GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
Q16621	P45983	0	phosphorylation	down-regulates quantity by destabilization	0.411	Through use of different approaches including nano-scale proteomics, we show that activated-JNK, or Phospho-JNK (P-JNK), physically interacts with p45/NF-E2 and phosphorylates its Ser157 residue. This reaction leads to the poly-ubiquitination of p45/NF-E2 at one or more of six Lys residues, one of which being also a sumoylation site, and its degradation through the proteasome pathway.	SIGNOR-275552
Q96T68	Q16695	1	methylation	up-regulates activity	0.2	Here, we have characterized a previously undescribed member of the histone H3K9 methyltransferase family named CLLD8 (or SETDB2 or KMT1F). This protein contributes to the trimethylation of both interspersed repetitive elements and centromere-associated repeats and participates in the recruitment of heterochromatin protein 1 to centromeres. Methylation of histone H3 at lysine 9 (H3K9) has emerged as an important player in the formation of heterochromatin, chromatin condensation, and transcriptional repression.	SIGNOR-263895
P07477	P55085	1	cleavage	up-regulates activity	0.388	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-263602
Q9NQS7	O96017	0	phosphorylation	up-regulates activity	0.261	Also, inhibition of Chk2 by Chk2 inhibitor II in cytokinesis after release of cells from a nocodazole-induced prometaphase block diminished INCENP localization to the midbody center in late midbodies (Fig. 1, M and N).\|In turn, active Chk2 phosphorylates human INCENP at the newly identified site Ser91 to promote INCENP binding to Mklp2, resulting in recruitment of the INCENP\u2013Mklp2 complex to the midbody center through Mklp2\u2019s interaction with the midbody protein Cep55 to delay abscission.	SIGNOR-279695
P04626	Q06124	0	dephosphorylation	down-regulates	0.838	...which in turn suggests the importance SHP2 dephosphorylation of pTyr992 in EGFR and pTyr1023 in HER2 to mediate signaling.\|More specifically, we show that acidic residues N-terminal to the substrate pTyr in EGFR and HER2 mediate specific binding by the SHP2 active site, leading to blockade of RasGAP binding and optimal signaling by the two receptors.	SIGNOR-262957
Q7Z6Z7	Q07869	1	ubiquitination	down-regulates quantity by destabilization	0.2	Furthermore, the E3 ubiquitin ligase HUWE1 was identified to mediate PPARalpha polyubiquitination.\|This notion is also supported by our finding that Huwe1 knockdown up-regulated the expression of PPARalpha target genes at the cellular level.	SIGNOR-278814
Q92698	P24941	0	phosphorylation	down-regulates activity	0.347	Effect of CDK2 phosphorylation on the RAD54 activities. We find that the RAD54 N-terminal domain (NTD) is responsible for initiation of BM through two coupled, but distinct steps; specific binding to Holliday junctions and RAD54 oligomerization. Furthermore, we find that the RAD54 oligomeric state can be controlled by NTD phosphorylation at S49, a CDK2 consensus site, which inhibits RAD54 oligomerization and, consequently, BM.	SIGNOR-273599
P08069	Q05397	0	phosphorylation	up-regulates quantity	0.535	Taken together, our data suggest that FAK mediates the phosphorylation of IGF-1R and stabilizes the receptor.In this study we demonstrate that FAK, mainly known for its role in integrin signaling pathways, associates with and phosphorylates IGF-1R independently of IGF-1R 's intrinsic tyrosine kinase activity.\|The impact of FAK on the expression levels of IGF-1R could be multilateral	SIGNOR-279565
P03372	Q9NRW4	0	dephosphorylation	down-regulates activity	0.261	These results strongly suggest that DUSP22 acts as a negative regulator of the ERalpha-mediated signaling pathway\|whereas E2-induced phosphorylation and activation of ERalpha was suppressed by overexpression of DUSP22 but not catalytically inactive mutants.	SIGNOR-248827
Q9BYX4	P36873	0	dephosphorylation	up-regulates activity	0.247	Exogenous PP1alpha or PP1gamma substantially decreased the S88 phosphorylation of Flag-MDA5\|we identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation.	SIGNOR-264579
Q13627	P35568	1	phosphorylation	up-regulates quantity	0.2	DYRK1A interacts with IRS-1 and phosphorylates IRS-1 at Ser-312 and Ser-616.\|We found that DYRK1A overexpression up-regulated IRS-1 expression by slowing the turnover of IRS-1 protein.	SIGNOR-279521
P50613	P21127	1	phosphorylation	up-regulates activity	0.335	We conclude that CDK7 phsphorylates Cdk11, dependent on the conserved Thr219 residue in the CDK11 T loop, and it is therefore likely to be a genuine Cdk11 activating kinase	SIGNOR-245871
Q13315	Q9UER7	1	phosphorylation	down-regulates	0.499	The main phosphorylation site of daxx is identified to be ser564, which is a direct target of atm. Phosphorylation of endogenous daxx at ser564 occurs rapidly during the dna damage response and precedes p53 activation. Blockage of this phosphorylation event prevents the separation of daxx from mdm2, stabilizes mdm2, and inhibits dna damage-induced p53 activation.	SIGNOR-200889
P00338	P11362	0	phosphorylation	up-regulates	0.366	We found that the oncogenic receptor tyrosine kinase fgfr1 directly phosphorylates ldh-a. Phosphorylation at y10 and y83 enhances ldh-a activity by enhancing the formation of active, tetrameric ldh-a and the binding of ldh-a substrate nadh, respectively.	SIGNOR-176730
Q9UPQ7	O15146	1	ubiquitination	down-regulates quantity	0.543	We have identified a PDZ domain containing RING finger 3 (PDZRN3) as a synapse-associated E3 ubiquitin ligase and have demonstrated that it regulates the surface expression of muscle-specific receptor tyrosine kinase (MuSK), the key organizer of postsynaptic development at the mammalian neuromuscular junction. PDZRN3 binds to MuSK and promotes its ubiquitination. Together, these data demonstrate that PDZRN3 is a catalytically active RING-type E3 ubiquitin ligase	SIGNOR-271664
P52757	P12931	0	phosphorylation	down-regulates	0.2	Here we report that beta2-chimaerin is tyrosine-phosphorylated by src-family kinases (sfks) upon cell stimulation with epidermal growth factor (egf). Mutational analysis identified tyr-21 in the n-terminal regulatory region as a major phosphorylation site. these results suggest tyr-21 phosphorylation as a novel, sfk-dependent mechanism that negatively regulates beta2-chimaerin rac-gap activity.	SIGNOR-155713
Q9P286	O43426	1	phosphorylation	up-regulates activity	0.2	We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo.	SIGNOR-263026
Q8TE77	P23528	1	dephosphorylation	up-regulates activity	0.717	Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.\|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH).	SIGNOR-248759
P68400	P49321	1	phosphorylation	down-regulates activity	0.2	Here, we show that somatic nuclear autoantigenic sperm protein (sNASP) binds to TRAF6 to prevent TRAF6 autoubiquitination in unstimulated macrophages. Following LPS stimulation, a complex consisting of sNASP, TRAF6, IRAK4, and casein kinase 2 (CK2) is formed. CK2 phosphorylates sNASP at serine 158, allowing sNASP to dissociate from TRAF6. Free TRAF6 is then autoubiquitinated, followed by activation of downstream signaling pathways.	SIGNOR-273627
