GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P04049	P53350	0	phosphorylation	up-regulates activity	0.289	An in vitro kinase assay demonstrated that PLK1 directly phosphorylated CRAF at S338 and S339, but not at S621 (XREF_FIG).\|These results demonstrate that PLK1 increases the stability of CRAF protein by preventing proteasome degradation.	SIGNOR-278190
P49761	P01106	0	transcriptional regulation	up-regulates quantity by expression	0.2	C-Myc enhances transcriptional activation of CLK3 promoter in CCA cells.	SIGNOR-274123
Q05655	P98082	1	phosphorylation	down-regulates	0.296	Mutational analysis revealed that a dab2 ser(24) phosphorylation mutant (s24a) abrogated the inhibitory function of dab2.	SIGNOR-127198
O95147	Q92844	0	ubiquitination	up-regulates activity	0.2	TRAF2-mediated Lys63-linked ubiquitination of DUSP14/MKP6 is essential for its phosphatase activity. Mass spectrometry and mutational analyses identified that DUSP14 was Lys63-linked ubiquitinated at lysine 103 residue.Here we report that DUSP14 was Lys63-linked ubiquitinated at Lys103 residue by the E3 ligase TRAF2 during TCR signaling. Furthermore, ubiquitination of DUSP14 was essential for its phosphatase activity.	SIGNOR-272811
P17812	P17252	0	phosphorylation	down-regulates	0.2	These data indicated that protein kinase c phosphorylation at ser(462) stimulates human ctp synthetase 1 activity, whereas phosphorylation at thr(455) inhibits activity.	SIGNOR-154621
Q13765	Q13418	0	phosphorylation	up-regulates	0.426	Ilk phosphorylated alpha-nac on residue ser-43. Ilk-dependent phosphorylation of alpha-nac induced the nuclear accumulation of the coactivator and that phosphorylation of alpha-nac by ilk is required for the potentiation of c-jun-mediated responses by the kinase.	SIGNOR-127694
P51812	P35916	0	phosphorylation	down-regulates	0.2	Upon truncation of this c-terminal stretch, or mutation of the tyr-707 residue alone, autoinhibition is attenuated, and the kinase becomes constitutively active. Based on these findings we propose that phosphorylation of the tyr-707 represents a novel alternative regulatory mechanism for p90rsk activation.	SIGNOR-98708
Q9UN19	P06239	0	phosphorylation	up-regulates activity	0.646	Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell lines\|yrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins.	SIGNOR-249373
Q96PY6	P40337	1	phosphorylation	down-regulates quantity by destabilization	0.257	Nek1 phosphorylates Von Hippel-Lindau tumor suppressor to promote its proteasomal degradation and ciliary destabilization. Mutation of pVHL at S-168 increases protein stability.	SIGNOR-276434
Q92915	P67870	0	phosphorylation	up-regulates activity	0.27	Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents.	SIGNOR-275745
Q9H063	P42345	0	phosphorylation	down-regulates	0.712	The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly.	SIGNOR-165795
P11678	P10153	1	post translational modification	up-regulates activity	0.476	Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism.	SIGNOR-261704
P29474	Q02156	0	phosphorylation	down-regulates activity	0.331	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251632
Q92597	O00141	0	phosphorylation	up-regulates	0.569	Transient expression of active (sgk1-s422d) and inactive (sgk1-k127a) sgk1 mutants confirmed that activating sgk1 stimulates ndrg1-thr(346/356/366) phosphorylation. dexamethasone (0.2 mum) acutely activated sgk1 and the peak of this response (2-3 h) coincided with the induction of g (na), and both responses were pi3k-dependent. While these data suggest that sgk1 might mediate the rise in g (na), transient expression of the inactive sgk1-k127a mutant did not affect the hormonal induction of g (na) but did suppress the activation of sgk1.	SIGNOR-180821
Q86V81	P31749	0	phosphorylation	up-regulates	0.449	Nuclear akt directly binds aly and phosphorylates it on the t219 residue. gfp-aly t219d displayed comparable activity to gfp control and wild-type aly, indicating that aly phosphorylation by akt is sufficient to enhance mrna export.	SIGNOR-252518
Q96GD4	Q53HL2	1	phosphorylation	up-regulates activity	0.82	AURKB directly phosphorylated CDCA8 at Ser(154), Ser(219), Ser(275), and Thr(278) and seemed to stabilize CDCA8 protein in cancer cells.\|Phosphorylation and activation of cell division cycle associated 8 by aurora kinase B plays a significant role in human lung carcinogenesis.	SIGNOR-279506
P38398	P42574	0	cleavage	down-regulates quantity by destabilization	0.473	We demonstrate the cleavage and the consequential downregulation of full-length BRCA1 by caspase-3 during UV-induced apoptosis. Finally, mutation of a caspase-3 specific cleavage site (D/A1154) rendered BRCA1 non-cleavable.	SIGNOR-256326
Q6ZNA4	P84022	1	ubiquitination	down-regulates activity	0.654	Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblasts. Arkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling.	SIGNOR-235388
P43403	Q9UQC2	1	phosphorylation	up-regulates activity	0.46	In the present study, we found that gab2 is phosphorylated by zap-70, associates with the tcr signaling complex, and acts as an inhibitory adaptor molecule via recruitment of shp-2 following tcr ligation.	SIGNOR-110731
Q02078	Q16539	0	phosphorylation	up-regulates activity	0.661	We show that mef2a, but not mef2b or mef2d, is a substrate for p38. Threonines 312 and 319 are the key regulatory phosphorylation sites by p38 in mef2a. Phosphorylation at these sites enhances transcriptional activity of mef2a	SIGNOR-62780
P09471	Q14469	1	null	down-regulates	0.2	GNAO1 overexpression enhances GSC differentiation by downregulating neural progenitor gene HES1	SIGNOR-278092
Q5T0T0	O00220	1	ubiquitination	down-regulates quantity	0.2	The collective data indicate that endogenous MARCH-8 ubiquitinates TRAIL-R1 to attenuate its cell surface expression.	SIGNOR-278570
P04150	P48775	1	transcriptional regulation	down-regulates quantity by repression	0.337	Repression of GR-mediated expression of the tryptophan oxygenase gene by the SWI/SNF complex during liver development.	SIGNOR-268995
O75386	Q8N6U8	1	relocalization	up-regulates activity	0.608	Upon knockdown of Tulp3 using siRNA in IMCD3 cells, ciliary localization of Gpr161 was severely reduced	SIGNOR-259938
P69905	P15169	0	cleavage	down-regulates activity	0.2	Both human plasma carboxypeptidase N (CPN) and membrane-bound carboxypeptidase M (CPM) released the C-terminal arginine (alpha-Arg141) of the alpha chain of human adult hemoglobin. Thus, the hydrolysis of hemoglobin by CPM and CPN demonstrated the contribution of the alpha-Arg141 residue to sustaining the tetrameric structure of hemoglobin and its normal oxygen affinity and vasoactivity.	SIGNOR-256508
P51668	Q9HAU4	0	ubiquitination	up-regulates activity	0.702	Our data further show that SMURF2 monoubiquitinates UBCH5 at lysine 144 to form an active complex required for efficient degradation of a RAS family E3, beta transducing repeat containing protein 1 (beta-TrCP1).	SIGNOR-278718
O94916	Q13315	0	phosphorylation	up-regulates	0.271	Tonebp/orebp contains atm consensus phosphorylation sites at ser-1197, ser-1247, and ser-1367. In conclusion, signaling via atm is necessary for full activation of tonebp/orebp	SIGNOR-125077
