GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
O75385	Q16543	1	phosphorylation	down-regulates activity	0.2	Serine/Threonine Kinase Unc-51-like Kinase-1 (Ulk1) Phosphorylates the Co-chaperone Cell Division Cycle Protein 37 (Cdc37) and Thereby Disrupts the Stability of Cdc37 Client Proteins.\|Ulk1-mediated phosphorylation of Ser-339 in Cdc37 compromised the recruitment of client kinases to a complex comprising Cdc37 and heat shock protein 90 (Hsp90) but only modestly affected Cdc37 binding to Hsp90.	SIGNOR-280158
O96017	Q96GD4	1	phosphorylation	up-regulates activity	0.324	Because Chk1 and Chk2 can share substrates ( ), we investigated whether Chk2 phosphorylates Aurora B-B-serine 331 in nocodazole.\|In addition, Chk2 promotes proper chromosome alignment through Aurora B-B-serine 331 phosphorylation.	SIGNOR-278906
P61586	P12931	0	phosphorylation	down-regulates activity	0.668	When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.\|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity	SIGNOR-271701
Q06265	P68400	0	phosphorylation	up-regulates	0.2	Indeed recombinant pmscl1 undergoes ck2-mediated phosphorylation in vitro at various serine residues, including serines 409 and 411, which reside within the phosphosim region. the exchange of hydrophobic core residues or serines 409 and 411 to alanine attenuates binding of sumo to the phosphosim-containing fragment of pmscl1 in a yeast two-hybrid assay	SIGNOR-184031
Q9Y243	Q92934	1	phosphorylation	down-regulates	0.542	Ser-136 is the major phosphoacceptor site for akt;akt can weakly phosphorilate ser-155.	SIGNOR-81122
Q7Z569	Q8IVT5	1	ubiquitination	down-regulates quantity by destabilization	0.661	Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15.	SIGNOR-272028
P13688	Q13557	0	phosphorylation	up-regulates	0.2	Camkiid specifically phosphorylates thr-457 on ceacam1-sf, which in turn regulates the process of lumen formation via apoptosis of the central acinar cells.	SIGNOR-203402
P31749	Q8TDN4	1	phosphorylation	down-regulates activity	0.34	Here, we report that Cables1 levels are controlled by a phosphorylation and 14-3-3-dependent mechanism. Mutagenic analyses identified two residues, T44 and T150, that are specifically critical for 14-3-3 binding and that serve as substrates for phosphorylation by the cell survival kinase Akt, which by binding directly to Cables1 recruits 14-3-3 to the complex.Ectopic expression of activated Akt (AKT1) prevented Cables1-induced apoptosis.	SIGNOR-276756
P05129	P09211	1	phosphorylation	up-regulates activity	0.2	Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently	SIGNOR-276018
Q16512	P29966	1	phosphorylation	down-regulates activity	0.365	PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163.	SIGNOR-249671
Q06187	Q00987	1	phosphorylation	down-regulates activity	0.278	Phosphorylation of MDM2 by BTK suppresses its ubiquitination activity.	SIGNOR-278330
P17252	P25098	1	phosphorylation	up-regulates activity	0.2	Phosphorylation of GRK2 by protein kinase C abolishes its inhibition by calmodulin. In vitro, GRK2 was preferentially phosphorylated by PKC isoforms alpha, gamma, and delta. Two-dimensional peptide mapping of PKCalpha-phosphorylated GRK2 showed a single site of phosphorylation, which was identified as serine 29 by HPLC-MS. A S29A mutant of GRK2 was not phosphorylated by PKC in vitro and showed no phorbol ester-stimulated phosphorylation when transfected into human embryonic kidney (HEK)293 cells.	SIGNOR-249058
P17612	Q9NP97	1	phosphorylation	up-regulates	0.2	Our results show that km23-1 is required for camp-responsive element (cre) transcriptional activation by tgf_, with s73-km23-1 being required for the cre-dependent tgf_ stimulation of fibronectin (fn) transcription.	SIGNOR-200456
P32519	P62714	0	dephosphorylation	down-regulates activity	0.2	Elf-1 enhances the expression of CD3zeta, whereas it suppresses the expression of FcRgamma gene and lupus T cells have decreased amounts of DNA-binding 98 kDa form of Elf-1. We show that the aberrantly increased PP2A in lupus T cells dephosphorylates Elf-1 at Thr-231. Dephosphorylation results in limited expression and binding of the 98 kDa Elf-1 form to the CD3zeta and FcRgamma promoters. Suppression of the expression of the PP2A leads to increased expression of CD3zeta and decreased expression of FcRgamma genes and correction of the early signaling response	SIGNOR-248591
Q13315	Q13535	0	phosphorylation	up-regulates activity	0.747	Atr-dependent phosphorylation and activation of atm in response to uv treatment or replication fork stalling. Here, we show that atm phosphorylation at ser1981, a characterised autophosphorylation site, is atr-dependent and atm-independent following replication fork stalling or uv treatment	SIGNOR-150870
Q14693	P35790	0	phosphorylation	down-regulates activity	0.273	Because CKI is a constitutively active kinase and ubiquitously distributed in many cell types, high mTORC1 activity depending on nutritional status may be a physiological cue for Lipin1 degradation mediated by CKI and beta-TRCP.\|Thus, we propose that mTORC1 may function as a priming kinase for CKI to promote the phosphorylation of the degron motif in Lipin1.	SIGNOR-280228
Q8IUX7	P28482	0	phosphorylation	up-regulates activity	0.2	We show that DNA binding by AEBP1 requires both the N- and C-terminal domains of AEBP1, and MAPK interaction with AEBP1 (through its N terminus) results in enhanced DNA binding. A threonine at position 623 within the C-terminal domain of AEBP1 plays an important role in DNA binding by AEBP1, because the mutation results in decreased DNA binding by AEBP1, which leads to a decrease in the transcriptional repression ability of AEBP1. We also show that in vitro phosphorylation of AEBP1 by MAPK is greatly reduced upon mutation of T623. These results suggest that MAPK regulates the transcriptional activity of AEBP1 by a novel dual mechanism, in which MAPK interaction enhances and subsequent phosphorylation decreases the DNA-binding ability of AEBP1.	SIGNOR-262897
P49841	P20807	0	cleavage	up-regulates activity	0.272	Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase	SIGNOR-251607
Q9UKX2	Q06413	0	transcriptional regulation	up-regulates quantity by expression	0.431	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238718
P31749	Q9UQC2	1	phosphorylation	down-regulates	0.699	Pkb constitutively associates with gab2, phosphorylates gab2 on a consensus phosphorylation site, ser159, in vitro and inhibits gab2 tyrosine phosphorylation.	SIGNOR-252468
P42229	Q06187	0	phosphorylation	up-regulates activity	0.467	Ectopically expressed BTK kinase domain was capable of tyrosine-phosphorylating STAT5A both in vitro and in vivo. BTK-mediated tyrosine phosphorylation of ectopically expressed wild type (but not Tyr(694) mutant) STAT5A enhanced its DNA binding activity.	SIGNOR-250603
O96028	O14965	0	phosphorylation	up-regulates quantity by stabilization	0.2	Mechanistically, Aurora A phosphorylated NSD2 at S56 residue to protect the protein from cleavage and degradation, thus methylation of Aurora A and phosphorylation of NSD2 bilaterally formed a positive regulating loop.	SIGNOR-275512
Q9P0L9	P17612	0	phosphorylation	up-regulates activity	0.2	PKD2L1 channel activation by PKA phosphorylation. In this study, we observed the activity of PKD2L1 channel increased by the downstream cascades of β2AR and found the clustered phosphorylation sites, Ser-682, Ser-685, and Ser-686 that are significant in the channel regulation by phosphorylation.	SIGNOR-273562
