GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P61586	O15085	0	guanine nucleotide exchange factor	up-regulates activity	0.903	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-260538
P05549	P54646	0	phosphorylation	up-regulates activity	0.307	Inhibition of AMPKalpha2 with either siRNA or compound C significantly suppressed the AngII- or nicotine enhanced AP-2alpha activity and the binding of AP-2alpha to DNA.\|We report that nicotine, a major component of cigarette smoke, activates AMPK in VSMCs and that AMPKalpha2 phosphorylates AP-2alpha at serine 219 resulting in aberrant expression of MMP2 and consequent AAA formation.	SIGNOR-279648
O14965	P62136	0	dephosphorylation	down-regulates	0.436	Pp1 is shown to dephosphorylate active stk15 and abolish its activity in vitro.	SIGNOR-110411
Q15121	Q9UQM7	0	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
Q08050	O14757	0	phosphorylation	up-regulates activity	0.371	In addition, upon treatment with genotoxic agents, the checkpoint kinases Chk1 and Chk2 also phosphorylate and activate FOXM1.	SIGNOR-280224
P26651	P49137	0	phosphorylation	down-regulates activity	0.699	We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated.	SIGNOR-250153
Q9P1W9	P14618	1	phosphorylation	up-regulates quantity by stabilization	0.37	Here, we identified the protein-serine/threonine kinase PIM2, a known oncogene, as a novel binding partner of PKM2. The interaction between PIM2 and PKM2 was confirmed by multiple biochemical approaches in vitro and in cultured cells. Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. Compared with wild type, PKM2 with the phosphorylation-defective mutation displayed a reduced effect on glycolysis	SIGNOR-267472
Q96JA1	P21860	1	ubiquitination	down-regulates	0.434	We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation.	SIGNOR-139951
P04637	Q86UR1	1	transcriptional regulation	up-regulates quantity by expression	0.26	As a transcription factor, p53 induces several pro-apoptotic Bcl-2 members including Bax, Puma, Noxa and Bid, and represses the transcription of certain anti-apoptotic genes, including those encoding Bcl-2, Bcl-xL and survivin 3_and_5.	SIGNOR-209687
P21815	P15036	0	transcriptional regulation	up-regulates quantity by expression	0.2	Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin	SIGNOR-259873
Q92908	P49840	0	phosphorylation	down-regulates quantity by destabilization	0.265	Through bioinformatics and cell-based experiments, we identified the AKT-repressed signal as glycogen synthase kinase 3 (GSK3)-catalyzed phosphorylation of Ser(37) on the long form of the transcription factor GATA6. Phosphorylation of GATA6 on Ser(37) promoted its degradation, thereby preventing GATA6 from repressing transcripts that are induced by TNF and attenuated by insulin	SIGNOR-253156
Q14765	Q16539	0	phosphorylation	up-regulates	0.599	All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below).	SIGNOR-154787
P02649	P02647	0	relocalization	up-regulates activity	0.738	ApoA-I stimulates apoE secretion in mature human adipocytes. The regulation of apoE secretion by apoA-I, is neither dependent upon an increase in gene transcription, nor upon increased release from the Golgi. It may therefore be assumed that, in macrophage models, apoE is stored mainly in the cytoplasm and/or on the cell surface, with apoA-I enabling secretion of this cytoplasmic pool	SIGNOR-252105
O00358	P07202	1	transcriptional regulation	up-regulates quantity by expression	0.382	TSH regulates TPO expression through the cAMP pathway and acts with thyroid-specific transcription factors such as TTF-1, TTF-2 and Pax-8	SIGNOR-267279
Q9UHP3	P43405	0	phosphorylation	down-regulates quantity	0.385	Altogether, these data strengthen our results that SYK specifically phosphorylates USP25 and suggest that Y740 is the most probable phosphorylated tyrosine on USP25.We also assessed whether the SYK mediated phosphorylation of USP25 alters its protease activity.\|Preliminary data indicate that proteasome inhibition by MG132 treatment did not modify the SYK dependent decrease of USP25 levels in contrary to accumulation of USP25 protein by MG132 treatment in the absence of SYK overexpression.	SIGNOR-278458