Q86YJ5	P05362	1	ubiquitination	down-regulates quantity by destabilization	0.2	MARCH-IX expression causes ubiquitination and downregulation of ICAM-1 and a short alternative transcript of MARCH-IX lacking the RING-CH domain, termed MARCH-IX RINGless, is shown to act as a positive regulator of MARCH-IX activity.\|MARCH-IX mediates ubiquitination and downregulation of ICAM-1.	SIGNOR-278821
O94953	Q99814	0	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-271584
P53667	P23470	0	dephosphorylation	down-regulates activity	0.26	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254711
Q14934	P45984	0	phosphorylation	up-regulates activity	0.419	Here, we showed that the nuclear factor of activated T3 (NFAT3) is phosphorylated by JNK1 or JNK2 at Ser(213) and Ser(217), which are located in the conserved SP motif.\|Moreover, a 3xNFAT-luc reporter gene assay indicated that NFAT3 transcriptional activity was increased in a dose-dependent manner by JNK1 or JNK2.	SIGNOR-280036
P30305	Q9UNH5	0	dephosphorylation	down-regulates activity	0.56	Cdc14A inhibits Cdc25A and Cdc25B activity, the latter through direct binding and dephosphorylation ( ).\|Together, these data indicate that Cdc14A dephosphorylates Cdc25B, inhibiting its catalytic activity.	SIGNOR-276968
P0CG48	Q96BN8	0	cleavage	up-regulates quantity	0.717	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270820
Q03060	P27361	0	phosphorylation	down-regulates quantity by destabilization	0.41	The MAPKs extracellular signal-regulated kinases 1 and 2 physically interact with ICER and mediated the phosphorylation of ICER on a critical serine residue (Ser-41). A mutant form of ICER in which Ser-41 was substituted by alanine had a half-life 4-5 h longer than its wild-type counterpart. This alteration in stability was due to the inability of the Ser-41-mutant ICER to be efficiently ubiquitinated and degraded via the ubiquitin-proteasome pathway.	SIGNOR-275978
Q16539	O95644	1	phosphorylation	down-regulates	0.622	We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats.	SIGNOR-74560
P07948	P31994	1	phosphorylation	up-regulates activity	0.43	Therefore, we conclude that FcgammaRIIb1 phosphorylation upon BCR-FcgammaR coligation is most likely due to BCR-associated Lyn	SIGNOR-249380
P28324	P24941	0	phosphorylation	up-regulates activity	0.363	Phosphorylation of ELK4 at Thr194 and Ser387 by CDK2 is required for EGF-induced cell transformation.	SIGNOR-278210
Q13164	P17302	1	phosphorylation	down-regulates activity	0.54	Activated BMK1 selectively phosphorylates Cx43 on Ser-255 in vitro and in vivo. These data demonstrate that BMK1 kinase activity alone is both a necessary and sufficient component in the mediation of EGF-induced Cx43 Ser-255 phosphorylation and subsequent inhibition of GJC.	SIGNOR-250115
Q8N884	O00743	0	dephosphorylation	down-regulates activity	0.2	In this study, we found that PPP6C suppressed phosphorylation of human cGAS (hcGAS) at S435 or mouse cGAS (mcGAS) at S420 in its substrate-binding pocket, thus preventing its binding to GTP and inhibiting the synthesis of cGAMP.\|These data suggest that PPP6C inhibits cGAS activity.	SIGNOR-276990
Q969G2	P28069	1	transcriptional regulation	up-regulates quantity by expression	0.514	We show that normal LHX4 binds to a human-specific element and subsequently activates transcription from the proximal upstream regulatory sequence of POUIF1, a gene encoding a POU homeodomain transcription factor known as the main regulator of GH expression.	SIGNOR-266056
P53350	Q9UBW7	1	phosphorylation	down-regulates quantity by destabilization	0.376	PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis\|Similar analyses with ZNF198 identified two clusters of putative Plk1 phosphorylation sites in vitro. A cluster of serine residues at the N-terminus of ZNF198, S303, S305, and S309, and a cluster at the C-terminus, S1056 and S1064. The triple Ser to Ala mutant, S303A/S305A/S309A, consistently exhibited the lowest level of phosphorylation in vitro, in comparison to the double S1056A/S1064A mutant	SIGNOR-275560
Q9UPW6	Q99717	0	transcriptional regulation	up-regulates quantity	0.259	Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation	SIGNOR-268939
P01106	P11908	1	transcriptional regulation	up-regulates quantity by expression	0.277	Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation.	SIGNOR-267376
Q9BQQ3	P28482	0	phosphorylation	down-regulates activity	0.27	Here we show that GRASP65 is phosphorylated on serine 277 in interphase cells, and this is strongly enhanced in response to the addition of serum or epidermal growth factor. This is directly mediated by ERK suggesting that GRASP65 has some role in growth factor signal transduction. These results argue against Ser-277 phosphorylation alone causing the dissolution of GRASP65 oligomers and cisternal unstacking, although it may make a significant contribution to these events.	SIGNOR-262841
P09619	P12931	1	phosphorylation	up-regulates activity	0.604	The increased Src activity is mainly due to the phosphorylation of Tyr-419, rather than the dephosphorylation of Tyr-530 of Src protein. PDGFR, not FAK or EGFR, appears to be the upstream protein tyrosine kinase responsible for the detachment-induced Src activation in the lung tumor cells.	SIGNOR-247979
O15297	Q00987	1	dephosphorylation	up-regulates	0.681	Wip1 interacts with and dephosphorylates mdm2 at serine 395, a site phosphorylated by the atm kinase. Dephosphorylated mdm2 has increased stability and affinity for p53, facilitating p53 ubiquitination and degradation.	SIGNOR-158328
Q6UB99	P23560	1	transcriptional regulation	up-regulates quantity by expression	0.2	Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons.	SIGNOR-266732
P32245	P17612	0	phosphorylation	down-regulates activity	0.308	Activation of MC4R by agonist is associated with protein kinase A (PKA) and GRK phosphorylation of serine/threonine residues in the C-terminal tail of MC4R, followed by -arrestin and dynamin-dependent internalization of the receptor. Thr312 and Ser329/330 in the C-terminal tail of MC4R are potential sites for PKA	SIGNOR-250016
Q16820	P05771	0	phosphorylation	down-regulates quantity	0.2	These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate.	SIGNOR-263173
P41161	Q12857	0	transcriptional regulation	down-regulates quantity	0.2	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268874
O14920	P62714	0	dephosphorylation	down-regulates activity	0.259	Permanent activation of the upstream kinase IKK beta results from UVB-induced inhibition of the catalytic subunit of Ser-Thr phosphatase PP2A (PP2Ac), leading to immediate phosphorylation and degradation of newly synthesized I kappaB alpha\|Chronic Ser 177/181 phosphorylation of IKKβ was due to UVB-induced inhibition of the catalytic subunit of the Ser-Thr phosphatase PP2A (PP2Ac)	SIGNOR-248580
Q8N4C8	Q15797	1	phosphorylation	down-regulates activity	0.2	Msn kinases directly phosphorylate α-helix 1 of Smad. we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for α-helix 1 phosphorylation.	SIGNOR-276336