P00533	P43378	0	dephosphorylation	down-regulates activity	0.309	Conversely, increasing expression of PTPN9 wild type (WT) inhibits tyrosyl phosphorylation of ErbB2 and EGFR.\|Protein-tyrosine phosphatase PTPN9 negatively regulates ErbB2 and epidermal growth factor receptor signaling in breast cancer cells.	SIGNOR-277130
Q01970	P17252	0	phosphorylation	down-regulates	0.481	These data establish that direct phosphorylation by pka of ser1105 in the putative g-box of plcbeta3 inhibits galphaq-stimulated plcbeta3 activity.	SIGNOR-58859
Q9NZJ5	P05198	1	phosphorylation	down-regulates activity	0.766	We now demonstrate a major role for Rheb in inhibiting protein synthesis by enhancing the phosphorylation of eIF2α by protein kinase-like ER kinase (PERK).	SIGNOR-260874
Q13188	Q7L9L4	1	phosphorylation	up-regulates	0.817	Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity	SIGNOR-201290
P08581	P22681	0	ubiquitination	down-regulates quantity by destabilization	0.732	Tyrosine y1001, which when phosphorylated upon met activation, is involved in cbl recruitment, allowing receptor ubiquitination and down regulation	SIGNOR-185680
Q14790	P49810	1	cleavage	up-regulates activity	0.332	In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329.	SIGNOR-261752
Q13554	P42224	1	phosphorylation	up-regulates	0.406	All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below).	SIGNOR-154771
P06493	Q15468	1	phosphorylation	down-regulates activity	0.32	Importantly, we show that CDK1 and CyclinB phosphorylates the N-terminal domain of STIL, but not the region encompassing the CC or STAN motifs.	SIGNOR-279145
Q86WB0	P06493	0	phosphorylation	down-regulates	0.253	Moreover, we found cyclin b1/cdk1 to phosphorylate nipa at ser-395 in mitosis. Mutation of both ser-359 and ser-395 impaired effective inactivation of the scfnipa complex, resulting in reduced levels of mitotic cyclin b1	SIGNOR-154047
P31751	Q92945	1	phosphorylation	down-regulates	0.343	AKT phosphorylates the mRNA decay-promoting factor KSRP at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents KSRP interaction with the exoribonucleolytic complex exosome. This impairs KSRPs ability to promote rapid mRNA decay.	SIGNOR-151220
Q96PM5	Q9Y253	1	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
Q96EV8	Q13049	0	ubiquitination	down-regulates quantity	0.537	TRIM32 is an E3 ubiquitin ligase for dysbindin. TRIM32 targets dysbindin for degradation.	SIGNOR-265658
Q15796	P35813	0	dephosphorylation	down-regulates	0.668	Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads.	SIGNOR-146919
Q92794	P04637	1	acetylation	up-regulates	0.67	We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression	SIGNOR-201486
P17252	Q9UJY1	1	phosphorylation	up-regulates activity	0.307	Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation	SIGNOR-107688
O14965	Q96EP1	0	polyubiquitination	down-regulates quantity by destabilization	0.471	Chfr, a mitotic stress checkpoint, plays an important role in cell cycle progression, tumor suppression and the processes that require the E3 ubiquitin ligase activity mediated by the RING finger domain. Chfr stimulates the formation of polyubiquitin chains by ub-conjugating enzymes, and induces the proteasome-dependent degradation of a number of cellular proteins including Plk1 and Aurora A.	SIGNOR-271463
P78527	Q14653	1	phosphorylation	up-regulates	0.43	Phosphorylation of irf-3 by dna-pk after virus infection results in its nuclear retention and delayed proteolysis	SIGNOR-115331
P53350	Q49MG5	1	phosphorylation	up-regulates	0.275	We also demonstrate that asap is a novel substrate of plk1 phosphorylation and have identified serine 289 as the major phosphorylation site by plk1 in vivo. Asap phosphorylated on serine 289 is localized to centrosomes during mitosis, but this phosphorylation is not required for its plk1-dependent localization at the spindle poles. We show that phosphorylated asap on serine 289 contributes to spindle pole stability in a microtubule-dependent manner	SIGNOR-166564
Q2T9J0	P22307	1	cleavage	up-regulates activity	0.503	Here, we demonstrate that Tysnd1, a previously uncharacterized protein, is responsible both for the removal of the leader peptide from PTS2 proteins and for the specific processing of PTS1 proteins. All of the identified Tysnd1 substrates catalyze peroxisomal β-oxidation. In vitro cleavage of Acox1, Scp2 and prethiolase by recombinant Tysnd1.	SIGNOR-261055
P17252	Q96KS0	1	phosphorylation	down-regulates	0.364	Thus, recombinant phd1 was examined for in vitro phosphorylation using protein kinase a, protein kinase calpha, casein kinase i and ii and erk2. The protein was most strongly phosphorylated by protein kinase calpha, and the phosphorylation sites were found to be ser-132, ser-226 and ser-234.Mutation Of ser-132 or ser-234 to asp or glu diminished the enzymatic activity to 25-60%, while mutation of ser-226 scarcely influenced the activity.	SIGNOR-180203
P15056	Q05639	1	phosphorylation	down-regulates quantity by destabilization	0.326	Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.	SIGNOR-276406
P39880	Q96FE7	1	transcriptional regulation	down-regulates quantity by repression	0.368	We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition.	SIGNOR-260072
Q13263	O14757	0	phosphorylation	up-regulates activity	0.282	These data suggested that KAP1 Ser473 phosphorylation by Chk1 and Chk2 does not take place predominantly at sites of DNA damage, and are consistent with previous work indicating that, following their DNA-damage-localized phosphorylation and activation by ATR and ATM, Chk1 and Chk2 dissociate from chromatin to phosphorylate their substrates , ].\|These results therefore indicated that both Chk1 and Chk2 can target KAP1 Ser473, and are in agreement with IR triggering both the ATM and Chk2 and ATR and Chk1 pathways .	SIGNOR-280226
P00519	Q06609	1	phosphorylation	up-regulates activity	0.773	C-Abl phosphorylates Rad51 in vitro and in vivo. phosphorylation of Rad51 by c-Abl enhances complex formation between Rad51 and Rad52, which cooperates with Rad51 in recombination and repair. c-Abl phosphorylates Rad51 Tyr315	SIGNOR-251434
P07478	P55085	1	cleavage	up-regulates activity	0.2	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases \| The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II\|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.\|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263606
P05771	P53004	0	phosphorylation	up-regulates	0.307	Human biliverdin reductase, a previously unknown activator of protein kinase c ?II the phosphorylation of thr500 was confirmed by immunoblotting of hbvr.pkc betaii immunocomplex.	SIGNOR-152181
P12931	P19174	1	phosphorylation	up-regulates activity	0.636	The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.	SIGNOR-247316
Q15759	Q15796	1	phosphorylation	down-regulates	0.352	Smads can also be phosphorylated in the linker region most prominently by the action of mitogen-activated protein (map) kinaseslinker region phosphorylation can prevent nuclear translocation of smads and inhibit tgf-_ signalling, potentially leading to oncogenesis.	SIGNOR-167848
Q5FWF5	O00311	0	phosphorylation	down-regulates	0.432	We show here that eco1 degradation requires the sequential actions of cdk1 and two additional kinases, cdc7-dbf4 and the gsk-3 homolog mck1.	SIGNOR-200397
Q8NEB9	Q00535	0	phosphorylation	down-regulates	0.357	Thr159 phosphorylation negatively regulates the ptdins3 kinase activity of vps34 and autophagy cdk5/p25, a neuronal cdk shown to play a role in alzheimer's disease, can also phosphorylate thr159 of vps34.	SIGNOR-165772