P41143	P01213	0	chemical activation	up-regulates activity	0.667	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258415
Q9UQC2	P43403	0	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
P35790	Q9Y6Q9	1	phosphorylation	down-regulates quantity by destabilization	0.2	First, by using purified recombinant SRC-3 (XREF_FIG) and CKI proteins, we found that CKI is able to phosphorylate SRC-3 (XREF_FIG).	SIGNOR-280229
P49674	P46937	1	phosphorylation	down-regulates	0.422	Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by Casein Kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ	SIGNOR-201170
P48729	O15169	1	phosphorylation	up-regulates activity	0.785	Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated (Supplementary Figure 3). Three of them (S80, S82, and S473) were also phosphorylated in vitro by CKI and are conserved between axin1 and axin2/conductin.\|This suggests that cumulative phosphorylation of axin is required for it to fully downregulate Wnt/beta_catenin signaling.	SIGNOR-249191
Q16539	P07949	0	phosphorylation	up-regulates	0.332	Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme.	SIGNOR-40493
Q6WCQ1	O75688	0	dephosphorylation	down-regulates activity	0.2	Ppm1b prevents Rip3 auto-activation in resting cells.\|Together, these data demonstrate that Ppm1b dephosphorylates Rip3 and thus negatively regulates TNF induced necroptosis in L929 cells.	SIGNOR-277019
P06493	Q8ND76	1	phosphorylation	down-regulates activity	0.595	Therefore, CDK1 may trigger CFP1 degradation through some indirect mechanisms rather than CFP1 phosphorylation.\|This result suggests that, although CDK1 triggers both phosphorylation and degradation of CFP1 protein, phosphorylation of CFP1 by CDK1 is not a prerequisite for its degradation during cell division.	SIGNOR-279012
P17706	P10912	1	dephosphorylation	down-regulates activity	0.295	PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates	SIGNOR-248394
Q15796	O14595	0	dephosphorylation	down-regulates activity	0.445	Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3\|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248299
P55211	P31751	0	phosphorylation	down-regulates	0.528	Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity	SIGNOR-61561
Q9UM54	O75914	0	phosphorylation	up-regulates activity	0.336	P21-activated kinase 3 phosphorylated myosin VI, and the site was identified as Thr(406). The phosphorylation of myosin VI significantly facilitated the actin-translocating activity of myosin VI.	SIGNOR-250244
P54646	P06213	1	phosphorylation	up-regulates	0.372	Ampk phosphorylates and activates theinsulinreceptor, providing a direct link between ampk and theinsulin pathway.	SIGNOR-195324
P57078	P98170	0	polyubiquitination	up-regulates activity	0.333	In this study, we report that in addition to RIP1 and RIP2, also RIP3 and RIP4 directly interact with XIAP, cIAP1 and cIAP2. When comparing the ability of these IAPs to directly conjugate RIP1–RIP4 with ubiquitin chains, we found that cIAP1 was the most effective E3 and was capable of ubiquitinating all four RIPs in the presence of the E2 component UbcH5a. On the contrary, XIAP was only capable of inducing weak ubiquitination of RIP4.	SIGNOR-272716
P10721	P23470	0	dephosphorylation	down-regulates activity	0.2	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-254710
Q15139	Q96QB1	1	phosphorylation	down-regulates	0.371	The tumor suppressor protein dlc1 is regulated by pkd-mediated gap domain phosphorylation.Our results thus show that pkd-mediated phosphorylation of dlc1 on serine 807 negatively regulates dlc1 cellular function.	SIGNOR-169994
P42575	P62140	0	dephosphorylation	up-regulates activity	0.2	Nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2.	SIGNOR-248576
P07339	P05067	1	cleavage	down-regulates quantity by destabilization	0.489	The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. \| two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism.	SIGNOR-261767
O15530	Q96PN8	1	phosphorylation	up-regulates activity	0.261	We elucidated the mechanism of regulation of TSSK3 activity showing that autophosphorylation and PDK1 phosphorylation in the ‘activation loop’ are necessary for activation.	SIGNOR-260786
Q9H9S0	Q9HCS4	0	transcriptional regulation	down-regulates quantity by repression	0.341	These experiments showed that Tcf3 is associated with chromatin in the Nanog promoter regions and that the DNA-binding activity of Tcf3 was required for repression.	SIGNOR-266081
P08581	O15409	0	transcriptional regulation	down-regulates quantity by repression	0.416	FOXP2 binds directly to the 5' regulatory region of MET, and overexpression of FOXP2 results in transcriptional repression of MET. The expression of MET in restricted human neocortical regions, and its regulation in part by FOXP2, is consistent with genetic evidence for MET contributing to ASD risk.	SIGNOR-269054
P24941	P23470	0	dephosphorylation	down-regulates activity	0.298	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-254695
Q8N5S9	Q14012	1	phosphorylation	up-regulates activity	0.414	Human calcium-calmodulin dependent protein kinase I: cDNA cloning, domain structure and activation by phosphorylation at threonine-177 by calcium-calmodulin dependent protein kinase I kinase.	SIGNOR-250717
Q8N1I0	P63000	1	guanine nucleotide exchange factor	up-regulates activity	0.586	DOCK4 (dedicator for cytokinesis 4), a guanine nucleotide exchange factor (GEF) for the small GTPase Rac1, is one of few genes that are associated with both ASD and dyslexia.	SIGNOR-266823
P78549	Q12899	0	ubiquitination	down-regulates quantity by destabilization	0.263	We also demonstrated that TRIM26 directly polyubiquitylates NTH1 in cells and that TRIM26 targets newly synthesized NTH1 protein for ubiquitylation dependent degradation.	SIGNOR-278733
P06396	P12931	0	phosphorylation	up-regulates	0.572	Identification of tyr438 as the major in vitro c-src phosphorylation site in human gelsolin recently	SIGNOR-67014
P00441	Q16236	0	transcriptional regulation	up-regulates quantity by expression	0.408	BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2	SIGNOR-254653
P04626	Q05397	1	phosphorylation	up-regulates activity	0.657	HER2, EGFR, and additional RTKs directly phosphorylate FAK FERM at Y397.\|To further confirm the mechanism of direct FAK activation by HER2, we performed a series of GST pull-down assays with purified recombinant proteins.	SIGNOR-278475
O43318	Q9BZR9	0	polyubiquitination	up-regulates activity	0.343	These results suggest that TRIM8 could mediate K63-linked polyubiquitination of TAK1 at residue K158.These results suggest that TRIM8 is involved in TNFα- and IL-1β–induced NF-κB activation by mediating K63-linked TAK1 polyubiquitination and subsequent activation.	SIGNOR-271890
Q66K64	Q14498	1	polyubiquitination	down-regulates quantity by destabilization	0.377	Indisulam promotes an interaction between RBM39 and the DCAF15 E3 ligase substrate receptor, leading to RBM39 ubiquitination and proteasome-mediated degradation.	SIGNOR-272203