P42224	Q99102	1	transcriptional regulation	up-regulates quantity by expression	0.393	Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level.	SIGNOR-254099
O14965	Q9Y657	1	phosphorylation	up-regulates activity	0.243	The Ser84 and Ser99 amino acids within SPINDLIN1 were further identified as the key functional sites in WNT/TCF-4 signaling activation. Mutation of these two sites of SPINDLIN1 abolished its effects on promoting WNT/TCF-4 signaling and cancer cell proliferation. We further found that Aurora-A could interact with and phosphorylate SPINDLIN1 at its key functional sites, Ser84 and Ser99, suggesting that phosphorylation of SPINDLIN1 is involved in its oncogenic function.	SIGNOR-273550
Q99742	P07101	1	transcriptional regulation	down-regulates quantity by repression	0.252	Overexpression and siRNA experiments revealed that NPAS1, in concert with ARNT, negatively regulates the expression of TH and that this regulation is mediated by a direct binding of NPAS1 on the TH promoter.	SIGNOR-253702
O00311	Q99459	1	phosphorylation	down-regulates activity	0.344	During SPOC, Dbf4 binds to Cdc5 and promotes Cdc7-mediated phosphorylation of Cdc5, which then presumably prevents Cdc5 from recognizing its substrates in the MEN pathway .	SIGNOR-280203
P54253	P31749	0	phosphorylation	up-regulates quantity by stabilization	0.411	Interaction of Ataxin-1 and 14-3-3 Requires Akt Phosphorylation at S776. 14-3-3 protein, a multifunctional regulatory molecule, mediates the neurotoxicity of ataxin-1 by binding to and stabilizing ataxin-1, thereby slowing its normal degradation.	SIGNOR-252561
Q15172	P17252	0	phosphorylation	down-regulates activity	0.341	In this study, we identified a novel phosphorylation site at Ser(41) of B56α. This phosphoamino acid residue was efficiently phosphorylated in vitro by PKCα.	SIGNOR-276603
P45983	Q05639	1	phosphorylation	down-regulates quantity by destabilization	0.374	Ribosome-associated JNK phosphorylates the eukaryotic translation elongation factor 1A isoform 2 (eEF1A2) on serines 205 and 358 to promote degradation of NSPs by the proteasome.	SIGNOR-276492
Q13131	Q86TI0	1	phosphorylation	down-regulates	0.425	In rat l6 myotubes, endogenous tbc1d1 is strongly phosphorylated on ser237 and binds to 14-3-3s in response to the ampk activators aicar	SIGNOR-159048
P12931	P02545	1	phosphorylation	up-regulates activity	0.51	In this study, we found that the constitutively active Src Y527F mutant caused the disassembly of lamin A/C. We demonstrate that Src directly phosphorylates lamin A mainly at Tyr45 both in vitro and in intact cells.	SIGNOR-279288
P48200	Q9UNH5	0	dephosphorylation	up-regulates activity	0.348	IRP2 Ser-157 is phosphorylated by Cdk1/cyclin B1 during G(2)/M and is dephosphorylated during mitotic exit by the phosphatase Cdc14A. Ser-157 phosphorylation during G(2)/M reduces IRP2 RNA-binding activity and increases ferritin synthesis, whereas Ser-157 dephosphorylation during mitotic exit restores IRP2 RNA-binding activity and represses ferritin synthesis.	SIGNOR-248829
P23771	Q99835	0	null	up-regulates activity	0.2	That GATA is a downstream effector of the hedgehog pathway.	SIGNOR-253527
P60953	Q9P107	0	gtpase-activating protein	down-regulates activity	0.512	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-260507
P62805	Q92993	0	acetylation	down-regulates activity	0.2	Thus, the TIP60 HAT complex is recruited to MYC-target genes and, probably with other other HATs, contributes to histone acetylation in response to mitogenic signals.	SIGNOR-262061
P49674	O14641	1	phosphorylation	up-regulates	0.693	We demonstrated that dvl2 is phosphorylated at s143 and t224 in a manner that requires both non-canonical wnt5a ligand and casein kinase 1 epsilon (ck1_), and that this event is critical to interact with plk1 in early stages of the cell cycle	SIGNOR-197555
P55212	P05067	1	cleavage	up-regulates activity	0.724	Inhibition of caspase-6 activity prevents serum deprivation-mediated increase of Ab. Caspase-6 directly cleaves APP at the C terminus and generates a C-terminal fragment of 3 kDa (Capp3) and an Ab-containing 6.5-kDa fragment, Capp6.5, that increases in serum-deprived neurons	SIGNOR-261762
P06493	Q92934	1	phosphorylation	up-regulates activity	0.2	CDK1-mediated Bcl-2 serine 70 phosphorylation enhances its pro-apoptotic function, whereas CDK1-mediated Bad serine 128 phosphorylation promotes apoptosis.	SIGNOR-267921
P46108	P00533	0	phosphorylation	down-regulates activity	0.74	To address these questions, we have developed an antibody that specifically recognizes the CrkII protein phosphorylated on Tyr221, and we found that the EGF receptor directly phosphorylates CrkII on Tyr221. Furthermore, we observed that the phosphorylation of Tyr221 of CrkII correlated with its dissociation from the EGF receptor, implicating the phosphorylation of Tyr221 in the negative feedback of binding to the EGF receptor.	SIGNOR-251091
P41240	Q00987	1	phosphorylation	up-regulates activity	0.2	Here we show that activated c-Src kinase phosphorylates Y281 and Y302 of Mdm2, resulting in an increase in Mdm2 stability and its association with Ubc12, the E2 enzyme of the neddylating complex.	SIGNOR-279163
Q00987	O43293	0	phosphorylation	up-regulates quantity by stabilization	0.342	Zip kinase was able to phosphorylate mdm2 at ser166, a site previously reported to be modified by akt kinase, thus demonstrating that zip kinase is a bona fide mdm2-binding protein.	SIGNOR-123159
P28482	Q01196	1	phosphorylation	up-regulates activity	0.2	We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation.	SIGNOR-138973
O43586	Q05209	0	dephosphorylation	down-regulates activity	0.61	We also demonstrate that PTP-PEST dephosphorylates PSTPIP at tyrosine 344. Importantly, we identified tyrosine 344 as the main phosphorylation site of PSTPIP by performing tryptic phosphopeptide maps. \|The biological functions of the complexes formed between PSTPIP and SH2 domain-containing tyrosine kinases may be to transmit the signals from activated EGF and PDGF receptor.\|Furthermore, we show that PSTPIP is phosphorylated downstream of the activated PDGF and EGF receptors. This phosphorylation of PSTPIP is most likely mediated by c-Abl	SIGNOR-248656
P48200	P06493	0	phosphorylation	down-regulates	0.353	Irp2 ser-157 is phosphorylated by cdk1/cyclin b1 during g(2)/m / ser-157 phosphorylation during g(2)/m reduces irp2 rna-binding activity	SIGNOR-179171
P31749	P62136	0	dephosphorylation	down-regulates activity	0.426	Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells\|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells	SIGNOR-252603
P62136	Q13422	1	dephosphorylation	up-regulates	0.279	Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway	SIGNOR-174859
Q03468	Q13216	0	ubiquitination	down-regulates quantity by destabilization	0.582	We have previously shown that CSA is a subunit of an E3 ubiquitin ligase complex. Here we demonstrate that CSB is a substrate of this ligase: Following UV irradiation, CSB is degraded at a late stage of the repair process in a proteasome- and CSA-dependent manner.	SIGNOR-271406