P06241	O14559	1	phosphorylation	down-regulates	0.461	Tcgap interacted with fyn and was phosphorylated by fyn, with tyr-406 in the gap domain as a major fyn-mediated phosphorylation site. Fyn suppressed the gap activity of wild-type tcgap	SIGNOR-147156
O43683	P04637	1	phosphorylation	up-regulates activity	0.484	In addition, purified Bub1 directly phosphorylates p53 on Ser-37 in vitro , possibly inducing cellular senescence [ xref ].\|Studies have shown that depletion and inhibition of Aurora A, Aurora B, Plk1, or Bub1 induces cellular senescence or cell death in a p53 dependent or -independent but p73 dependent manner in many different cell types , - ].	SIGNOR-280199
P43250	O14745	1	phosphorylation	down-regulates activity	0.405	GRK6A phosphorylates NHERF on Ser289, the primary site of constitutive phosphorylation of NHERF in HEK-293 cells. The interaction of NHERF and NHE3 is mediated by the region of NHERF encompassing the second PDZ domain and the tail (25), and it is therefore reasonable that phosphorylation of the serine-rich stretch in the center of this region (including Ser289) might affect the physical interaction of NHERF with NHE3.	SIGNOR-251214
Q08209	P21333	1	dephosphorylation	down-regulates	0.259	We report that a purified c-terminal recombinant region of filamin is a suitable substrate for calcineurin in vitro. Furthermore, 1 microm cyclosporin a (csa), a specific calcineurin inhibitor, reduced the dephosphorylation of the recombinant fragment in 293ft cells	SIGNOR-143979
Q9Y6E0	Q05209	1	phosphorylation	down-regulates activity	0.272	In addition, MST3 can phosphorylate PTP-PEST and inhibit the tyrosine phosphatase activity of PTP-PEST.\|MST3 directly phosphorylates and inactivates protein tyrosine phosphatase PTP-PEST, which enhances cell migration by enhancing the tyrosine phosphorylation of paxillin Y31 and Y118 [ ].	SIGNOR-279127
P51168	P27361	0	phosphorylation	down-regulates quantity by destabilization	0.278	Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4.	SIGNOR-249447
Q13224	P53355	0	phosphorylation	up-regulates activity	0.497	DAPK1 Activation Enhances the NR1 and NR2B Channel Conductance.\|Thus, an activated DAPK1 enhances NR1 and NR2B receptor channel conductance by phosphorylating NR2B subunit at Ser 1303.	SIGNOR-278397
P67775	P04637	1	dephosphorylation	down-regulates activity	0.59	Phosphorylation of p53 at serine 37 is important for transcriptional activity and regulation in response to DNA damage\| Furthermore, in vitro phosphatase assays show that PP2A dephosphorylates p53 at S37.	SIGNOR-248619
P40763	Q13882	0	phosphorylation	up-regulates activity	0.622	29 PTK6 promotes activating phosphorylation of STAT3 at tyrosine residue 705.\|STAT3 has been shown to promote tumor initiation of different tumor types, including those of the gastrointestinal tract and skin, and PTK6 was previously shown to promote STAT3 activation and tumorigenesis in mouse models of colon and skin cancer.	SIGNOR-278346
Q14493	P0DPK2	1	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265419
Q92974	Q16512	0	phosphorylation	down-regulates	0.291	Here we identify a region in the carboxyl terminus of gef-h1 that is important for suppression of its guanine nucleotide exchange activity by microtubules. This portion of the protein includes a coiled-coil motif, a proline-rich motif that may interact with src homology 3 domain-containing proteins, and a potential binding site for 14-3-3 proteins. We show that phosphorylation of gef-h1 at ser(885) by pak1 induces 14-3-3 binding to the exchange factor and relocation of 14-3-3 to microtubules.	SIGNOR-122191
Q9UEW8	Q96J92	0	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
P05129	Q7Z2E3	1	phosphorylation	up-regulates	0.32	We show the novel molecular consequences of increased kinase activities of mutants: aprataxin (aptx), a dna repair protein causative for autosomal recessive ataxia, was found to be a preferential substrate of mutant pkc gamma, and phosphorylation inhibited its nuclear entry. ollectively, phosphorylation occurred at thr111, reducing nuclear aptx.	SIGNOR-186409
P34897	P19474	0	ubiquitination	down-regulates quantity	0.2	The expression of TRIM21, but not the expression of the ligase-dead (LD) mutant TRIM21 (C16A, C31A and H33W) 36, increased SHMT2 ubiquitylation, which suggests that TRIM21 is the E3 ligase for SHMT2 and that the E3 ligase activity of TRIM21 is required for SHMT2 ubiquitylation.\|We found that the overexpression of TRIM21 increased the degradation of SHMT2 in high glucose conditions by binding more K63-ubiquitin.	SIGNOR-278792
P08908	Q6P1N0	0	transcriptional regulation	down-regulates quantity by repression	0.371	Akt kinase-interacting protein 1 (Aki1)/Freud-1/CC2D1A is localized in the cytosol, nucleus, and centrosome. Aki1 plays distinct roles depending on its localization. In the cytosol, it acts as a scaffold protein in the phosphoinositide 3-kinase (PI3K)/3-phosphoinositide-dependent protein kinase 1 (PDK1)/Akt pathway. In the nucleus, it is a transcriptional repressor of the serotonin-1A (5-HT1A) receptor.	SIGNOR-268295
P49023	Q9Y2U5	0	phosphorylation	down-regulates quantity	0.362	As MEKK2 kinase activity is required for this function, our findings support a model of paxillin modification wherein MEKK2 directly phosphorylates and targets paxillin for ubiquitylation.	SIGNOR-278955
Q02962	O75688	0	dephosphorylation	down-regulates activity	0.2	PPM1B can dephosphorylate the Pax2 activation domain and displace the adaptor protein PTIP, thus inhibiting H3K4 methylation and gene activation	SIGNOR-251712
P67870	P18848	1	phosphorylation	down-regulates quantity by destabilization	0.2	By using mutants of ATF4 we identified serine 215 as the main CK2 phosphorylation site. The ATF4 S215A mutant turned out to be more stable than the wild-type form.	SIGNOR-276424
Q6UUV9	Q96EB6	0	deacetylation	up-regulates	0.281	Sirt1 deacetylates and activates torc1	SIGNOR-191568
O60260	O15354	1	ubiquitination	down-regulates quantity by destabilization	0.2	Parkin is a protein of 465 amino acids, and its structure includes a ubiquitin homologous domain in its N terminus and two RING finger domains in its C terminus. Molecular studies have determined that parkin is an E3 ubiquitin ligase function, implicating parkin in the ubiquitin-proteasome system, and raising the possibility that mutations in the gene lead to loss or diminished function. Three substrates for the ubiquitin-ligase function of parkin have been identified to date.1. A 22kDa glycosolated form of alpha-synuclei\|2. Parkin-associated endothelin receptor-like receptor (Pael-R).	SIGNOR-249706
Q9UPR3	Q9UNE7	0	polyubiquitination	down-regulates quantity by destabilization	0.398	Here, we report that the human ortholog of the yeast ever-shorter telomeres 1B (EST1B) binds HDAC8. This interaction is regulated by protein kinase A-mediated HDAC8 phosphorylation and protects human EST1B (hEST1B) from ubiquitin-mediated degradation. Phosphorylated HDAC8 preferentially recruits Hsp70 to a complex that inhibits the CHIP (C-terminal heat shock protein interacting protein) E3 ligase-mediated degradation of hEST1B.	SIGNOR-272649
P17252	Q9UEY8	1	phosphorylation	down-regulates quantity by destabilization	0.334	Results of in vitro experiments with recombinant alpha adducin demonstrated that PKC-phosphorylated adducin was proteolyzed by calpain more quickly than unphosphorylated adducin. \| Phosphorylation of adducin by PKC may be a common mechanism for regulating adducin proteolysis by several proteases. \| The antibody used in panel B is specific for the PKC-phosphorylated form of adducin. This antibody was raised against the phosphopeptide CKKFRTP[pS]FLKKNK, corresponding to amino acids 656-668 of human gamma adducin	SIGNOR-249143