P06748	P53350	0	phosphorylation	up-regulates	0.425	Phosphorylated at ser-4 by plk1 and plk2. Phosphorylation at ser-4 by plk2 in s phase is required for centriole duplication and is sufficient to trigger centriole replication. Phosphorylation at ser-4 by plk1 takes place during mitosis.	SIGNOR-125666
Q96KS0	Q969H0	0	ubiquitination	down-regulates quantity by destabilization	0.349	Mechanistically, we further show that FBW7, an E3 ligase complex component that is frequently downregulated in TNBC, negatively regulates EglN2 protein stability.	SIGNOR-261997
P06493	O15350	1	phosphorylation	down-regulates activity	0.556	Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73.Furthermore, cyclin a/cdk1/2, cyclin b/cdk1/2, and cyclin e/cdk2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86.	SIGNOR-99742
P00533	O95477	1	phosphorylation	down-regulates quantity by destabilization	0.295	We further provide in vitro evidence that epidermal growth factor receptor (EGFR)-mediated phosphorylation regulated ABCA1 ubiquitination \|The EGFR selective inhibitor PD168393 blocked the EGFR-ABCA1 interaction and abolished ABCA1Ser2054 phosphorylation\|	SIGNOR-264419
Q13418	Q9HBI1	1	phosphorylation	up-regulates activity	0.965	These results indicate that affixin directly associates with \u03b1-actinin only when its CH2 domain is phosphorylated by ILK.\|This may indicate that phosphorylation of the CH2 domain by ILK induces a conformational change of the CH2 domain of affixin, which enables affixin to interact with alpha-actinin to evoke the subsequent maturation of the FA complex.	SIGNOR-278259
P49841	Q07812	1	phosphorylation	up-regulates	0.376	Glycogen synthase kinase-3beta phosphorylates bax and promotes its mitochondrial localization during neuronal apoptosis. Gsk-3beta directly phosphorylated bax(alpha) on ser163	SIGNOR-130141
P45985	P19793	1	phosphorylation	down-regulates	0.2	Phosphorylation by mkk4/sek1 had profound effects on the biochemical properties of rxr, inhibiting the expression of genes activated by rxr-retinoic acid receptor complexes. Tyr-249 in the rxr de region was required for the inhibitory effect of mkk4/sek1.	SIGNOR-80619
P52565	Q05209	0	dephosphorylation	up-regulates activity	0.2	Integrin-bound PTP-PEST dephosphorylates RhoGDI1.\|Translocation of Src phosphorylated RhoGDI1 to the cell 's leading edge promotes local activation of Rac1 and Cdc42, whereas dephosphorylation of RhoGDI1 by integrin bound PTP-PEST promotes RhoGDI1 release from the membrane and sequestration of inactive Rac1 and Cdc42 in the cytoplasm.\|Translocation of Src-phosphorylated RhoGDI1 to the cell's leading edge promotes local activation of Rac1 and Cdc42, whereas dephosphorylation of RhoGDI1 by integrin-bound PTP-PEST promotes RhoGDI1 release from the membrane and sequestration of inactive Rac1/Cdc42 in the cytoplasm.	SIGNOR-277175
P56524	P67775	0	dephosphorylation	up-regulates	0.35	Different signal-regulated serine/threonine kinases phosphorylate class ii histone deacetylases (hdacs) to promote nuclear export, cytosolic accumulation, and activation of gene transcriptionhere we show that hdac4 forms a complex with the pp2a holoenzyme c alpha, a alpha, b/pr55 alpha. In vitro and in vivo binding studies demonstrate that the n-terminus of hdac4 interacts with the catalytic subunit of pp2a. Hdac4 is dephosphorylated by pp2a	SIGNOR-159492
Q14938	Q14393	1	transcriptional regulation	down-regulates quantity	0.205	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-268888
P27361	P49407	1	phosphorylation	down-regulates	0.716	Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation	SIGNOR-67634
Q9Y2K2	Q15831	0	phosphorylation	up-regulates	0.488	Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold	SIGNOR-122835
P31749	Q15672	1	phosphorylation	up-regulates	0.438	Moreover, phosphorylation of twist-1 at ser42 was shown in vivo in various human cancer tissues, suggesting that this post-translational modification ensures functional activation of twist-1 after promotion of survival during carcinogenesis.	SIGNOR-164884
Q13043	P67775	0	dephosphorylation	down-regulates	0.367	Rassf1a apparently protects mst1/2 against inactivation by pp2a , the phosphatases that dephosphorylate the stimulatory thr-183 and thr-180 of mst1 andmst2, respectively.	SIGNOR-201270
Q09472	Q13131	0	phosphorylation	down-regulates	0.376	The mechanism of ampk-mediated anti- inflammation involves the induction of p300 ser89 phosphor- ylation and subsequent inactivation of p300 hat activity.	SIGNOR-176637
Q6R327	P49841	0	phosphorylation	down-regulates quantity by destabilization	0.409	We show that this process is dependent on glycogen synthase kinase 3 (GSK3): GSK3 was associated with rictor and directly phosphorylated the Thr-1695 site in a putative CDC4 phospho-degron motif of rictor; mutation of this site impaired the interaction between rictor and FBXW7, decreased rictor ubiquitination, and increased rictor stability.	SIGNOR-276898
Q01892	P68400	0	phosphorylation	down-regulates	0.429	Serine residues 37 in the transactivation domain and 129, 144 and 146 in the pest domain of spi-b are phosphorylated by ckii in vitro. The ckii phosphorylation sites mapped in vitro are phosphorylated in vivo. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability	SIGNOR-73891
P08254	P07585	1	cleavage	down-regulates quantity by destabilization	0.673	Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues.	SIGNOR-256353
P85298	P61586	1	gtpase-activating protein	down-regulates activity	0.427	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-260463
P54764	O60674	1	phosphorylation	up-regulates activity	0.281	EphA4 phosphorylates JAK2.\|These findings suggest that EphA4 activates not only growth hormone receptor, as shown above, but also JAK2 by direct phosphorylation.	SIGNOR-279040
Q13464	Q99717	1	phosphorylation	up-regulates activity	0.306	The results showed that SMAD5 was directly phosphorylated at Ser463/465 by ROCK1 (Fig.\u00a04g).\|These data indicated that the activation of SMAD5 induced by TEM8 was mediated directly by the RhoC/ROCK1 pathway.To evaluate the effect of SMAD5 on the cellular functions of TEM8, SMAD5 was knockdown in TEM8-overexpressing cells.	SIGNOR-280107
P98177	O75874	1	transcriptional regulation	up-regulates quantity by expression	0.264	We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH.	SIGNOR-260102
Q9UBK2	O00327	1	transcriptional regulation	up-regulates quantity by expression	0.519	Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism. Here we show that PGC-1alpha (Ppargc1a), a transcriptional coactivator that regulates energy metabolism, is rhythmically expressed in the liver and skeletal muscle of mice. PGC-1alpha stimulates the expression of clock genes, notably Bmal1 (Arntl) and Rev-erbalpha (Nr1d1), through coactivation of the ROR family of orphan nuclear receptors.	SIGNOR-268031
Q13541	P68400	0	phosphorylation	down-regulates	0.341	Phosphorylation at s112 directly affects binding of 4e-bp1 to eif4e without influencing phosphorylation of other sites.	SIGNOR-98280
Q9BVJ7	Q9NP62	1	dephosphorylation	up-regulates quantity by stabilization	0.464	DUSP23 prevents GCM1 from ubiquitination and prolongs the half-life of GCM1.\|Second, DUSP23 is able to dephosphorylate Ser322 in GCM1 in vitro and in a stable cell line expressing HA-GCM1.	SIGNOR-276982