Q8NEM2	Q96GD4	0	phosphorylation	up-regulates activity	0.372	AurB phosphorylates Ser634 of SHCBP1 during mitosis. We generated a phosphorylation site mutant, S634A-SHCBP1, which was prematurely recruited to the central spindle during anaphase and inhibited furrowing.	SIGNOR-273552
Q96EZ8	O14965	0	phosphorylation	up-regulates activity	0.316	We conclude that Aurora-A phosphorylates MCRS1 on Ser35/36 specifically during mitosis.	SIGNOR-278232
P00533	P15941	1	phosphorylation	up-regulates activity	0.577	We also show that the activated egf-r phosphorylates the muc1 cytoplasmic tail on tyrosine at a yekv motif that functions as a binding site for the c-src sh2 domain. The results demonstrate that egf-r-mediated phosphorylation of muc1 induces binding of muc1 to c-src in cells	SIGNOR-109538
O60716	P17612	0	phosphorylation	down-regulates	0.2	We showed that pkc_ phosphorylation of p120 at serine (s)879 in response to thrombin or lipopolysaccharide challenge reduced p120 binding affinity for ve-cadherin and mediated aj disassembly secondary to ve-cadherin internalization	SIGNOR-198288
P11831	P35354	1	null	up-regulates	0.252	Srf within myofibers modulates Il6 and Cox2/Il4 expressions and, therefore, exerts a paracrine control of satellite cell proliferation and fusion, respectively, which in turn support skeletal muscle hypertrophy.	SIGNOR-255965
O75144	P17252	0	phosphorylation	up-regulates activity	0.2	PKCα and PKCβ are required for phosphorylation of ICOSL and ICOSL-mediated cytokine induction. Therefore, S285 is required for PKC substrate (serine) phosphorylation of ICOSL, and each of the upstream arginines is similarly required for this phosphorylation.	SIGNOR-273798
P11308	O60216	0	relocalization	down-regulates activity	0.2	Large-scale AML genome re-sequencing efforts have identified novel recurrently mutated genes, including the members of the cohesin complex (RAD21, SMC3, SMC1A, and STAG2), implicated in the pathogenesis of this disease.Using ATAC-seq, we determined that mutant cohesin lead to a state of elevated chromatin accessibility and higher predicted binding at transcription factor binding sites for ERG, GATA2, and RUNX1. Moreover, using ChIP-Seq, we formally demonstrated increased binding of GATA2 and RUNX1 to these sites. Finally, we demonstrated that knockdown of these three TFs in human HSPC can revert the differentiation block induced by mutant cohesin. These results support a model in which mutant cohesin impairs hematopoietic differentiation and enforces stem cell programs through the modulation of ERG, GATA2, and RUNX1 chromatin accessibility, expression, and activity.	SIGNOR-261515
Q8NFG4	Q9NQL2	1	gtpase-activating protein	up-regulates activity	0.683	The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1 [..} RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP-bound for the interaction to occur	SIGNOR-256504
Q07955	P17612	0	phosphorylation	up-regulates	0.2	Here, we show that pka phosphorylates srsf1 on serine 119 in vitro. Phosphorylation of srsf1 on this site enhanced the rna binding capacity of srsf1 in vivo	SIGNOR-196397
P25440	Q12888	1	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
Q9UQM7	Q12959	1	phosphorylation	down-regulates activity	0.649	Synapse-associated protein 97 (SAP97), a member of membrane-associated guanylate kinase protein family, has been implicated in the processes of targeting ionotropic glutamate receptors at postsynaptic sites. \| We show here that SAP97 is directly associated with NR2A through its PDZ1 domain, and CaMKII-dependent phosphorylation of SAP97-Ser-232 disrupts NR2A interaction both in an in vitro pull-out assay and in transfected COS-7 cells. Moreover, expression of SAP97(S232D) mutant has effects similar to those observed upon constitutively activating CaMKII.	SIGNOR-250618
P22694	Q92934	1	phosphorylation	down-regulates	0.429	Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136.	SIGNOR-81141
P18848	P23381	1	transcriptional regulation	up-regulates quantity by expression	0.2	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269429
P17706	P52333	1	dephosphorylation	down-regulates activity	0.697	Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5.	SIGNOR-133078
Q8N6F7	P07948	0	phosphorylation	up-regulates activity	0.245	Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148. Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation.	SIGNOR-273560
Q96RI1	Q05513	0	phosphorylation	up-regulates	0.38	The effect of fic1 on fxr phosphorylation and nuclear localization and its effects on bsep promoter activity could be blocked with protein kinase c zeta (pkc zeta) inhibitors (pseudosubstrate or small interfering rna silencing). Recombinant pkc zeta directly phosphorylated immunoprecipitated fxr. The mutation of threonine 442 of fxr to alanine yielded a dominant negative protein,	SIGNOR-179771
Q7Z570	O15247	1	transcriptional regulation	down-regulates quantity by repression	0.2	ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3).	SIGNOR-269465
P04626	Q9BXH1	1	phosphorylation	down-regulates quantity by destabilization	0.281	HER2 phosphorylates and destabilizes pro-apoptotic PUMA. Using an intracellular assay, we found PUMA to be phosphorylated in breast cancer cells with activated HER2. Via cell-free HER2 kinase assay, we observed that PUMA was directly phosphorylated by HER2. Activation of HER2 decreased PUMA protein half-life.	SIGNOR-276474
P55075	P40424	0	transcriptional regulation	down-regulates quantity by repression	0.271	Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription	SIGNOR-265803
Q9NPP4	Q5S007	0	phosphorylation	up-regulates activity	0.359	LRRK2 phosphorylates NLRC4 at Ser533 upon inflammasome activation.\|These data suggest that LRRK2 promotes NLRC4 inflammasome activation through its kinase activity.	SIGNOR-279338
P27348	P48729	0	phosphorylation	down-regulates activity	0.516	This protein kinase has been identified as casein kinase Ialpha (CKIalpha) by peptide mapping analysis and sequencing. Among mammalian 14-3-3, only 14-3-3 tau possesses a phosphorylatable residue at the same position (Ser-233), and we show that this residue is also phosphorylated by CKI. In addition, we show that 14-3-3 zeta is exclusively phosphorylated on Thr-233 in human embryonic kidney 293 cells. The residue 233 is located within a region shown to be important for the association of 14-3-3 to target proteins.	SIGNOR-250795
Q9NY61	Q07812	1	transcriptional regulation	down-regulates quantity	0.2	We identify the transcriptional regulator apoptosis-antagonizing transcription factor (AATF)/Che-1 as a critical regulator of the cellular outcome of the p53 response. Upon genotoxic stress, AATF is phosphorylated by the checkpoint kinase MK2. Phosphorylation results in the release of AATF from cytoplasmic MRLC3 and subsequent nuclear translocation where AATF binds to the PUMA, BAX and BAK promoter regions to repress p53-driven expression of these pro-apoptotic genes.	SIGNOR-259916
P37840	Q5S007	0	phosphorylation	down-regulates activity	0.624	Here we show that full-length Lrrk2 or fragments containing its kinase domain have a significant capacity to phosphorylate recombinant alpha synuclein (Asyn) at serine 129. Such phosphorylated Asyn is the major component of pathological deposits in PD.	SIGNOR-249690

