factor receptor (EGFR) and the Hippo pathway effector TAZ in human cancer cells.

SIGNOR-265955

Q06124

Q02556

1

dephosphorylation

down-regulates activity

0.353

We found that Bcr-abl-induced, Shp2 dependent dephosphorylation of Icsbp impaired repression of GAS2 by this transcription factor.

SIGNOR-277173

Q14CB8

P61586

1

gtpase-activating protein

down-regulates activity

0.568

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-260471