P12931	Q9NRY4	1	phosphorylation	up-regulates	0.772	Phosphorylation of y1105, but not the minor site, was modulated in vivo to a greater extent by overexpression of c-src than by the egf receptor and was efficiently catalyzed by c-src in vitro. Mutation of y1105 from tyr to phe resulted in complete loss of p-tyr-dependent complex formation, indicating that p-y1105 was the sole p-tyr residue mediating binding to p120	SIGNOR-61670
P00519	Q8TDZ2	1	phosphorylation	up-regulates activity	0.312	Biochemical assays revealed Abl phosphorylates Mical to directly amplify Mical Redox-mediated F-actin disassembly.\|We now find that the Abl non receptor protein tyrosine kinase and oncoprotein signaling pathway activates Mical to direct multiple cellular effects - including extending and shaping cellular processes, guiding axons, and orchestrating cancer cell invasion, colony formation, and survival.	SIGNOR-279674
P68400	P25963	1	phosphorylation	down-regulates	0.581	Casein kinase ii phosphorylates i kappa b alpha at s-283, s-289, s-293, and t-291 and is required for its degradation.	SIGNOR-40502
Q13485	P53350	0	phosphorylation	down-regulates quantity by destabilization	0.254	We observed that PLK1 could significantly promote the ubiquitination and degradation of Smad4 wild type, Smad4 S171A, Smad4 S187A, Smad4 S191A, respectively, but PLK1-induced the ubiquitination and degradation of Smad4 T197A were obviously inhibited (Fig. 1M).	SIGNOR-277591
P50750	P84022	1	phosphorylation	down-regulates activity	0.622	Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-161589
P62136	P46937	1	dephosphorylation	up-regulates activity	0.668	In the present study, we demonstrate that PP1A (catalytic subunit of protein phosphatase-1) interacts with and dephosphorylates YAP2 in vitro and in vivo, and PP1A-mediated dephosphorylation induces the nuclear accumulation and transcriptional activation of YAP2.\|PP1A dephosphorylates endogenous YAP2 at serine 127.	SIGNOR-276999
O00743	Q9UKV8	1	dephosphorylation	up-regulates activity	0.328	Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression.	SIGNOR-276515
O43464	O15033	0	ubiquitination	down-regulates quantity by destabilization	0.406	Furthermore, the ubiquitination and degradation of SMAC, HtrA2, and ARTS were significantly enhanced in AREL1-expressing cells following apoptotic stimulation, indicating that AREL1 binds to and ubiquitinates cytosolic but not mitochondria-associated forms of IAP antagonists	SIGNOR-267669
Q9UQM7	Q15121	1	phosphorylation	up-regulates	0.2	Pea-15 is a phosphoprotein containing a ser-104 phosphorylated by protein kinase c and a ser-116 phosphorylated by camkii (calcium/calmodulin-dependent protein kinase ii) or akt. Phosphorylation of ser-104 is implicated in the regulation of glucose metabolism, while phosphorylation at ser-116 is required for pea-15 recruitment to the disc (death-initiation signalling complex)	SIGNOR-137614
P35354	P11831	0	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
Q17RY0	P28482	0	phosphorylation	up-regulates activity	0.325	Our results indicate that CPEB4 activation is driven by ERK2- and Cdk1 mediated hyperphosphorylation of at least 12 residues in the intrinsically disordered NTD.\|We concluded that, in interphase, unphosphorylated CPEB4 phase separates into liquid like droplets that recruit mRNAs but are inactive for cytoplasmic polyadenylation and translation, whereas in M-phase, CPEB4 is phosphorylated by ERK2 and Cdk1 and recovers its monomeric form, which can drive the cytoplasmic polyadenylation of target mRNAs.	SIGNOR-280021
P53350	P18031	1	phosphorylation	up-regulates activity	0.354	Cdk1-cyclin B1 directly phosphorylates PTP1B at serine 386 in a kinase assay. Recombinant Plk1 phosphorylates PTP1B on serine 286 and 393 in vitro, however, it requires a priming phosphorylation by Cdk1 at serine 386 highlighting a novel co-operation between Cdk1 and Plk1 in the regulation of PTP1B.\|Finally, phosphorylation on serine 286 enhanced PTP1B phosphatase activity.	SIGNOR-272990
O14744	P12931	0	phosphorylation	down-regulates activity	0.261	Here, we demonstrate that PRMT5 is phosphorylated at residue Y324 by Src kinase, a negative regulator of its activity.	SIGNOR-277523
P00519	Q14498	1	phosphorylation	up-regulates activity	0.322	In this paper, we report that RBM39 interacts with the nonreceptor tyrosine kinase c-Abl. Both the Src homology (SH) 2 and SH3 domains of c-Abl interact with RBM39. The major tyrosine phosphorylation sites on RBM39 that are phosphorylated by c-Abl are Y95 and Y99, as demonstrated by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and mutational analysis. c-Abl was shown boost the transcriptional coactivation activity of RBM39 for ERα and PRβ in a tyrosine kinase-dependent manner.	SIGNOR-262609
Q9NQT8	Q00535	0	phosphorylation	down-regulates activity	0.365	Overexpression of Cdk5 or its activator p35 promoted and inhibition of Cdk5 activity prevented the KIF13B-TRPV1 association, indicating that Cdk5 promotes TRPV1 anterograde transport by mediating the motor-cargo association. Cdk5 phosphorylates KIF13B at Thr-506, a residue located in the FHA domain. T506A mutation reduced the motor-cargo interaction and the cell-permeable TAT-T506 peptide, targeting to the Thr-506, decreased TRPV1 surface localization, demonstrating the essential role of Thr-506 phosphorylation in TRPV1 transport.	SIGNOR-262737
P46937	P51955	0	phosphorylation	up-regulates quantity by stabilization	0.2	NEK2 promotes the migration and proliferation of ESCC via stabilization of YAP1 by phosphorylation at Thr-143	SIGNOR-276586
Q9Y2U5	Q02750	1	phosphorylation	up-regulates	0.414	Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation	SIGNOR-107692
P09651	P01106	0	transcriptional regulation	up-regulates quantity by expression	0.456	We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2,	SIGNOR-268690
O14920	P35568	1	phosphorylation	down-regulates activity	0.654	IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways.	SIGNOR-251297
P05129	P19429	1	phosphorylation	down-regulates	0.2	Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction.	SIGNOR-134632
Q8NBJ5	P02462	1	glycosylation	up-regulates activity	0.402	Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues.	SIGNOR-261155
Q6P0Q8	P48764	1	phosphorylation	down-regulates activity	0.456	Coexpression of MAST205 inhibits the activity of Na +/H+ exchanger NHE3.\|Consistent with these results, we found that MAST205 phosphorylated NHE3 under in vitro conditions.	SIGNOR-279229
O15194	P84022	1	dephosphorylation	up-regulates activity	0.424	Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3\|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248306
P41743	P10636-2	1	phosphorylation	down-regulates activity	0.265	We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs.	SIGNOR-275446
P28482	P46527	1	phosphorylation	up-regulates	0.346	Phosphorylation on ser-10 of kip1 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability.	SIGNOR-77651
P68400	P05114	1	phosphorylation	down-regulates	0.2	Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools.	SIGNOR-76274