P04049

P53350

0

phosphorylation

up-regulates activity

0.289

An in vitro kinase assay demonstrated that PLK1 directly phosphorylated CRAF at S338 and S339, but not at S621 (XREF_FIG).|These results demonstrate that PLK1 increases the stability of CRAF protein by preventing proteasome degradation.

SIGNOR-278190

P49761

P01106

0

transcriptional regulation

up-regulates quantity by expression

0.2

C-Myc enhances transcriptional activation of CLK3 promoter in CCA cells.

SIGNOR-274123

Q05655

P98082

1

phosphorylation

down-regulates

0.296

Mutational analysis revealed that a dab2 ser(24) phosphorylation mutant (s24a) abrogated the inhibitory function of dab2.

SIGNOR-127198

O95147

Q92844

0

ubiquitination

up-regulates activity

0.2

TRAF2-mediated Lys63-linked ubiquitination of DUSP14/MKP6 is essential for its phosphatase activity. Mass spectrometry and mutational analyses identified that DUSP14 was Lys63-linked ubiquitinated at lysine 103 residue.Here we report that DUSP14 was Lys63-linked ubiquitinated at Lys103 residue by the E3 ligase TRAF2 during TCR signaling. Furthermore, ubiquitination of DUSP14 was essential for its phosphatase activity.

SIGNOR-272811

P17812

P17252

0

phosphorylation

down-regulates

0.2

These data indicated that protein kinase c phosphorylation at ser(462) stimulates human ctp synthetase 1 activity, whereas phosphorylation at thr(455) inhibits activity.

SIGNOR-154621

Q13765

Q13418

0

phosphorylation

up-regulates

0.426

Ilk phosphorylated alpha-nac on residue ser-43. Ilk-dependent phosphorylation of alpha-nac induced the nuclear accumulation of the coactivator and that phosphorylation of alpha-nac by ilk is required for the potentiation of c-jun-mediated responses by the kinase.

SIGNOR-127694

P51812

P35916

0

phosphorylation

down-regulates

0.2

Upon truncation of this c-terminal stretch, or mutation of the tyr-707 residue alone, autoinhibition is attenuated, and the kinase becomes constitutively active. Based on these findings we propose that phosphorylation of the tyr-707 represents a novel alternative regulatory mechanism for p90rsk activation.

SIGNOR-98708

Q9UN19

P06239

0

phosphorylation

up-regulates activity

0.646

Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell lines|yrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins.

SIGNOR-249373

Q96PY6

P40337

1

phosphorylation

down-regulates quantity by destabilization

0.257

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

SIGNOR-276434

Q92915

P67870

0

phosphorylation

up-regulates activity

0.27

Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents.

SIGNOR-275745

Q9H063

P42345

0

phosphorylation

down-regulates

0.712

The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly.

SIGNOR-165795

P11678

P10153

1

post translational modification

up-regulates activity

0.476

Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism.

SIGNOR-261704

P29474

Q02156

0

phosphorylation

down-regulates activity

0.331

The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites

SIGNOR-251632

Q92597

O00141

0

phosphorylation

up-regulates

0.569

Transient expression of active (sgk1-s422d) and inactive (sgk1-k127a) sgk1 mutants confirmed that activating sgk1 stimulates ndrg1-thr(346/356/366) phosphorylation. dexamethasone (0.2 mum) acutely activated sgk1 and the peak of this response (2-3 h) coincided with the induction of g (na), and both responses were pi3k-dependent. While these data suggest that sgk1 might mediate the rise in g (na), transient expression of the inactive sgk1-k127a mutant did not affect the hormonal induction of g (na) but did suppress the activation of sgk1.

SIGNOR-180821

Q86V81

P31749

0

phosphorylation

up-regulates

0.449

Nuclear akt directly binds aly and phosphorylates it on the t219 residue. gfp-aly t219d displayed comparable activity to gfp control and wild-type aly, indicating that aly phosphorylation by akt is sufficient to enhance mrna export.

SIGNOR-252518

Q96GD4

Q53HL2

1

phosphorylation

up-regulates activity

0.82

AURKB directly phosphorylated CDCA8 at Ser(154), Ser(219), Ser(275), and Thr(278) and seemed to stabilize CDCA8 protein in cancer cells.|Phosphorylation and activation of cell division cycle associated 8 by aurora kinase B plays a significant role in human lung carcinogenesis.

SIGNOR-279506

P38398

P42574

0

cleavage

down-regulates quantity by destabilization

0.473

We demonstrate the cleavage and the consequential downregulation of full-length BRCA1 by caspase-3 during UV-induced apoptosis. Finally, mutation of a caspase-3 specific cleavage site (D/A1154) rendered BRCA1 non-cleavable.

SIGNOR-256326

Q6ZNA4

P84022

1

ubiquitination

down-regulates activity

0.654

Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblasts. Arkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling.

SIGNOR-235388

P43403

Q9UQC2

1

phosphorylation

up-regulates activity

0.46

In the present study, we found that gab2 is phosphorylated by zap-70, associates with the tcr signaling complex, and acts as an inhibitory adaptor molecule via recruitment of shp-2 following tcr ligation.

SIGNOR-110731

Q02078

Q16539

0

phosphorylation

up-regulates activity

0.661

We show that mef2a, but not mef2b or mef2d, is a substrate for p38. Threonines 312 and 319 are the key regulatory phosphorylation sites by p38 in mef2a. Phosphorylation at these sites enhances transcriptional activity of mef2a

SIGNOR-62780

P09471

Q14469

1

null

down-regulates

0.2

GNAO1 overexpression enhances GSC differentiation by downregulating neural progenitor gene HES1

SIGNOR-278092

Q5T0T0

O00220

1

ubiquitination

down-regulates quantity

0.2

The collective data indicate that endogenous MARCH-8 ubiquitinates TRAIL-R1 to attenuate its cell surface expression.

SIGNOR-278570

P04150

P48775

1

transcriptional regulation

down-regulates quantity by repression

0.337

Repression of GR-mediated expression of the tryptophan oxygenase gene by the SWI/SNF complex during liver development.

SIGNOR-268995

O75386

Q8N6U8

1

relocalization

up-regulates activity

0.608

Upon knockdown of Tulp3 using siRNA in IMCD3 cells, ciliary localization of Gpr161 was severely reduced

SIGNOR-259938

P69905

P15169

0

cleavage

down-regulates activity

0.2

Both human plasma carboxypeptidase N (CPN) and membrane-bound carboxypeptidase M (CPM) released the C-terminal arginine (alpha-Arg141) of the alpha chain of human adult hemoglobin. Thus, the hydrolysis of hemoglobin by CPM and CPN demonstrated the contribution of the alpha-Arg141 residue to sustaining the tetrameric structure of hemoglobin and its normal oxygen affinity and vasoactivity.

SIGNOR-256508

P51668

Q9HAU4

0

ubiquitination

up-regulates activity

0.702

Our data further show that SMURF2 monoubiquitinates UBCH5 at lysine 144 to form an active complex required for efficient degradation of a RAS family E3, beta transducing repeat containing protein 1 (beta-TrCP1).