P12931	P00519	1	phosphorylation	up-regulates activity	0.538	c-Src-induced c-Abl activation involves phosphorylation of Y245 and Y412, two residues required for c-Abl mitogenic function.	SIGNOR-246311
P29279	Q15561	0	transcriptional regulation	up-regulates quantity by expression	0.2	The multifunctional cytokine TGF-β has been identified as a potent inducer of CTGF expression, activating CTGF transcription through the canonical Smad signaling pathway. It is worth noting that TGF-β synergizes with Hippo–Yes-associated protein (YAP) signaling, a key regulator of tumorigenesis, to induce the expression of CTGF by the formation of a YAP-TEAD4-Smad3-p300 complex on the CTGF promoter	SIGNOR-277686
Q9P0J1	P24752	0	acetylation	down-regulates activity	0.34	We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1)	SIGNOR-267635
Q16539	Q9HBH9	1	phosphorylation	up-regulates	0.415	Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity	SIGNOR-48349
Q14012	Q9NXK8	0	ubiquitination	down-regulates quantity	0.475	Here, we show that a ubiquitin E3 ligase component, F-box protein Fbxl12, mediates CaMKI degradation via a proteasome-directed pathway leading to disruption of cyclin D1/cdk4 complex. Endogenous Fbxl12 and CaMKI interacted as demonstrated after Fbxl12 immuno-precipitation followed by immunoblot analysis with CaMKI antibodies assembly and resultantG1 arrest in lung epithelia. Fbxl12 targets CaMKI for ubiquitination.	SIGNOR-261193
P35222	P36888	0	phosphorylation	up-regulates activity	0.409	Endogenous beta-catenin co-immunoprecipitated with endogenous activated FLT3, and recombinant activated FLT3 directly phosphorylated recombinant beta-catenin. Finally, FLT3 inhibitor decreased tyrosine phosphorylation of beta-catenin in leukemia cells obtained from FLT3-ITD-positive AML patients. These data demonstrate that FLT3 activation induces beta-catenin tyrosine phosphorylation and nuclear localization, and thus suggest a mechanism for the association of FLT3 activation and beta-catenin oncogeneic signaling in AML.	SIGNOR-260124
Q14258	O95786	1	ubiquitination	up-regulates activity	0.803	Lys63 linked polyubiquitination of RIG-I at Lys 172 catalyzed by TRIM25 is an important step for RIG-I activation.	SIGNOR-278730
P43403	Q9UJU6	1	phosphorylation	up-regulates	0.64	We found an interaction between the tyrosine kinase zap-70 and hip-55, which was induced by tcr stimulation. Zap-70 phosphorylated hip-55 at tyr-334 and tyr-344, which were shown to be the tyrosine phosphorylation sites of hip-55 in stimulated t cells.Our results demonstrate for the first time that hip-55 is an important adaptor protein for the jnk kinase cascade in tcr signaling.	SIGNOR-118695
Q96E17	Q9UQ26	0	relocalization	up-regulates activity	0.558	N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle	SIGNOR-264378
P33076	P49841	0	phosphorylation	up-regulates	0.346	Here we report that CIITA represses collagen transcription through a phosphorylation-dependent interaction between its proline/serine/threonine domain and co-repressor molecules such as histone deacetylase (HDAC2) and Sin3B. Mutation of a serine (S373A) in CIITA, within a glycogen synthase kinase 3 (GSK3) consensus site, decreases repression of collagen transcription by blocking interaction with Sin3B	SIGNOR-158959
O60674	P16410	1	phosphorylation	up-regulates quantity by stabilization	0.445	Janus Kinase 2 (Jak2) was directly associated with a box 1-like motif in the cytoplasmic tail of CTLA-4 molecule. Jak2 phosphorylated Y-165 residue in the cytoplasmic region of CTLA-4. It has been reported that phosphorylation and dephosphorylation of tyrosine residue Y-165 in the cytoplasmic region of CTLA-4 play an important role in its negative signaling and cell surface expression. Some signaling molecules such as Src homology 2 protein tyrosine phosphatase 2 (SHP-2) and the p85 subunit of phosphatidylinositol 3 kinase (PI3 kinase) associate with phosphorylated tyrosine residue Y-165, through Src homology 2 (SH2) domains. On the other hand, the adapter complex proteins, AP-2 and AP-50 interact with the same tyrosine residue when unphosphorylated, resulting in clathrin-mediated endocytosis of CTLA-4 molecules.	SIGNOR-251346