Q9Y4K3	P42336	1	ubiquitination	up-regulates activity	0.458	In contrast to NEDD4L, overexpression of TRAF6 increases the stability of PIK3CA protein and promotes PI3K activation.\|TRAF6 ubiquitinates PIK3CA in vivo.	SIGNOR-278727
O95863	Q92630	0	phosphorylation	down-regulates activity	0.346	DYRK2 mediated Snail degradation protects against tumor cell metastasis.\|DYRK2 phosphorylation of Snail at Ser104 triggers sequential phosphorylation by GSK3.	SIGNOR-279328
O15525	P27361	0	phosphorylation	up-regulates quantity	0.368	By contrast, MAFG-S124A was not phosphorylated, indicating that ERK1 phosphorylates MAFG at S124.\|Notably, cotransfection of ERK1 increased total levels of wild-type MAFG and MAFG-T3A but not MAFG-S124A, indicating that phosphorylation increased MAFG stability.	SIGNOR-280027
Q13315	P50542	1	phosphorylation	up-regulates activity	0.497	Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141, which promotes PEX5 monoubiquitylation at Lys 209, and recognition of ubiquitylated PEX5 by the autophagy adaptor protein p62, directing the autophagosome to peroxisomes to induce pexophagy.	SIGNOR-262792
Q9UEW8	P55017	1	phosphorylation	down-regulates activity	0.484	SPAK directly phosphorylates NCC and its effects on NCC are universally associated with phosphorylation\|This adds to the evidence that SPAK-mediated phosphorylation acts primarily to increase activity of individual cotransporters without affecting the amount of NCC on the surface\| the kinase (SPAK) that phosphorylates NCC at T53	SIGNOR-264623
Q12888	P25440	0	relocalization	up-regulates activity	0.269	BRD2 is required to recruit 53BP1 to DSBs.\|When BRD2 recruitment was blocked with shRNA or JQ1 (Fig. 3a and Supplementary Figure 3c) or a panel of BRD2 siRNAs (Supplementary Figure 3a), the recruitment of 53BP1 to DSBs was significantly delayed.	SIGNOR-262035
Q14790	P29350	0	dephosphorylation	up-regulates activity	0.354	Caspase-8 is tyrosine-phosphorylated in freshly isolated neutrophils but spontaneously dephosphorylates in culture, in association with the progression of constitutive apoptosis. Phosphorylation of caspase-8 on Tyr-310 facilitates its interaction with the Src-homology domain 2 containing tyrosine phosphatase-1 (SHP-1) and enables SHP-1 to dephosphorylate caspase-8, permitting apoptosis to proceed. The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. Exposure to lipopolysaccharide reduces SHP-1 activity and binding to caspase-8, caspase-8 activity, and rates of spontaneous apoptosis.	SIGNOR-248478
Q06187	P51813	1	phosphorylation	up-regulates	0.335	Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism.	SIGNOR-98028
P08151	P41743	0	phosphorylation	up-regulates activity	0.402	Although functioning downstream of SMO, aPKC-\u03b9/\u03bb phosphorylates and activates GLI1, resulting in maximal DNA binding and transcriptional activation [ xref ].	SIGNOR-279262
O14503	P48729	0	phosphorylation	down-regulates quantity by destabilization	0.2	CK1α-mediated phosphorylation of DEC1 on a conserved degron is required for DEC1 degradation.	SIGNOR-276851
P47712	Q8IW41	0	phosphorylation	up-regulates activity	0.334	The p38-activated protein kinases MNK1, MSK1, and PRAK1 phosphorylate cPLA2 in vitro uniquely on Ser-727. By using Chinese hamster ovary, HeLa, and HEK293 cells stably transfected with wild type and phosphorylation site mutant forms of cPLA2, we show that phosphorylation of cPLA2 at both Ser-505 and Ser-727 and elevation of Ca(2+) leads to its activation in agonist-stimulated cells.	SIGNOR-250162
P61586	O43182	0	gtpase-activating protein	down-regulates activity	0.581	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-260462
P12931	P23743	1	phosphorylation	up-regulates	0.459	Diacylglycerol kinase-alpha phosphorylation by src on y335 is required for activation, membrane recruitment and hgf-induced cell motility.	SIGNOR-157365
Q9Y4G8	O14920	0	phosphorylation	down-regulates quantity by destabilization	0.2	Taken together, these results indicate that IKK\u03b2-dependent phosphorylation of RAPGEF2 is required for RAPGEF2 degradation induced by HGF and mediated by \u03b2TrCP.	SIGNOR-279807
Q05655	P48048	1	null	up-regulates activity	0.307	To determine whether this channel is a substrate for PKA, ROMK tagged with the hemagglutinin epitope was transiently transfected into HEK293 cells. In vitro labeling of immunoprecipitated proteins from transfected cells showed that ROMK could be phosphorylated by PKA. \| Taken together, these results provide strong evidence that direct phosphorylation of the channel polypeptide by PKA is involved in channel regulation and PKA-dependent phosphorylation is essential for ROMK channel activity.	SIGNOR-248943
Q9NYY3	P05067	1	phosphorylation	up-regulates activity	0.348	Here we show that Polo-like kinase 2 (Plk2), an activity-inducible regulator of homeostatic plasticity, directly binds and phosphorylates threonine-668 and serine-675 of APP in\u00a0vitro and associates with APP in\u00a0vivo.\|Plk2 was necessary and sufficient to induce BACE-1-mediated APP amyloidogenic processing following overexcitation, associated intimately with APP, and directly phosphorylated the APP C-terminus.	SIGNOR-279424
Q14469	P36888	1	transcriptional regulation	down-regulates quantity by repression	0.2	We then found that Hes1 directly bound to the promoter region of the FMS-like tyrosine kinase 3 (FLT3) gene and downregulated the promoter activity.	SIGNOR-261563
Q8N122	P28482	0	phosphorylation	up-regulates activity	0.518	We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1.	SIGNOR-188916
Q16665	Q9Y2K7	1	transcriptional regulation	up-regulates quantity by expression	0.2	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271566
Q12772	P27169	1	transcriptional regulation	up-regulates quantity by expression	0.297	we conclude that quercetin exhibits its antiatherogenic property by eliciting the translocation of the mature SREBP2 from endoplasmic reticulum to the nucleus, where it binds to SRE-like sequence in the PON1 promoter and up-regulates PON1 gene transcription and PON1 activity.	SIGNOR-255224
O14921	P17612	0	phosphorylation	up-regulates quantity by stabilization	0.334	Phosphorylation of RGS13 by the cyclic AMP-dependent protein kinase inhibits RGS13 degradation.we show that PKA activation also leads to increased steady-state RGS13 expression through RGS13 phosphorylation, which inhibits RGS13 protein degradation. RGS13 phosphorylation was diminished by mutation of an N-terminal Thr residue (T41) identified as a phosphorylation site by mass spectrometry.	SIGNOR-259835
P55265	P31749	0	phosphorylation	down-regulates activity	0.281	AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively	SIGNOR-276193
P62805	Q58F21	1	relocalization	up-regulates activity	0.2	BRDT interacts with acetylated nucleosomes via its BD1 domain. Binding may be initiated through non-specific interactions with DNA, which allow BRDT to localize to chromatin. Specificity is generated through recognition of tandem acetylated lysine residues (K5ac/K8ac) on the histone H4 tail,	SIGNOR-262066
P17535	P45983	0	phosphorylation	up-regulates	0.796	Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase.	SIGNOR-196038
Q13188	P42336	1	phosphorylation	down-regulates activity	0.2	MST1/2 and HGK inhibit catalytic activity of p110α through phosphorylation at T1061	SIGNOR-277922