SIGNOR-278718

O94916

Q13315

0

phosphorylation

up-regulates

0.271

Tonebp/orebp contains atm consensus phosphorylation sites at ser-1197, ser-1247, and ser-1367. In conclusion, signaling via atm is necessary for full activation of tonebp/orebp

SIGNOR-125077

Q86YJ5

P05362

1

ubiquitination

down-regulates quantity by destabilization

0.2

MARCH-IX expression causes ubiquitination and downregulation of ICAM-1 and a short alternative transcript of MARCH-IX lacking the RING-CH domain, termed MARCH-IX RINGless, is shown to act as a positive regulator of MARCH-IX activity.|MARCH-IX mediates ubiquitination and downregulation of ICAM-1.

SIGNOR-278821

O94953

Q99814

0

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-271584

P53667

P23470

0

dephosphorylation

down-regulates activity

0.26

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

SIGNOR-254711

Q14934

P45984

0

phosphorylation

up-regulates activity

0.419

Here, we showed that the nuclear factor of activated T3 (NFAT3) is phosphorylated by JNK1 or JNK2 at Ser(213) and Ser(217), which are located in the conserved SP motif.|Moreover, a 3xNFAT-luc reporter gene assay indicated that NFAT3 transcriptional activity was increased in a dose-dependent manner by JNK1 or JNK2.

SIGNOR-280036

P30305

Q9UNH5

0

dephosphorylation

down-regulates activity

0.56

Cdc14A inhibits Cdc25A and Cdc25B activity, the latter through direct binding and dephosphorylation ( ).|Together, these data indicate that Cdc14A dephosphorylates Cdc25B, inhibiting its catalytic activity.

SIGNOR-276968

P0CG48

Q96BN8

0

cleavage

up-regulates quantity

0.717

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

SIGNOR-270820

Q03060

P27361

0

phosphorylation

down-regulates quantity by destabilization

0.41

The MAPKs extracellular signal-regulated kinases 1 and 2 physically interact with ICER and mediated the phosphorylation of ICER on a critical serine residue (Ser-41). A mutant form of ICER in which Ser-41 was substituted by alanine had a half-life 4-5 h longer than its wild-type counterpart. This alteration in stability was due to the inability of the Ser-41-mutant ICER to be efficiently ubiquitinated and degraded via the ubiquitin-proteasome pathway.

SIGNOR-275978

Q16539

O95644

1

phosphorylation

down-regulates

0.622

We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats.

SIGNOR-74560

P07948

P31994

1

phosphorylation

up-regulates activity

0.43

Therefore, we conclude that FcgammaRIIb1 phosphorylation upon BCR-FcgammaR coligation is most likely due to BCR-associated Lyn

SIGNOR-249380

P28324

P24941

0

phosphorylation

up-regulates activity

0.363

Phosphorylation of ELK4 at Thr194 and Ser387 by CDK2 is required for EGF-induced cell transformation.

SIGNOR-278210

Q13164

P17302

1

phosphorylation

down-regulates activity

0.54

Activated BMK1 selectively phosphorylates Cx43 on Ser-255 in vitro and in vivo. These data demonstrate that BMK1 kinase activity alone is both a necessary and sufficient component in the mediation of EGF-induced Cx43 Ser-255 phosphorylation and subsequent inhibition of GJC.

SIGNOR-250115

Q8N884

O00743

0

dephosphorylation

down-regulates activity

0.2

In this study, we found that PPP6C suppressed phosphorylation of human cGAS (hcGAS) at S435 or mouse cGAS (mcGAS) at S420 in its substrate-binding pocket, thus preventing its binding to GTP and inhibiting the synthesis of cGAMP.|These data suggest that PPP6C inhibits cGAS activity.

SIGNOR-276990

Q969G2

P28069

1

transcriptional regulation

up-regulates quantity by expression

0.514

We show that normal LHX4 binds to a human-specific element and subsequently activates transcription from the proximal upstream regulatory sequence of POUIF1, a gene encoding a POU homeodomain transcription factor known as the main regulator of GH expression.

SIGNOR-266056

P53350

Q9UBW7

1

phosphorylation

down-regulates quantity by destabilization

0.376

PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|Similar analyses with ZNF198 identified two clusters of putative Plk1 phosphorylation sites in vitro. A cluster of serine residues at the N-terminus of ZNF198, S303, S305, and S309, and a cluster at the C-terminus, S1056 and S1064. The triple Ser to Ala mutant, S303A/S305A/S309A, consistently exhibited the lowest level of phosphorylation in vitro, in comparison to the double S1056A/S1064A mutant

SIGNOR-275560

Q9UPW6

Q99717

0

transcriptional regulation

up-regulates quantity

0.259

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

SIGNOR-268939

P01106

P11908

1

transcriptional regulation

up-regulates quantity by expression

0.277

Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation.

SIGNOR-267376

Q9BQQ3

P28482

0

phosphorylation

down-regulates activity

0.27

Here we show that GRASP65 is phosphorylated on serine 277 in interphase cells, and this is strongly enhanced in response to the addition of serum or epidermal growth factor. This is directly mediated by ERK suggesting that GRASP65 has some role in growth factor signal transduction. These results argue against Ser-277 phosphorylation alone causing the dissolution of GRASP65 oligomers and cisternal unstacking, although it may make a significant contribution to these events.

SIGNOR-262841

P09619

P12931

1

phosphorylation

up-regulates activity

0.604

The increased Src activity is mainly due to the phosphorylation of Tyr-419, rather than the dephosphorylation of Tyr-530 of Src protein. PDGFR, not FAK or EGFR, appears to be the upstream protein tyrosine kinase responsible for the detachment-induced Src activation in the lung tumor cells.

SIGNOR-247979

O15297

Q00987

1

dephosphorylation

up-regulates

0.681

Wip1 interacts with and dephosphorylates mdm2 at serine 395, a site phosphorylated by the atm kinase. Dephosphorylated mdm2 has increased stability and affinity for p53, facilitating p53 ubiquitination and degradation.

SIGNOR-158328

Q6UB99

P23560

1

transcriptional regulation

up-regulates quantity by expression

0.2

Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons.

SIGNOR-266732

P32245

P17612

0

phosphorylation

down-regulates activity

0.308

Activation of MC4R by agonist is associated with protein kinase A (PKA) and GRK phosphorylation of serine/threonine residues in the C-terminal tail of MC4R, followed by -arrestin and dynamin-dependent internalization of the receptor. Thr312 and Ser329/330 in the C-terminal tail of MC4R are potential sites for PKA

SIGNOR-250016

Q16820

P05771

0

phosphorylation

down-regulates quantity

0.2

These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate.

SIGNOR-263173

P41161

Q12857

0

transcriptional regulation

down-regulates quantity

0.2

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

SIGNOR-268874

O14920

P62714

0

dephosphorylation

down-regulates activity

0.259

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

SIGNOR-248580

Q8N4C8

Q15797

1

phosphorylation

down-regulates activity

0.2

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

SIGNOR-276336

P42224

Q99102

1

transcriptional regulation

up-regulates quantity by expression

0.393

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

SIGNOR-254099

O14965

Q9Y657

1

phosphorylation

up-regulates activity

0.243

The Ser84 and Ser99 amino acids within SPINDLIN1 were further identified as the key functional sites in WNT/TCF-4 signaling activation. Mutation of these two sites of SPINDLIN1 abolished its effects on promoting WNT/TCF-4 signaling and cancer cell proliferation. We further found that Aurora-A could interact with and phosphorylate SPINDLIN1 at its key functional sites, Ser84 and Ser99, suggesting that phosphorylation of SPINDLIN1 is involved in its oncogenic function.