Q16621

P45983

0

phosphorylation

down-regulates quantity by destabilization

0.411

Through use of different approaches including nano-scale proteomics, we show that activated-JNK, or Phospho-JNK (P-JNK), physically interacts with p45/NF-E2 and phosphorylates its Ser157 residue. This reaction leads to the poly-ubiquitination of p45/NF-E2 at one or more of six Lys residues, one of which being also a sumoylation site, and its degradation through the proteasome pathway.

SIGNOR-275552

Q96T68

Q16695

1

methylation

up-regulates activity

0.2

Here, we have characterized a previously undescribed member of the histone H3K9 methyltransferase family named CLLD8 (or SETDB2 or KMT1F). This protein contributes to the trimethylation of both interspersed repetitive elements and centromere-associated repeats and participates in the recruitment of heterochromatin protein 1 to centromeres. Methylation of histone H3 at lysine 9 (H3K9) has emerged as an important player in the formation of heterochromatin, chromatin condensation, and transcriptional repression.

SIGNOR-263895

P07477

P55085

1

cleavage

up-regulates activity

0.388

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-263602

Q9NQS7

O96017

0

phosphorylation

up-regulates activity

0.261

Also, inhibition of Chk2 by Chk2 inhibitor II in cytokinesis after release of cells from a nocodazole-induced prometaphase block diminished INCENP localization to the midbody center in late midbodies (Fig. 1, M and N).|In turn, active Chk2 phosphorylates human INCENP at the newly identified site Ser91 to promote INCENP binding to Mklp2, resulting in recruitment of the INCENP\u2013Mklp2 complex to the midbody center through Mklp2\u2019s interaction with the midbody protein Cep55 to delay abscission.

SIGNOR-279695

P04626

Q06124

0

dephosphorylation

down-regulates

0.838

...which in turn suggests the importance SHP2 dephosphorylation of pTyr992 in EGFR and pTyr1023 in HER2 to mediate signaling.|More specifically, we show that acidic residues N-terminal to the substrate pTyr in EGFR and HER2 mediate specific binding by the SHP2 active site, leading to blockade of RasGAP binding and optimal signaling by the two receptors.

SIGNOR-262957

Q7Z6Z7

Q07869

1

ubiquitination

down-regulates quantity by destabilization

0.2

Furthermore, the E3 ubiquitin ligase HUWE1 was identified to mediate PPARalpha polyubiquitination.|This notion is also supported by our finding that Huwe1 knockdown up-regulated the expression of PPARalpha target genes at the cellular level.

SIGNOR-278814

Q92698

P24941

0

phosphorylation

down-regulates activity

0.347

Effect of CDK2 phosphorylation on the RAD54 activities. We find that the RAD54 N-terminal domain (NTD) is responsible for initiation of BM through two coupled, but distinct steps; specific binding to Holliday junctions and RAD54 oligomerization. Furthermore, we find that the RAD54 oligomeric state can be controlled by NTD phosphorylation at S49, a CDK2 consensus site, which inhibits RAD54 oligomerization and, consequently, BM.

SIGNOR-273599

P08069

Q05397

0

phosphorylation

up-regulates quantity

0.535

Taken together, our data suggest that FAK mediates the phosphorylation of IGF-1R and stabilizes the receptor.In this study we demonstrate that FAK, mainly known for its role in integrin signaling pathways, associates with and phosphorylates IGF-1R independently of IGF-1R 's intrinsic tyrosine kinase activity.|The impact of FAK on the expression levels of IGF-1R could be multilateral

SIGNOR-279565

P03372

Q9NRW4

0

dephosphorylation

down-regulates activity

0.261

These results strongly suggest that DUSP22 acts as a negative regulator of the ERalpha-mediated signaling pathway|whereas E2-induced phosphorylation and activation of ERalpha was suppressed by overexpression of DUSP22 but not catalytically inactive mutants.

SIGNOR-248827

Q9BYX4

P36873

0

dephosphorylation

up-regulates activity

0.247

Exogenous PP1alpha or PP1gamma substantially decreased the S88 phosphorylation of Flag-MDA5|we identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation.

SIGNOR-264579

Q13627

P35568

1

phosphorylation

up-regulates quantity

0.2

DYRK1A interacts with IRS-1 and phosphorylates IRS-1 at Ser-312 and Ser-616.|We found that DYRK1A overexpression up-regulated IRS-1 expression by slowing the turnover of IRS-1 protein.

SIGNOR-279521

P50613

P21127

1

phosphorylation

up-regulates activity

0.335

We conclude that CDK7 phsphorylates Cdk11, dependent on the conserved Thr219 residue in the CDK11 T loop, and it is therefore likely to be a genuine Cdk11 activating kinase

SIGNOR-245871

Q13315

Q9UER7

1

phosphorylation

down-regulates

0.499

The main phosphorylation site of daxx is identified to be ser564, which is a direct target of atm. Phosphorylation of endogenous daxx at ser564 occurs rapidly during the dna damage response and precedes p53 activation. Blockage of this phosphorylation event prevents the separation of daxx from mdm2, stabilizes mdm2, and inhibits dna damage-induced p53 activation.

SIGNOR-200889

P00338

P11362

0

phosphorylation

up-regulates

0.366

We found that the oncogenic receptor tyrosine kinase fgfr1 directly phosphorylates ldh-a. Phosphorylation at y10 and y83 enhances ldh-a activity by enhancing the formation of active, tetrameric ldh-a and the binding of ldh-a substrate nadh, respectively.

SIGNOR-176730

Q9UPQ7

O15146

1

ubiquitination

down-regulates quantity

0.543

We have identified a PDZ domain containing RING finger 3 (PDZRN3) as a synapse-associated E3 ubiquitin ligase and have demonstrated that it regulates the surface expression of muscle-specific receptor tyrosine kinase (MuSK), the key organizer of postsynaptic development at the mammalian neuromuscular junction. PDZRN3 binds to MuSK and promotes its ubiquitination. Together, these data demonstrate that PDZRN3 is a catalytically active RING-type E3 ubiquitin ligase

SIGNOR-271664

P52757

P12931

0

phosphorylation

down-regulates

0.2

Here we report that beta2-chimaerin is tyrosine-phosphorylated by src-family kinases (sfks) upon cell stimulation with epidermal growth factor (egf). Mutational analysis identified tyr-21 in the n-terminal regulatory region as a major phosphorylation site. these results suggest tyr-21 phosphorylation as a novel, sfk-dependent mechanism that negatively regulates beta2-chimaerin rac-gap activity.

SIGNOR-155713

Q9P286

O43426

1

phosphorylation

up-regulates activity

0.2

We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo.

SIGNOR-263026

Q8TE77

P23528

1

dephosphorylation

up-regulates activity

0.717

Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH).