O75385

Q16543

1

phosphorylation

down-regulates activity

0.2

Serine/Threonine Kinase Unc-51-like Kinase-1 (Ulk1) Phosphorylates the Co-chaperone Cell Division Cycle Protein 37 (Cdc37) and Thereby Disrupts the Stability of Cdc37 Client Proteins.|Ulk1-mediated phosphorylation of Ser-339 in Cdc37 compromised the recruitment of client kinases to a complex comprising Cdc37 and heat shock protein 90 (Hsp90) but only modestly affected Cdc37 binding to Hsp90.

SIGNOR-280158

O96017

Q96GD4

1

phosphorylation

up-regulates activity

0.324

Because Chk1 and Chk2 can share substrates ( ), we investigated whether Chk2 phosphorylates Aurora B-B-serine 331 in nocodazole.|In addition, Chk2 promotes proper chromosome alignment through Aurora B-B-serine 331 phosphorylation.

SIGNOR-278906

P61586

P12931

0

phosphorylation

down-regulates activity

0.668

When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity

SIGNOR-271701

Q06265

P68400

0

phosphorylation

up-regulates

0.2

Indeed recombinant pmscl1 undergoes ck2-mediated phosphorylation in vitro at various serine residues, including serines 409 and 411, which reside within the phosphosim region. the exchange of hydrophobic core residues or serines 409 and 411 to alanine attenuates binding of sumo to the phosphosim-containing fragment of pmscl1 in a yeast two-hybrid assay

SIGNOR-184031

Q9Y243

Q92934

1

phosphorylation

down-regulates

0.542

Ser-136 is the major phosphoacceptor site for akt;akt can weakly phosphorilate ser-155.

SIGNOR-81122

Q7Z569

Q8IVT5

1

ubiquitination

down-regulates quantity by destabilization

0.661

Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15.

SIGNOR-272028

P13688

Q13557

0

phosphorylation

up-regulates

0.2

Camkiid specifically phosphorylates thr-457 on ceacam1-sf, which in turn regulates the process of lumen formation via apoptosis of the central acinar cells.

SIGNOR-203402

P31749

Q8TDN4

1

phosphorylation

down-regulates activity

0.34

Here, we report that Cables1 levels are controlled by a phosphorylation and 14-3-3-dependent mechanism. Mutagenic analyses identified two residues, T44 and T150, that are specifically critical for 14-3-3 binding and that serve as substrates for phosphorylation by the cell survival kinase Akt, which by binding directly to Cables1 recruits 14-3-3 to the complex.Ectopic expression of activated Akt (AKT1) prevented Cables1-induced apoptosis.

SIGNOR-276756

P05129

P09211

1

phosphorylation

up-regulates activity

0.2

Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently

SIGNOR-276018

Q16512

P29966

1

phosphorylation

down-regulates activity

0.365

PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163.

SIGNOR-249671

Q06187

Q00987

1

phosphorylation

down-regulates activity

0.278

Phosphorylation of MDM2 by BTK suppresses its ubiquitination activity.

SIGNOR-278330

P17252

P25098

1

phosphorylation

up-regulates activity

0.2

Phosphorylation of GRK2 by protein kinase C abolishes its inhibition by calmodulin. In vitro, GRK2 was preferentially phosphorylated by PKC isoforms alpha, gamma, and delta. Two-dimensional peptide mapping of PKCalpha-phosphorylated GRK2 showed a single site of phosphorylation, which was identified as serine 29 by HPLC-MS. A S29A mutant of GRK2 was not phosphorylated by PKC in vitro and showed no phorbol ester-stimulated phosphorylation when transfected into human embryonic kidney (HEK)293 cells.

SIGNOR-249058

P17612

Q9NP97

1

phosphorylation

up-regulates

0.2

Our results show that km23-1 is required for camp-responsive element (cre) transcriptional activation by tgf_, with s73-km23-1 being required for the cre-dependent tgf_ stimulation of fibronectin (fn) transcription.

SIGNOR-200456

P32519

P62714

0

dephosphorylation

down-regulates activity

0.2

Elf-1 enhances the expression of CD3zeta, whereas it suppresses the expression of FcRgamma gene and lupus T cells have decreased amounts of DNA-binding 98 kDa form of Elf-1. We show that the aberrantly increased PP2A in lupus T cells dephosphorylates Elf-1 at Thr-231. Dephosphorylation results in limited expression and binding of the 98 kDa Elf-1 form to the CD3zeta and FcRgamma promoters. Suppression of the expression of the PP2A leads to increased expression of CD3zeta and decreased expression of FcRgamma genes and correction of the early signaling response

SIGNOR-248591

Q13315

Q13535

0

phosphorylation

up-regulates activity

0.747

Atr-dependent phosphorylation and activation of atm in response to uv treatment or replication fork stalling. Here, we show that atm phosphorylation at ser1981, a characterised autophosphorylation site, is atr-dependent and atm-independent following replication fork stalling or uv treatment

SIGNOR-150870

Q14693

P35790

0

phosphorylation

down-regulates activity

0.273

Because CKI is a constitutively active kinase and ubiquitously distributed in many cell types, high mTORC1 activity depending on nutritional status may be a physiological cue for Lipin1 degradation mediated by CKI and beta-TRCP.|Thus, we propose that mTORC1 may function as a priming kinase for CKI to promote the phosphorylation of the degron motif in Lipin1.

SIGNOR-280228

Q8IUX7

P28482

0

phosphorylation

up-regulates activity

0.2

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

SIGNOR-262897

P49841

P20807

0

cleavage

up-regulates activity

0.272

Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase

SIGNOR-251607

Q9UKX2

Q06413

0

transcriptional regulation

up-regulates quantity by expression

0.431

Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation

SIGNOR-238718

P31749

Q9UQC2

1

phosphorylation

down-regulates

0.699

Pkb constitutively associates with gab2, phosphorylates gab2 on a consensus phosphorylation site, ser159, in vitro and inhibits gab2 tyrosine phosphorylation.

SIGNOR-252468

P42229

Q06187

0

phosphorylation

up-regulates activity

0.467

Ectopically expressed BTK kinase domain was capable of tyrosine-phosphorylating STAT5A both in vitro and in vivo. BTK-mediated tyrosine phosphorylation of ectopically expressed wild type (but not Tyr(694) mutant) STAT5A enhanced its DNA binding activity.

SIGNOR-250603

O96028

O14965

0

phosphorylation

up-regulates quantity by stabilization

0.2

Mechanistically, Aurora A phosphorylated NSD2 at S56 residue to protect the protein from cleavage and degradation, thus methylation of Aurora A and phosphorylation of NSD2 bilaterally formed a positive regulating loop.

SIGNOR-275512

Q9P0L9

P17612

0

phosphorylation

up-regulates activity

0.2

PKD2L1 channel activation by PKA phosphorylation. In this study, we observed the activity of PKD2L1 channel increased by the downstream cascades of β2AR and found the clustered phosphorylation sites, Ser-682, Ser-685, and Ser-686 that are significant in the channel regulation by phosphorylation.

SIGNOR-273562

P00533

P43378

0

dephosphorylation

down-regulates activity

0.309

Conversely, increasing expression of PTPN9 wild type (WT) inhibits tyrosyl phosphorylation of ErbB2 and EGFR.|Protein-tyrosine phosphatase PTPN9 negatively regulates ErbB2 and epidermal growth factor receptor signaling in breast cancer cells.