SIGNOR-273550

Q99742

P07101

1

transcriptional regulation

down-regulates quantity by repression

0.252

Overexpression and siRNA experiments revealed that NPAS1, in concert with ARNT, negatively regulates the expression of TH and that this regulation is mediated by a direct binding of NPAS1 on the TH promoter.

SIGNOR-253702

O00311

Q99459

1

phosphorylation

down-regulates activity

0.344

During SPOC, Dbf4 binds to Cdc5 and promotes Cdc7-mediated phosphorylation of Cdc5, which then presumably prevents Cdc5 from recognizing its substrates in the MEN pathway .

SIGNOR-280203

P54253

P31749

0

phosphorylation

up-regulates quantity by stabilization

0.411

Interaction of Ataxin-1 and 14-3-3 Requires Akt Phosphorylation at S776. 14-3-3 protein, a multifunctional regulatory molecule, mediates the neurotoxicity of ataxin-1 by binding to and stabilizing ataxin-1, thereby slowing its normal degradation.

SIGNOR-252561

Q15172

P17252

0

phosphorylation

down-regulates activity

0.341

In this study, we identified a novel phosphorylation site at Ser(41) of B56α. This phosphoamino acid residue was efficiently phosphorylated in vitro by PKCα.

SIGNOR-276603

P45983

Q05639

1

phosphorylation

down-regulates quantity by destabilization

0.374

Ribosome-associated JNK phosphorylates the eukaryotic translation elongation factor 1A isoform 2 (eEF1A2) on serines 205 and 358 to promote degradation of NSPs by the proteasome.

SIGNOR-276492

Q13131

Q86TI0

1

phosphorylation

down-regulates

0.425

In rat l6 myotubes, endogenous tbc1d1 is strongly phosphorylated on ser237 and binds to 14-3-3s in response to the ampk activators aicar

SIGNOR-159048

P12931

P02545

1

phosphorylation

up-regulates activity

0.51

In this study, we found that the constitutively active Src Y527F mutant caused the disassembly of lamin A/C. We demonstrate that Src directly phosphorylates lamin A mainly at Tyr45 both in vitro and in intact cells.

SIGNOR-279288

P48200

Q9UNH5

0

dephosphorylation

up-regulates activity

0.348

IRP2 Ser-157 is phosphorylated by Cdk1/cyclin B1 during G(2)/M and is dephosphorylated during mitotic exit by the phosphatase Cdc14A. Ser-157 phosphorylation during G(2)/M reduces IRP2 RNA-binding activity and increases ferritin synthesis, whereas Ser-157 dephosphorylation during mitotic exit restores IRP2 RNA-binding activity and represses ferritin synthesis.

SIGNOR-248829

P23771

Q99835

0

null

up-regulates activity

0.2

That GATA is a downstream effector of the hedgehog pathway.

SIGNOR-253527

P60953

Q9P107

0

gtpase-activating protein

down-regulates activity

0.512

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-260507

P62805

Q92993

0

acetylation

down-regulates activity

0.2

Thus, the TIP60 HAT complex is recruited to MYC-target genes and, probably with other other HATs, contributes to histone acetylation in response to mitogenic signals.

SIGNOR-262061

P49674

O14641

1

phosphorylation

up-regulates

0.693

We demonstrated that dvl2 is phosphorylated at s143 and t224 in a manner that requires both non-canonical wnt5a ligand and casein kinase 1 epsilon (ck1_), and that this event is critical to interact with plk1 in early stages of the cell cycle

SIGNOR-197555

P55212

P05067

1

cleavage

up-regulates activity

0.724

Inhibition of caspase-6 activity prevents serum deprivation-mediated increase of Ab. Caspase-6 directly cleaves APP at the C terminus and generates a C-terminal fragment of 3 kDa (Capp3) and an Ab-containing 6.5-kDa fragment, Capp6.5, that increases in serum-deprived neurons

SIGNOR-261762

P06493

Q92934

1

phosphorylation

up-regulates activity

0.2

CDK1-mediated Bcl-2 serine 70 phosphorylation enhances its pro-apoptotic function, whereas CDK1-mediated Bad serine 128 phosphorylation promotes apoptosis.

SIGNOR-267921

P46108

P00533

0

phosphorylation

down-regulates activity

0.74

To address these questions, we have developed an antibody that specifically recognizes the CrkII protein phosphorylated on Tyr221, and we found that the EGF receptor directly phosphorylates CrkII on Tyr221. Furthermore, we observed that the phosphorylation of Tyr221 of CrkII correlated with its dissociation from the EGF receptor, implicating the phosphorylation of Tyr221 in the negative feedback of binding to the EGF receptor.

SIGNOR-251091

P41240

Q00987

1

phosphorylation

up-regulates activity

0.2

Here we show that activated c-Src kinase phosphorylates Y281 and Y302 of Mdm2, resulting in an increase in Mdm2 stability and its association with Ubc12, the E2 enzyme of the neddylating complex.

SIGNOR-279163

Q00987

O43293

0

phosphorylation

up-regulates quantity by stabilization

0.342

Zip kinase was able to phosphorylate mdm2 at ser166, a site previously reported to be modified by akt kinase, thus demonstrating that zip kinase is a bona fide mdm2-binding protein.

SIGNOR-123159

P28482

Q01196

1

phosphorylation

up-regulates activity

0.2

We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation.

SIGNOR-138973

O43586

Q05209

0

dephosphorylation

down-regulates activity

0.61

We also demonstrate that PTP-PEST dephosphorylates PSTPIP at tyrosine 344. Importantly, we identified tyrosine 344 as the main phosphorylation site of PSTPIP by performing tryptic phosphopeptide maps. |The biological functions of the complexes formed between PSTPIP and SH2 domain-containing tyrosine kinases may be to transmit the signals from activated EGF and PDGF receptor.|Furthermore, we show that PSTPIP is phosphorylated downstream of the activated PDGF and EGF receptors. This phosphorylation of PSTPIP is most likely mediated by c-Abl

SIGNOR-248656

P48200

P06493

0

phosphorylation

down-regulates

0.353

Irp2 ser-157 is phosphorylated by cdk1/cyclin b1 during g(2)/m / ser-157 phosphorylation during g(2)/m reduces irp2 rna-binding activity

SIGNOR-179171

P31749

P62136

0

dephosphorylation

down-regulates activity

0.426

Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells

SIGNOR-252603

P62136

Q13422

1

dephosphorylation

up-regulates

0.279

Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway

SIGNOR-174859

Q03468

Q13216

0

ubiquitination

down-regulates quantity by destabilization

0.582

We have previously shown that CSA is a subunit of an E3 ubiquitin ligase complex. Here we demonstrate that CSB is a substrate of this ligase: Following UV irradiation, CSB is degraded at a late stage of the repair process in a proteasome- and CSA-dependent manner.