SIGNOR-248759

P68400

P49321

1

phosphorylation

down-regulates activity

0.2

Here, we show that somatic nuclear autoantigenic sperm protein (sNASP) binds to TRAF6 to prevent TRAF6 autoubiquitination in unstimulated macrophages. Following LPS stimulation, a complex consisting of sNASP, TRAF6, IRAK4, and casein kinase 2 (CK2) is formed. CK2 phosphorylates sNASP at serine 158, allowing sNASP to dissociate from TRAF6. Free TRAF6 is then autoubiquitinated, followed by activation of downstream signaling pathways.

SIGNOR-273627

P41143

P01213

0

chemical activation

up-regulates activity

0.667

Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.

SIGNOR-258415

Q9UQC2

P43403

0

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

P35790

Q9Y6Q9

1

phosphorylation

down-regulates quantity by destabilization

0.2

First, by using purified recombinant SRC-3 (XREF_FIG) and CKI proteins, we found that CKI is able to phosphorylate SRC-3 (XREF_FIG).

SIGNOR-280229

P49674

P46937

1

phosphorylation

down-regulates

0.422

Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by Casein Kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ

SIGNOR-201170

P48729

O15169

1

phosphorylation

up-regulates activity

0.785

Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated (Supplementary Figure 3). Three of them (S80, S82, and S473) were also phosphorylated in vitro by CKI and are conserved between axin1 and axin2/conductin.|This suggests that cumulative phosphorylation of axin is required for it to fully downregulate Wnt/beta_catenin signaling.

SIGNOR-249191

Q16539

P07949

0

phosphorylation

up-regulates

0.332

Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme.

SIGNOR-40493

Q6WCQ1

O75688

0

dephosphorylation

down-regulates activity

0.2

Ppm1b prevents Rip3 auto-activation in resting cells.|Together, these data demonstrate that Ppm1b dephosphorylates Rip3 and thus negatively regulates TNF induced necroptosis in L929 cells.

SIGNOR-277019

P06493

Q8ND76

1

phosphorylation

down-regulates activity

0.595

Therefore, CDK1 may trigger CFP1 degradation through some indirect mechanisms rather than CFP1 phosphorylation.|This result suggests that, although CDK1 triggers both phosphorylation and degradation of CFP1 protein, phosphorylation of CFP1 by CDK1 is not a prerequisite for its degradation during cell division.

SIGNOR-279012

P17706

P10912

1

dephosphorylation

down-regulates activity

0.295

PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates

SIGNOR-248394

Q15796

O14595

0

dephosphorylation

down-regulates activity

0.445

Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity

SIGNOR-248299

P55211

P31751

0

phosphorylation

down-regulates

0.528

Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity

SIGNOR-61561

Q9UM54

O75914

0

phosphorylation

up-regulates activity

0.336

P21-activated kinase 3 phosphorylated myosin VI, and the site was identified as Thr(406). The phosphorylation of myosin VI significantly facilitated the actin-translocating activity of myosin VI.

SIGNOR-250244

P54646

P06213

1

phosphorylation

up-regulates

0.372

Ampk phosphorylates and activates theinsulinreceptor, providing a direct link between ampk and theinsulin pathway.

SIGNOR-195324

P57078

P98170

0

polyubiquitination

up-regulates activity

0.333

In this study, we report that in addition to RIP1 and RIP2, also RIP3 and RIP4 directly interact with XIAP, cIAP1 and cIAP2. When comparing the ability of these IAPs to directly conjugate RIP1–RIP4 with ubiquitin chains, we found that cIAP1 was the most effective E3 and was capable of ubiquitinating all four RIPs in the presence of the E2 component UbcH5a. On the contrary, XIAP was only capable of inducing weak ubiquitination of RIP4.

SIGNOR-272716

P10721

P23470

0

dephosphorylation

down-regulates activity

0.2

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-254710

Q15139

Q96QB1

1

phosphorylation

down-regulates

0.371

The tumor suppressor protein dlc1 is regulated by pkd-mediated gap domain phosphorylation.Our results thus show that pkd-mediated phosphorylation of dlc1 on serine 807 negatively regulates dlc1 cellular function.

SIGNOR-169994

P42575

P62140

0

dephosphorylation

up-regulates activity

0.2

Nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2.

SIGNOR-248576

P07339

P05067

1

cleavage

down-regulates quantity by destabilization

0.489

The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism.

SIGNOR-261767

O15530

Q96PN8

1

phosphorylation

up-regulates activity

0.261

We elucidated the mechanism of regulation of TSSK3 activity showing that autophosphorylation and PDK1 phosphorylation in the ‘activation loop’ are necessary for activation.

SIGNOR-260786

Q9H9S0

Q9HCS4

0

transcriptional regulation

down-regulates quantity by repression

0.341

These experiments showed that Tcf3 is associated with chromatin in the Nanog promoter regions and that the DNA-binding activity of Tcf3 was required for repression.

SIGNOR-266081

P08581

O15409

0

transcriptional regulation

down-regulates quantity by repression

0.416

FOXP2 binds directly to the 5' regulatory region of MET, and overexpression of FOXP2 results in transcriptional repression of MET. The expression of MET in restricted human neocortical regions, and its regulation in part by FOXP2, is consistent with genetic evidence for MET contributing to ASD risk.

SIGNOR-269054

P24941

P23470

0

dephosphorylation

down-regulates activity

0.298

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-254695

Q8N5S9

Q14012

1

phosphorylation

up-regulates activity

0.414

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

SIGNOR-250717

Q8N1I0

P63000

1

guanine nucleotide exchange factor

up-regulates activity

0.586

DOCK4 (dedicator for cytokinesis 4), a guanine nucleotide exchange factor (GEF) for the small GTPase Rac1, is one of few genes that are associated with both ASD and dyslexia.

SIGNOR-266823

P78549

Q12899

0

ubiquitination

down-regulates quantity by destabilization

0.263

We also demonstrated that TRIM26 directly polyubiquitylates NTH1 in cells and that TRIM26 targets newly synthesized NTH1 protein for ubiquitylation dependent degradation.

SIGNOR-278733

P06396

P12931

0

phosphorylation

up-regulates

0.572

Identification of tyr438 as the major in vitro c-src phosphorylation site in human gelsolin recently

SIGNOR-67014

P00441

Q16236

0

transcriptional regulation

up-regulates quantity by expression

0.408

BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2

SIGNOR-254653

P04626

Q05397

1

phosphorylation

up-regulates activity

0.657

HER2, EGFR, and additional RTKs directly phosphorylate FAK FERM at Y397.|To further confirm the mechanism of direct FAK activation by HER2, we performed a series of GST pull-down assays with purified recombinant proteins.

SIGNOR-278475

O43318

Q9BZR9

0

polyubiquitination

up-regulates activity

0.343

These results suggest that TRIM8 could mediate K63-linked polyubiquitination of TAK1 at residue K158.These results suggest that TRIM8 is involved in TNFα- and IL-1β–induced NF-κB activation by mediating K63-linked TAK1 polyubiquitination and subsequent activation.

SIGNOR-271890

Q66K64

Q14498

1

polyubiquitination

down-regulates quantity by destabilization

0.377

Indisulam promotes an interaction between RBM39 and the DCAF15 E3 ligase substrate receptor, leading to RBM39 ubiquitination and proteasome-mediated degradation.