SIGNOR-277130

Q01970

P17252

0

phosphorylation

down-regulates

0.481

These data establish that direct phosphorylation by pka of ser1105 in the putative g-box of plcbeta3 inhibits galphaq-stimulated plcbeta3 activity.

SIGNOR-58859

Q9NZJ5

P05198

1

phosphorylation

down-regulates activity

0.766

We now demonstrate a major role for Rheb in inhibiting protein synthesis by enhancing the phosphorylation of eIF2α by protein kinase-like ER kinase (PERK).

SIGNOR-260874

Q13188

Q7L9L4

1

phosphorylation

up-regulates

0.817

Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity

SIGNOR-201290

P08581

P22681

0

ubiquitination

down-regulates quantity by destabilization

0.732

Tyrosine y1001, which when phosphorylated upon met activation, is involved in cbl recruitment, allowing receptor ubiquitination and down regulation

SIGNOR-185680

Q14790

P49810

1

cleavage

up-regulates activity

0.332

In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329.

SIGNOR-261752

Q13554

P42224

1

phosphorylation

up-regulates

0.406

All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below).

SIGNOR-154771

P06493

Q15468

1

phosphorylation

down-regulates activity

0.32

Importantly, we show that CDK1 and CyclinB phosphorylates the N-terminal domain of STIL, but not the region encompassing the CC or STAN motifs.

SIGNOR-279145

Q86WB0

P06493

0

phosphorylation

down-regulates

0.253

Moreover, we found cyclin b1/cdk1 to phosphorylate nipa at ser-395 in mitosis. Mutation of both ser-359 and ser-395 impaired effective inactivation of the scfnipa complex, resulting in reduced levels of mitotic cyclin b1

SIGNOR-154047

P31751

Q92945

1

phosphorylation

down-regulates

0.343

AKT phosphorylates the mRNA decay-promoting factor KSRP at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents KSRP interaction with the exoribonucleolytic complex exosome. This impairs KSRPs ability to promote rapid mRNA decay.

SIGNOR-151220

Q96PM5

Q9Y253

1

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

Q96EV8

Q13049

0

ubiquitination

down-regulates quantity

0.537

TRIM32 is an E3 ubiquitin ligase for dysbindin. TRIM32 targets dysbindin for degradation.

SIGNOR-265658

Q15796

P35813

0

dephosphorylation

down-regulates

0.668

Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads.

SIGNOR-146919

Q92794

P04637

1

acetylation

up-regulates

0.67

We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression

SIGNOR-201486

P17252

Q9UJY1

1

phosphorylation

up-regulates activity

0.307

Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation

SIGNOR-107688

O14965

Q96EP1

0

polyubiquitination

down-regulates quantity by destabilization

0.471

Chfr, a mitotic stress checkpoint, plays an important role in cell cycle progression, tumor suppression and the processes that require the E3 ubiquitin ligase activity mediated by the RING finger domain. Chfr stimulates the formation of polyubiquitin chains by ub-conjugating enzymes, and induces the proteasome-dependent degradation of a number of cellular proteins including Plk1 and Aurora A.

SIGNOR-271463

P78527

Q14653

1

phosphorylation

up-regulates

0.43

Phosphorylation of irf-3 by dna-pk after virus infection results in its nuclear retention and delayed proteolysis

SIGNOR-115331

P53350

Q49MG5

1

phosphorylation

up-regulates

0.275

We also demonstrate that asap is a novel substrate of plk1 phosphorylation and have identified serine 289 as the major phosphorylation site by plk1 in vivo. Asap phosphorylated on serine 289 is localized to centrosomes during mitosis, but this phosphorylation is not required for its plk1-dependent localization at the spindle poles. We show that phosphorylated asap on serine 289 contributes to spindle pole stability in a microtubule-dependent manner

SIGNOR-166564

Q2T9J0

P22307

1

cleavage

up-regulates activity

0.503

Here, we demonstrate that Tysnd1, a previously uncharacterized protein, is responsible both for the removal of the leader peptide from PTS2 proteins and for the specific processing of PTS1 proteins. All of the identified Tysnd1 substrates catalyze peroxisomal β-oxidation. In vitro cleavage of Acox1, Scp2 and prethiolase by recombinant Tysnd1.

SIGNOR-261055

P17252

Q96KS0

1

phosphorylation

down-regulates

0.364

Thus, recombinant phd1 was examined for in vitro phosphorylation using protein kinase a, protein kinase calpha, casein kinase i and ii and erk2. The protein was most strongly phosphorylated by protein kinase calpha, and the phosphorylation sites were found to be ser-132, ser-226 and ser-234.Mutation Of ser-132 or ser-234 to asp or glu diminished the enzymatic activity to 25-60%, while mutation of ser-226 scarcely influenced the activity.

SIGNOR-180203

P15056

Q05639

1

phosphorylation

down-regulates quantity by destabilization

0.326

Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.

SIGNOR-276406

P39880

Q96FE7

1

transcriptional regulation

down-regulates quantity by repression

0.368

We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition.

SIGNOR-260072

Q13263

O14757

0

phosphorylation

up-regulates activity

0.282

These data suggested that KAP1 Ser473 phosphorylation by Chk1 and Chk2 does not take place predominantly at sites of DNA damage, and are consistent with previous work indicating that, following their DNA-damage-localized phosphorylation and activation by ATR and ATM, Chk1 and Chk2 dissociate from chromatin to phosphorylate their substrates , ].|These results therefore indicated that both Chk1 and Chk2 can target KAP1 Ser473, and are in agreement with IR triggering both the ATM and Chk2 and ATR and Chk1 pathways .

SIGNOR-280226

P00519

Q06609

1

phosphorylation

up-regulates activity

0.773

C-Abl phosphorylates Rad51 in vitro and in vivo. phosphorylation of Rad51 by c-Abl enhances complex formation between Rad51 and Rad52, which cooperates with Rad51 in recombination and repair. c-Abl phosphorylates Rad51 Tyr315

SIGNOR-251434

P07478

P55085

1

cleavage

up-regulates activity

0.2

PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3

SIGNOR-263606

P05771

P53004

0

phosphorylation

up-regulates

0.307

Human biliverdin reductase, a previously unknown activator of protein kinase c ?II the phosphorylation of thr500 was confirmed by immunoblotting of hbvr.pkc betaii immunocomplex.

SIGNOR-152181

P12931

P19174

1

phosphorylation

up-regulates activity

0.636

The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.

SIGNOR-247316

Q15759

Q15796

1

phosphorylation

down-regulates

0.352

Smads can also be phosphorylated in the linker region most prominently by the action of mitogen-activated protein (map) kinaseslinker region phosphorylation can prevent nuclear translocation of smads and inhibit tgf-_ signalling, potentially leading to oncogenesis.

SIGNOR-167848

Q5FWF5

O00311

0

phosphorylation

down-regulates

0.432

We show here that eco1 degradation requires the sequential actions of cdk1 and two additional kinases, cdc7-dbf4 and the gsk-3 homolog mck1.

SIGNOR-200397

Q8NEB9

Q00535

0

phosphorylation

down-regulates

0.357

Thr159 phosphorylation negatively regulates the ptdins3 kinase activity of vps34 and autophagy cdk5/p25, a neuronal cdk shown to play a role in alzheimer's disease, can also phosphorylate thr159 of vps34.