SIGNOR-271406

Q8NEM2

Q96GD4

0

phosphorylation

up-regulates activity

0.372

AurB phosphorylates Ser634 of SHCBP1 during mitosis. We generated a phosphorylation site mutant, S634A-SHCBP1, which was prematurely recruited to the central spindle during anaphase and inhibited furrowing.

SIGNOR-273552

Q96EZ8

O14965

0

phosphorylation

up-regulates activity

0.316

We conclude that Aurora-A phosphorylates MCRS1 on Ser35/36 specifically during mitosis.

SIGNOR-278232

P00533

P15941

1

phosphorylation

up-regulates activity

0.577

We also show that the activated egf-r phosphorylates the muc1 cytoplasmic tail on tyrosine at a yekv motif that functions as a binding site for the c-src sh2 domain. The results demonstrate that egf-r-mediated phosphorylation of muc1 induces binding of muc1 to c-src in cells

SIGNOR-109538

O60716

P17612

0

phosphorylation

down-regulates

0.2

We showed that pkc_ phosphorylation of p120 at serine (s)879 in response to thrombin or lipopolysaccharide challenge reduced p120 binding affinity for ve-cadherin and mediated aj disassembly secondary to ve-cadherin internalization

SIGNOR-198288

P11831

P35354

1

null

up-regulates

0.252

Srf within myofibers modulates Il6 and Cox2/Il4 expressions and, therefore, exerts a paracrine control of satellite cell proliferation and fusion, respectively, which in turn support skeletal muscle hypertrophy.

SIGNOR-255965

O75144

P17252

0

phosphorylation

up-regulates activity

0.2

PKCα and PKCβ are required for phosphorylation of ICOSL and ICOSL-mediated cytokine induction. Therefore, S285 is required for PKC substrate (serine) phosphorylation of ICOSL, and each of the upstream arginines is similarly required for this phosphorylation.

SIGNOR-273798

P11308

O60216

0

relocalization

down-regulates activity

0.2

Large-scale AML genome re-sequencing efforts have identified novel recurrently mutated genes, including the members of the cohesin complex (RAD21, SMC3, SMC1A, and STAG2), implicated in the pathogenesis of this disease.Using ATAC-seq, we determined that mutant cohesin lead to a state of elevated chromatin accessibility and higher predicted binding at transcription factor binding sites for ERG, GATA2, and RUNX1. Moreover, using ChIP-Seq, we formally demonstrated increased binding of GATA2 and RUNX1 to these sites. Finally, we demonstrated that knockdown of these three TFs in human HSPC can revert the differentiation block induced by mutant cohesin. These results support a model in which mutant cohesin impairs hematopoietic differentiation and enforces stem cell programs through the modulation of ERG, GATA2, and RUNX1 chromatin accessibility, expression, and activity.

SIGNOR-261515

Q8NFG4

Q9NQL2

1

gtpase-activating protein

up-regulates activity

0.683

The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1 [..} RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP-bound for the interaction to occur

SIGNOR-256504

Q07955

P17612

0

phosphorylation

up-regulates

0.2

Here, we show that pka phosphorylates srsf1 on serine 119 in vitro. Phosphorylation of srsf1 on this site enhanced the rna binding capacity of srsf1 in vivo

SIGNOR-196397

P25440

Q12888

1

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

Q9UQM7

Q12959

1

phosphorylation

down-regulates activity

0.649

Synapse-associated protein 97 (SAP97), a member of membrane-associated guanylate kinase protein family, has been implicated in the processes of targeting ionotropic glutamate receptors at postsynaptic sites. | We show here that SAP97 is directly associated with NR2A through its PDZ1 domain, and CaMKII-dependent phosphorylation of SAP97-Ser-232 disrupts NR2A interaction both in an in vitro pull-out assay and in transfected COS-7 cells. Moreover, expression of SAP97(S232D) mutant has effects similar to those observed upon constitutively activating CaMKII.

SIGNOR-250618

P22694

Q92934

1

phosphorylation

down-regulates

0.429

Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136.

SIGNOR-81141

P18848

P23381

1

transcriptional regulation

up-regulates quantity by expression

0.2

QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.

SIGNOR-269429

P17706

P52333

1

dephosphorylation

down-regulates activity

0.697

Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5.

SIGNOR-133078

Q8N6F7

P07948

0

phosphorylation

up-regulates activity

0.245

Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148. Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation.

SIGNOR-273560

Q96RI1

Q05513

0

phosphorylation

up-regulates

0.38

The effect of fic1 on fxr phosphorylation and nuclear localization and its effects on bsep promoter activity could be blocked with protein kinase c zeta (pkc zeta) inhibitors (pseudosubstrate or small interfering rna silencing). Recombinant pkc zeta directly phosphorylated immunoprecipitated fxr. The mutation of threonine 442 of fxr to alanine yielded a dominant negative protein,

SIGNOR-179771

Q7Z570

O15247

1

transcriptional regulation

down-regulates quantity by repression

0.2

ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3).

SIGNOR-269465

P04626

Q9BXH1

1

phosphorylation

down-regulates quantity by destabilization

0.281

HER2 phosphorylates and destabilizes pro-apoptotic PUMA. Using an intracellular assay, we found PUMA to be phosphorylated in breast cancer cells with activated HER2. Via cell-free HER2 kinase assay, we observed that PUMA was directly phosphorylated by HER2. Activation of HER2 decreased PUMA protein half-life.

SIGNOR-276474

P55075

P40424

0

transcriptional regulation

down-regulates quantity by repression

0.271

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

SIGNOR-265803

Q9NPP4

Q5S007

0

phosphorylation

up-regulates activity

0.359

LRRK2 phosphorylates NLRC4 at Ser533 upon inflammasome activation.|These data suggest that LRRK2 promotes NLRC4 inflammasome activation through its kinase activity.

SIGNOR-279338

P27348

P48729

0

phosphorylation

down-regulates activity

0.516

This protein kinase has been identified as casein kinase Ialpha (CKIalpha) by peptide mapping analysis and sequencing. Among mammalian 14-3-3, only 14-3-3 tau possesses a phosphorylatable residue at the same position (Ser-233), and we show that this residue is also phosphorylated by CKI. In addition, we show that 14-3-3 zeta is exclusively phosphorylated on Thr-233 in human embryonic kidney 293 cells. The residue 233 is located within a region shown to be important for the association of 14-3-3 to target proteins.

SIGNOR-250795

Q9NY61

Q07812

1

transcriptional regulation

down-regulates quantity

0.2

We identify the transcriptional regulator apoptosis-antagonizing transcription factor (AATF)/Che-1 as a critical regulator of the cellular outcome of the p53 response. Upon genotoxic stress, AATF is phosphorylated by the checkpoint kinase MK2. Phosphorylation results in the release of AATF from cytoplasmic MRLC3 and subsequent nuclear translocation where AATF binds to the PUMA, BAX and BAK promoter regions to repress p53-driven expression of these pro-apoptotic genes.

SIGNOR-259916

P37840

Q5S007

0

phosphorylation

down-regulates activity

0.624

Here we show that full-length Lrrk2 or fragments containing its kinase domain have a significant capacity to phosphorylate recombinant alpha synuclein (Asyn) at serine 129. Such phosphorylated Asyn is the major component of pathological deposits in PD.

SIGNOR-249690