SIGNOR-272203

P06748

P53350

0

phosphorylation

up-regulates

0.425

Phosphorylated at ser-4 by plk1 and plk2. Phosphorylation at ser-4 by plk2 in s phase is required for centriole duplication and is sufficient to trigger centriole replication. Phosphorylation at ser-4 by plk1 takes place during mitosis.

SIGNOR-125666

Q96KS0

Q969H0

0

ubiquitination

down-regulates quantity by destabilization

0.349

Mechanistically, we further show that FBW7, an E3 ligase complex component that is frequently downregulated in TNBC, negatively regulates EglN2 protein stability.

SIGNOR-261997

P06493

O15350

1

phosphorylation

down-regulates activity

0.556

Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73.Furthermore, cyclin a/cdk1/2, cyclin b/cdk1/2, and cyclin e/cdk2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86.

SIGNOR-99742

P00533

O95477

1

phosphorylation

down-regulates quantity by destabilization

0.295

We further provide in vitro evidence that epidermal growth factor receptor (EGFR)-mediated phosphorylation regulated ABCA1 ubiquitination |The EGFR selective inhibitor PD168393 blocked the EGFR-ABCA1 interaction and abolished ABCA1Ser2054 phosphorylation|

SIGNOR-264419

Q13418

Q9HBI1

1

phosphorylation

up-regulates activity

0.965

These results indicate that affixin directly associates with \u03b1-actinin only when its CH2 domain is phosphorylated by ILK.|This may indicate that phosphorylation of the CH2 domain by ILK induces a conformational change of the CH2 domain of affixin, which enables affixin to interact with alpha-actinin to evoke the subsequent maturation of the FA complex.

SIGNOR-278259

P49841

Q07812

1

phosphorylation

up-regulates

0.376

Glycogen synthase kinase-3beta phosphorylates bax and promotes its mitochondrial localization during neuronal apoptosis. Gsk-3beta directly phosphorylated bax(alpha) on ser163

SIGNOR-130141

P45985

P19793

1

phosphorylation

down-regulates

0.2

Phosphorylation by mkk4/sek1 had profound effects on the biochemical properties of rxr, inhibiting the expression of genes activated by rxr-retinoic acid receptor complexes. Tyr-249 in the rxr de region was required for the inhibitory effect of mkk4/sek1.

SIGNOR-80619

P52565

Q05209

0

dephosphorylation

up-regulates activity

0.2

Integrin-bound PTP-PEST dephosphorylates RhoGDI1.|Translocation of Src phosphorylated RhoGDI1 to the cell 's leading edge promotes local activation of Rac1 and Cdc42, whereas dephosphorylation of RhoGDI1 by integrin bound PTP-PEST promotes RhoGDI1 release from the membrane and sequestration of inactive Rac1 and Cdc42 in the cytoplasm.|Translocation of Src-phosphorylated RhoGDI1 to the cell's leading edge promotes local activation of Rac1 and Cdc42, whereas dephosphorylation of RhoGDI1 by integrin-bound PTP-PEST promotes RhoGDI1 release from the membrane and sequestration of inactive Rac1/Cdc42 in the cytoplasm.

SIGNOR-277175

P56524

P67775

0

dephosphorylation

up-regulates

0.35

Different signal-regulated serine/threonine kinases phosphorylate class ii histone deacetylases (hdacs) to promote nuclear export, cytosolic accumulation, and activation of gene transcriptionhere we show that hdac4 forms a complex with the pp2a holoenzyme c alpha, a alpha, b/pr55 alpha. In vitro and in vivo binding studies demonstrate that the n-terminus of hdac4 interacts with the catalytic subunit of pp2a. Hdac4 is dephosphorylated by pp2a

SIGNOR-159492

Q14938

Q14393

1

transcriptional regulation

down-regulates quantity

0.205

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-268888

P27361

P49407

1

phosphorylation

down-regulates

0.716

Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation

SIGNOR-67634

Q9Y2K2

Q15831

0

phosphorylation

up-regulates

0.488

Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold

SIGNOR-122835

P31749

Q15672

1

phosphorylation

up-regulates

0.438

Moreover, phosphorylation of twist-1 at ser42 was shown in vivo in various human cancer tissues, suggesting that this post-translational modification ensures functional activation of twist-1 after promotion of survival during carcinogenesis.

SIGNOR-164884

Q13043

P67775

0

dephosphorylation

down-regulates

0.367

Rassf1a apparently protects mst1/2 against inactivation by pp2a , the phosphatases that dephosphorylate the stimulatory thr-183 and thr-180 of mst1 andmst2, respectively.

SIGNOR-201270

Q09472

Q13131

0

phosphorylation

down-regulates

0.376

The mechanism of ampk-mediated anti- inflammation involves the induction of p300 ser89 phosphor- ylation and subsequent inactivation of p300 hat activity.

SIGNOR-176637

Q6R327

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.409

We show that this process is dependent on glycogen synthase kinase 3 (GSK3): GSK3 was associated with rictor and directly phosphorylated the Thr-1695 site in a putative CDC4 phospho-degron motif of rictor; mutation of this site impaired the interaction between rictor and FBXW7, decreased rictor ubiquitination, and increased rictor stability.

SIGNOR-276898

Q01892

P68400

0

phosphorylation

down-regulates

0.429

Serine residues 37 in the transactivation domain and 129, 144 and 146 in the pest domain of spi-b are phosphorylated by ckii in vitro. The ckii phosphorylation sites mapped in vitro are phosphorylated in vivo. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability

SIGNOR-73891

P08254

P07585

1

cleavage

down-regulates quantity by destabilization

0.673

Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues.

SIGNOR-256353

P85298

P61586

1

gtpase-activating protein

down-regulates activity

0.427

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-260463

P54764

O60674

1

phosphorylation

up-regulates activity

0.281

EphA4 phosphorylates JAK2.|These findings suggest that EphA4 activates not only growth hormone receptor, as shown above, but also JAK2 by direct phosphorylation.

SIGNOR-279040

Q13464

Q99717

1

phosphorylation

up-regulates activity

0.306

The results showed that SMAD5 was directly phosphorylated at Ser463/465 by ROCK1 (Fig.\u00a04g).|These data indicated that the activation of SMAD5 induced by TEM8 was mediated directly by the RhoC/ROCK1 pathway.To evaluate the effect of SMAD5 on the cellular functions of TEM8, SMAD5 was knockdown in TEM8-overexpressing cells.

SIGNOR-280107

P98177

O75874

1

transcriptional regulation

up-regulates quantity by expression

0.264

We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH.

SIGNOR-260102

Q9UBK2

O00327

1

transcriptional regulation

up-regulates quantity by expression

0.519

Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism. Here we show that PGC-1alpha (Ppargc1a), a transcriptional coactivator that regulates energy metabolism, is rhythmically expressed in the liver and skeletal muscle of mice. PGC-1alpha stimulates the expression of clock genes, notably Bmal1 (Arntl) and Rev-erbalpha (Nr1d1), through coactivation of the ROR family of orphan nuclear receptors.

SIGNOR-268031

Q13541

P68400

0

phosphorylation

down-regulates

0.341

Phosphorylation at s112 directly affects binding of 4e-bp1 to eif4e without influencing phosphorylation of other sites.