SIGNOR-165772

P06241

O14559

1

phosphorylation

down-regulates

0.461

Tcgap interacted with fyn and was phosphorylated by fyn, with tyr-406 in the gap domain as a major fyn-mediated phosphorylation site. Fyn suppressed the gap activity of wild-type tcgap

SIGNOR-147156

O43683

P04637

1

phosphorylation

up-regulates activity

0.484

In addition, purified Bub1 directly phosphorylates p53 on Ser-37 in vitro , possibly inducing cellular senescence [ xref ].|Studies have shown that depletion and inhibition of Aurora A, Aurora B, Plk1, or Bub1 induces cellular senescence or cell death in a p53 dependent or -independent but p73 dependent manner in many different cell types , - ].

SIGNOR-280199

P43250

O14745

1

phosphorylation

down-regulates activity

0.405

GRK6A phosphorylates NHERF on Ser289, the primary site of constitutive phosphorylation of NHERF in HEK-293 cells. The interaction of NHERF and NHE3 is mediated by the region of NHERF encompassing the second PDZ domain and the tail (25), and it is therefore reasonable that phosphorylation of the serine-rich stretch in the center of this region (including Ser289) might affect the physical interaction of NHERF with NHE3.

SIGNOR-251214

Q08209

P21333

1

dephosphorylation

down-regulates

0.259

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

SIGNOR-143979

Q9Y6E0

Q05209

1

phosphorylation

down-regulates activity

0.272

In addition, MST3 can phosphorylate PTP-PEST and inhibit the tyrosine phosphatase activity of PTP-PEST.|MST3 directly phosphorylates and inactivates protein tyrosine phosphatase PTP-PEST, which enhances cell migration by enhancing the tyrosine phosphorylation of paxillin Y31 and Y118 [ ].

SIGNOR-279127

P51168

P27361

0

phosphorylation

down-regulates quantity by destabilization

0.278

Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4.

SIGNOR-249447

Q13224

P53355

0

phosphorylation

up-regulates activity

0.497

DAPK1 Activation Enhances the NR1 and NR2B Channel Conductance.|Thus, an activated DAPK1 enhances NR1 and NR2B receptor channel conductance by phosphorylating NR2B subunit at Ser 1303.

SIGNOR-278397

P67775

P04637

1

dephosphorylation

down-regulates activity

0.59

Phosphorylation of p53 at serine 37 is important for transcriptional activity and regulation in response to DNA damage| Furthermore, in vitro phosphatase assays show that PP2A dephosphorylates p53 at S37.

SIGNOR-248619

P40763

Q13882

0

phosphorylation

up-regulates activity

0.622

29 PTK6 promotes activating phosphorylation of STAT3 at tyrosine residue 705.|STAT3 has been shown to promote tumor initiation of different tumor types, including those of the gastrointestinal tract and skin, and PTK6 was previously shown to promote STAT3 activation and tumorigenesis in mouse models of colon and skin cancer.

SIGNOR-278346

Q14493

P0DPK2

1

translation regulation

up-regulates quantity by expression

0.2

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

SIGNOR-265419

Q92974

Q16512

0

phosphorylation

down-regulates

0.291

Here we identify a region in the carboxyl terminus of gef-h1 that is important for suppression of its guanine nucleotide exchange activity by microtubules. This portion of the protein includes a coiled-coil motif, a proline-rich motif that may interact with src homology 3 domain-containing proteins, and a potential binding site for 14-3-3 proteins. We show that phosphorylation of gef-h1 at ser(885) by pak1 induces 14-3-3 binding to the exchange factor and relocation of 14-3-3 to microtubules.

SIGNOR-122191

Q9UEW8

Q96J92

0

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

P05129

Q7Z2E3

1

phosphorylation

up-regulates

0.32

We show the novel molecular consequences of increased kinase activities of mutants: aprataxin (aptx), a dna repair protein causative for autosomal recessive ataxia, was found to be a preferential substrate of mutant pkc gamma, and phosphorylation inhibited its nuclear entry. ollectively, phosphorylation occurred at thr111, reducing nuclear aptx.

SIGNOR-186409

P34897

P19474

0

ubiquitination

down-regulates quantity

0.2

The expression of TRIM21, but not the expression of the ligase-dead (LD) mutant TRIM21 (C16A, C31A and H33W) 36, increased SHMT2 ubiquitylation, which suggests that TRIM21 is the E3 ligase for SHMT2 and that the E3 ligase activity of TRIM21 is required for SHMT2 ubiquitylation.|We found that the overexpression of TRIM21 increased the degradation of SHMT2 in high glucose conditions by binding more K63-ubiquitin.

SIGNOR-278792

P08908

Q6P1N0

0

transcriptional regulation

down-regulates quantity by repression

0.371

Akt kinase-interacting protein 1 (Aki1)/Freud-1/CC2D1A is localized in the cytosol, nucleus, and centrosome. Aki1 plays distinct roles depending on its localization. In the cytosol, it acts as a scaffold protein in the phosphoinositide 3-kinase (PI3K)/3-phosphoinositide-dependent protein kinase 1 (PDK1)/Akt pathway. In the nucleus, it is a transcriptional repressor of the serotonin-1A (5-HT1A) receptor.

SIGNOR-268295

P49023

Q9Y2U5

0

phosphorylation

down-regulates quantity

0.362

As MEKK2 kinase activity is required for this function, our findings support a model of paxillin modification wherein MEKK2 directly phosphorylates and targets paxillin for ubiquitylation.

SIGNOR-278955

Q02962

O75688

0

dephosphorylation

down-regulates activity

0.2

PPM1B can dephosphorylate the Pax2 activation domain and displace the adaptor protein PTIP, thus inhibiting H3K4 methylation and gene activation

SIGNOR-251712

P67870

P18848

1

phosphorylation

down-regulates quantity by destabilization

0.2

By using mutants of ATF4 we identified serine 215 as the main CK2 phosphorylation site. The ATF4 S215A mutant turned out to be more stable than the wild-type form.

SIGNOR-276424

Q6UUV9

Q96EB6

0

deacetylation

up-regulates

0.281

Sirt1 deacetylates and activates torc1

SIGNOR-191568

O60260

O15354

1

ubiquitination

down-regulates quantity by destabilization

0.2

Parkin is a protein of 465 amino acids, and its structure includes a ubiquitin homologous domain in its N terminus and two RING finger domains in its C terminus. Molecular studies have determined that parkin is an E3 ubiquitin ligase function, implicating parkin in the ubiquitin-proteasome system, and raising the possibility that mutations in the gene lead to loss or diminished function. Three substrates for the ubiquitin-ligase function of parkin have been identified to date.1. A 22kDa glycosolated form of alpha-synuclei|2. Parkin-associated endothelin receptor-like receptor (Pael-R).

SIGNOR-249706

Q9UPR3

Q9UNE7

0

polyubiquitination

down-regulates quantity by destabilization

0.398

Here, we report that the human ortholog of the yeast ever-shorter telomeres 1B (EST1B) binds HDAC8. This interaction is regulated by protein kinase A-mediated HDAC8 phosphorylation and protects human EST1B (hEST1B) from ubiquitin-mediated degradation. Phosphorylated HDAC8 preferentially recruits Hsp70 to a complex that inhibits the CHIP (C-terminal heat shock protein interacting protein) E3 ligase-mediated degradation of hEST1B.

SIGNOR-272649

P17252

Q9UEY8

1

phosphorylation

down-regulates quantity by destabilization

0.334

Results of in vitro experiments with recombinant alpha adducin demonstrated that PKC-phosphorylated adducin was proteolyzed by calpain more quickly than unphosphorylated adducin. | Phosphorylation of adducin by PKC may be a common mechanism for regulating adducin proteolysis by several proteases. | The antibody used in panel B is specific for the PKC-phosphorylated form of adducin. This antibody was raised against the phosphopeptide CKKFRTP[pS]FLKKNK, corresponding to amino acids 656-668 of human gamma adducin

SIGNOR-249143

Q9Y4K3

P42336

1

ubiquitination

up-regulates activity

0.458

In contrast to NEDD4L, overexpression of TRAF6 increases the stability of PIK3CA protein and promotes PI3K activation.|TRAF6 ubiquitinates PIK3CA in vivo.

SIGNOR-278727

O95863

Q92630

0

phosphorylation

down-regulates activity

0.346

DYRK2 mediated Snail degradation protects against tumor cell metastasis.|DYRK2 phosphorylation of Snail at Ser104 triggers sequential phosphorylation by GSK3.

SIGNOR-279328

O15525

P27361

0

phosphorylation

up-regulates quantity

0.368

By contrast, MAFG-S124A was not phosphorylated, indicating that ERK1 phosphorylates MAFG at S124.|Notably, cotransfection of ERK1 increased total levels of wild-type MAFG and MAFG-T3A but not MAFG-S124A, indicating that phosphorylation increased MAFG stability.

SIGNOR-280027

Q13315

P50542

1

phosphorylation

up-regulates activity

0.497

Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141, which promotes PEX5 monoubiquitylation at Lys 209, and recognition of ubiquitylated PEX5 by the autophagy adaptor protein p62, directing the autophagosome to peroxisomes to induce pexophagy.

SIGNOR-262792

Q9UEW8

P55017

1

phosphorylation

down-regulates activity

0.484

SPAK directly phosphorylates NCC and its effects on NCC are universally associated with phosphorylation|This adds to the evidence that SPAK-mediated phosphorylation acts primarily to increase activity of individual cotransporters without affecting the amount of NCC on the surface| the kinase (SPAK) that phosphorylates NCC at T53

SIGNOR-264623

Q12888

P25440

0

relocalization

up-regulates activity

0.269

BRD2 is required to recruit 53BP1 to DSBs.|When BRD2 recruitment was blocked with shRNA or JQ1 (Fig. 3a and Supplementary Figure 3c) or a panel of BRD2 siRNAs (Supplementary Figure 3a), the recruitment of 53BP1 to DSBs was significantly delayed.

SIGNOR-262035

Q14790

P29350

0

dephosphorylation

up-regulates activity

0.354

Caspase-8 is tyrosine-phosphorylated in freshly isolated neutrophils but spontaneously dephosphorylates in culture, in association with the progression of constitutive apoptosis. Phosphorylation of caspase-8 on Tyr-310 facilitates its interaction with the Src-homology domain 2 containing tyrosine phosphatase-1 (SHP-1) and enables SHP-1 to dephosphorylate caspase-8, permitting apoptosis to proceed. The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. Exposure to lipopolysaccharide reduces SHP-1 activity and binding to caspase-8, caspase-8 activity, and rates of spontaneous apoptosis.

SIGNOR-248478

Q06187

P51813

1

phosphorylation

up-regulates

0.335

Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism.

SIGNOR-98028

P08151

P41743

0

phosphorylation

up-regulates activity

0.402

Although functioning downstream of SMO, aPKC-\u03b9/\u03bb phosphorylates and activates GLI1, resulting in maximal DNA binding and transcriptional activation [ xref ].

SIGNOR-279262

O14503

P48729

0

phosphorylation

down-regulates quantity by destabilization

0.2

CK1α-mediated phosphorylation of DEC1 on a conserved degron is required for DEC1 degradation.

SIGNOR-276851

P47712

Q8IW41

0

phosphorylation

up-regulates activity

0.334

The p38-activated protein kinases MNK1, MSK1, and PRAK1 phosphorylate cPLA2 in vitro uniquely on Ser-727. By using Chinese hamster ovary, HeLa, and HEK293 cells stably transfected with wild type and phosphorylation site mutant forms of cPLA2, we show that phosphorylation of cPLA2 at both Ser-505 and Ser-727 and elevation of Ca(2+) leads to its activation in agonist-stimulated cells.

SIGNOR-250162

P61586

O43182

0

gtpase-activating protein

down-regulates activity

0.581

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-260462

P12931

P23743

1

phosphorylation

up-regulates

0.459

Diacylglycerol kinase-alpha phosphorylation by src on y335 is required for activation, membrane recruitment and hgf-induced cell motility.

SIGNOR-157365

Q9Y4G8

O14920

0

phosphorylation

down-regulates quantity by destabilization

0.2

Taken together, these results indicate that IKK\u03b2-dependent phosphorylation of RAPGEF2 is required for RAPGEF2 degradation induced by HGF and mediated by \u03b2TrCP.

SIGNOR-279807

Q05655

P48048

1

null

up-regulates activity

0.307

To determine whether this channel is a substrate for PKA, ROMK tagged with the hemagglutinin epitope was transiently transfected into HEK293 cells. In vitro labeling of immunoprecipitated proteins from transfected cells showed that ROMK could be phosphorylated by PKA. | Taken together, these results provide strong evidence that direct phosphorylation of the channel polypeptide by PKA is involved in channel regulation and PKA-dependent phosphorylation is essential for ROMK channel activity.

SIGNOR-248943

Q9NYY3

P05067

1

phosphorylation

up-regulates activity

0.348

Here we show that Polo-like kinase 2 (Plk2), an activity-inducible regulator of homeostatic plasticity, directly binds and phosphorylates threonine-668 and serine-675 of APP in\u00a0vitro and associates with APP in\u00a0vivo.|Plk2 was necessary and sufficient to induce BACE-1-mediated APP amyloidogenic processing following overexcitation, associated intimately with APP, and directly phosphorylated the APP C-terminus.

SIGNOR-279424

Q14469

P36888

1

transcriptional regulation

down-regulates quantity by repression

0.2

We then found that Hes1 directly bound to the promoter region of the FMS-like tyrosine kinase 3 (FLT3) gene and downregulated the promoter activity.

SIGNOR-261563

Q8N122

P28482

0

phosphorylation

up-regulates activity

0.518

We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1.

SIGNOR-188916

Q16665

Q9Y2K7

1

transcriptional regulation

up-regulates quantity by expression

0.2

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

SIGNOR-271566

Q12772

P27169

1

transcriptional regulation

up-regulates quantity by expression

0.297

we conclude that quercetin exhibits its antiatherogenic property by eliciting the translocation of the mature SREBP2 from endoplasmic reticulum to the nucleus, where it binds to SRE-like sequence in the PON1 promoter and up-regulates PON1 gene transcription and PON1 activity.

SIGNOR-255224

O14921

P17612

0

phosphorylation

up-regulates quantity by stabilization

0.334

Phosphorylation of RGS13 by the cyclic AMP-dependent protein kinase inhibits RGS13 degradation.we show that PKA activation also leads to increased steady-state RGS13 expression through RGS13 phosphorylation, which inhibits RGS13 protein degradation. RGS13 phosphorylation was diminished by mutation of an N-terminal Thr residue (T41) identified as a phosphorylation site by mass spectrometry.

SIGNOR-259835

P55265

P31749

0

phosphorylation

down-regulates activity

0.281

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

SIGNOR-276193

P62805

Q58F21

1

relocalization

up-regulates activity

0.2

BRDT interacts with acetylated nucleosomes via its BD1 domain. Binding may be initiated through non-specific interactions with DNA, which allow BRDT to localize to chromatin. Specificity is generated through recognition of tandem acetylated lysine residues (K5ac/K8ac) on the histone H4 tail,

SIGNOR-262066

P17535

P45983

0

phosphorylation

up-regulates

0.796

Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase.

SIGNOR-196038

Q13188

P42336

1

phosphorylation

down-regulates activity

0.2

MST1/2 and HGK inhibit catalytic activity of p110α through phosphorylation at T1061

SIGNOR-277922