SIGNOR-98280

Q9BVJ7

Q9NP62

1

dephosphorylation

up-regulates quantity by stabilization

0.464

DUSP23 prevents GCM1 from ubiquitination and prolongs the half-life of GCM1.|Second, DUSP23 is able to dephosphorylate Ser322 in GCM1 in vitro and in a stable cell line expressing HA-GCM1.

SIGNOR-276982

P12931

Q9NRY4

1

phosphorylation

up-regulates

0.772

Phosphorylation of y1105, but not the minor site, was modulated in vivo to a greater extent by overexpression of c-src than by the egf receptor and was efficiently catalyzed by c-src in vitro. Mutation of y1105 from tyr to phe resulted in complete loss of p-tyr-dependent complex formation, indicating that p-y1105 was the sole p-tyr residue mediating binding to p120

SIGNOR-61670

P00519

Q8TDZ2

1

phosphorylation

up-regulates activity

0.312

Biochemical assays revealed Abl phosphorylates Mical to directly amplify Mical Redox-mediated F-actin disassembly.|We now find that the Abl non receptor protein tyrosine kinase and oncoprotein signaling pathway activates Mical to direct multiple cellular effects - including extending and shaping cellular processes, guiding axons, and orchestrating cancer cell invasion, colony formation, and survival.

SIGNOR-279674

P68400

P25963

1

phosphorylation

down-regulates

0.581

Casein kinase ii phosphorylates i kappa b alpha at s-283, s-289, s-293, and t-291 and is required for its degradation.

SIGNOR-40502

Q13485

P53350

0

phosphorylation

down-regulates quantity by destabilization

0.254

We observed that PLK1 could significantly promote the ubiquitination and degradation of Smad4 wild type, Smad4 S171A, Smad4 S187A, Smad4 S191A, respectively, but PLK1-induced the ubiquitination and degradation of Smad4 T197A were obviously inhibited (Fig. 1M).

SIGNOR-277591

P50750

P84022

1

phosphorylation

down-regulates activity

0.622

Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.

SIGNOR-161589

P62136

P46937

1

dephosphorylation

up-regulates activity

0.668

In the present study, we demonstrate that PP1A (catalytic subunit of protein phosphatase-1) interacts with and dephosphorylates YAP2 in vitro and in vivo, and PP1A-mediated dephosphorylation induces the nuclear accumulation and transcriptional activation of YAP2.|PP1A dephosphorylates endogenous YAP2 at serine 127.

SIGNOR-276999

O00743

Q9UKV8

1

dephosphorylation

up-regulates activity

0.328

Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression.

SIGNOR-276515

O43464

O15033

0

ubiquitination

down-regulates quantity by destabilization

0.406

Furthermore, the ubiquitination and degradation of SMAC, HtrA2, and ARTS were significantly enhanced in AREL1-expressing cells following apoptotic stimulation, indicating that AREL1 binds to and ubiquitinates cytosolic but not mitochondria-associated forms of IAP antagonists

SIGNOR-267669

Q9UQM7

Q15121

1

phosphorylation

up-regulates

0.2

Pea-15 is a phosphoprotein containing a ser-104 phosphorylated by protein kinase c and a ser-116 phosphorylated by camkii (calcium/calmodulin-dependent protein kinase ii) or akt. Phosphorylation of ser-104 is implicated in the regulation of glucose metabolism, while phosphorylation at ser-116 is required for pea-15 recruitment to the disc (death-initiation signalling complex)

SIGNOR-137614

P35354

P11831

0

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

Q17RY0

P28482

0

phosphorylation

up-regulates activity

0.325

Our results indicate that CPEB4 activation is driven by ERK2- and Cdk1 mediated hyperphosphorylation of at least 12 residues in the intrinsically disordered NTD.|We concluded that, in interphase, unphosphorylated CPEB4 phase separates into liquid like droplets that recruit mRNAs but are inactive for cytoplasmic polyadenylation and translation, whereas in M-phase, CPEB4 is phosphorylated by ERK2 and Cdk1 and recovers its monomeric form, which can drive the cytoplasmic polyadenylation of target mRNAs.

SIGNOR-280021

P53350

P18031

1

phosphorylation

up-regulates activity

0.354

Cdk1-cyclin B1 directly phosphorylates PTP1B at serine 386 in a kinase assay. Recombinant Plk1 phosphorylates PTP1B on serine 286 and 393 in vitro, however, it requires a priming phosphorylation by Cdk1 at serine 386 highlighting a novel co-operation between Cdk1 and Plk1 in the regulation of PTP1B.|Finally, phosphorylation on serine 286 enhanced PTP1B phosphatase activity.

SIGNOR-272990

O14744

P12931

0

phosphorylation

down-regulates activity

0.261

Here, we demonstrate that PRMT5 is phosphorylated at residue Y324 by Src kinase, a negative regulator of its activity.

SIGNOR-277523

P00519

Q14498

1

phosphorylation

up-regulates activity

0.322

In this paper, we report that RBM39 interacts with the nonreceptor tyrosine kinase c-Abl. Both the Src homology (SH) 2 and SH3 domains of c-Abl interact with RBM39. The major tyrosine phosphorylation sites on RBM39 that are phosphorylated by c-Abl are Y95 and Y99, as demonstrated by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and mutational analysis. c-Abl was shown boost the transcriptional coactivation activity of RBM39 for ERα and PRβ in a tyrosine kinase-dependent manner.

SIGNOR-262609

Q9NQT8

Q00535

0

phosphorylation

down-regulates activity

0.365

Overexpression of Cdk5 or its activator p35 promoted and inhibition of Cdk5 activity prevented the KIF13B-TRPV1 association, indicating that Cdk5 promotes TRPV1 anterograde transport by mediating the motor-cargo association. Cdk5 phosphorylates KIF13B at Thr-506, a residue located in the FHA domain. T506A mutation reduced the motor-cargo interaction and the cell-permeable TAT-T506 peptide, targeting to the Thr-506, decreased TRPV1 surface localization, demonstrating the essential role of Thr-506 phosphorylation in TRPV1 transport.

SIGNOR-262737

P46937

P51955

0

phosphorylation

up-regulates quantity by stabilization

0.2

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

SIGNOR-276586

Q9Y2U5

Q02750

1

phosphorylation

up-regulates

0.414

Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation

SIGNOR-107692

P09651

P01106

0

transcriptional regulation

up-regulates quantity by expression

0.456

We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2,

SIGNOR-268690

O14920

P35568

1

phosphorylation

down-regulates activity

0.654

IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways.

SIGNOR-251297

P05129

P19429

1

phosphorylation

down-regulates

0.2

Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction.

SIGNOR-134632

Q8NBJ5

P02462

1

glycosylation

up-regulates activity

0.402

Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues.

SIGNOR-261155

Q6P0Q8

P48764

1

phosphorylation

down-regulates activity

0.456

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

SIGNOR-279229

O15194

P84022

1

dephosphorylation

up-regulates activity

0.424

Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity

SIGNOR-248306

P41743

P10636-2

1

phosphorylation

down-regulates activity

0.265

We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs.

SIGNOR-275446

P28482

P46527

1

phosphorylation

up-regulates

0.346

Phosphorylation on ser-10 of kip1 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability.

SIGNOR-77651

P68400

P05114

1

phosphorylation

down-regulates

0.2

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

SIGNOR-76274