O43734	Q14164	0	phosphorylation	up-regulates activity	0.416	IKKi was required for IL-17-induced phosphorylation of Act1 on Ser311, adjacent to a putative TRAF-binding motif. Substitution of the serine at position 311 with alanine impaired the IL-17-mediated Act1-TRAF2-TRAF5 interaction and gene expression. Thus, IKKi is a kinase newly identified as modulating IL-17 signaling through its effect on Act1 phosphorylation and consequent function.	SIGNOR-262883
P28482	P41162	1	phosphorylation	down-regulates activity	0.403	We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. Among the ERK2 substrates, we identified the E-twenty six (ETS) domain-containing protein ETV3. We determined that phosphorylation of this protein by ERK2 was functionally relevant, abrogating the DNA-binding activity of ETV3 at thousands of targets across the genome, thereby providing an additional mechanism for transcriptional regulation downstream of ERK2 activation.	SIGNOR-262758
Q5JQC9	Q9BYT3	0	phosphorylation	up-regulates quantity by stabilization	0.2	Differential phosphoproteomic analysis and in vitro kinase assay identified novel phosphorylation substrates of STK33, fibrous sheath components AKAP3 and AKAP4, whose expression levels decreased in testis after deletion of Stk33.	SIGNOR-272956
O14757	Q96AV8	1	phosphorylation	down-regulates activity	0.387	Chk1 inhibits the transcriptional repressor function of E2F7 and E2F8 to promote cell cycle progression and prevent apoptosis.\|Here, we demonstrate that Chk1 phosphorylates both E2F7 and E2F8 in response to DNA damage.	SIGNOR-279692
P36507	O15530	0	phosphorylation	up-regulates	0.256	The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation.	SIGNOR-125176
P17252	Q86UX7	1	phosphorylation	up-regulates activity	0.2	PKC-induced phosphorylation events, as we have shown kindlin-3 to be a PKC phosphorylation target (Fig. 6C), are often followed by rapid activation of phosphatases (38).	SIGNOR-266415
P48729	P16220	1	phosphorylation	up-regulates	0.312	Ser108, ser111 and ser114, located in a region matching the consensus sequence for the casein kinase ii target, were required.These results strongly suggest that the casein kinase ii target region is involved in cell cycle-regulated phosphorylation of the creb protein and also in transcriptional enhancement.	SIGNOR-64258
P0C0L4	P48740	0	cleavage	up-regulates activity	0.606	The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.\|Activation of C4 by Ct sand MASP-2 on western blots.	SIGNOR-263438
Q16816	P06737	1	phosphorylation	up-regulates activity	0.54	It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15	SIGNOR-267399
Q8NE35	O76050	0	ubiquitination	up-regulates activity	0.47	If Neurl1 interacts and modulates the activity of CPEB3 and increases the translation of GluA1 and GluA2 mRNAs, this effect would be blocked if we abolished the interaction between CPEB3 and Neurl1.\|Neurl1 Interacts with and Ubiquitinates a Translational Regulator of GluA1 and GluA2 : the Cytoplasmic Polyadenylation Element Binding Protein 3.	SIGNOR-278588
Q14814	Q00535	0	phosphorylation	down-regulates activity	0.415	In this case, cdk5 phosphorylates MEF2D on Ser444 suppressing its transcriptional activity.	SIGNOR-279509
Q9UBF8	Q15208	0	phosphorylation	up-regulates activity	0.267	We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation.	SIGNOR-263033
P40337	P06493	0	phosphorylation	up-regulates activity	0.2	Mechanistically, CDK1 directly phosphorylates pVHL at Ser80, which primes the recognition of pVHL by PIN1.\|PIN1 and CDK1 cooperatively modulate the protein turnover of pVHL, thereby conferring tumor growth, chemotherapeutic resistance and metastasis both in vitro and in vivo.	SIGNOR-280207
P23246	P49841	0	phosphorylation	down-regulates	0.345	Psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. / threonine phosphorylation of psf by gsk3 primarily occurs on residue t687	SIGNOR-168392
Q00535	P04150	1	phosphorylation	down-regulates activity	0.481	Cdk5 phosphorylated gr at multiple serines, including ser203 and ser211 of its n-terminal domain, and suppressed the transcriptional activity of this receptor on glucocorticoid-responsive promoters by attenuating attraction of transcriptional cofactors to dna.\| the effect of CDK5 on GR-induced transcriptional activity is specific to gene promoter, and possibly, to tissue	SIGNOR-154405
Q8NHV4	Q8TD19	0	phosphorylation	up-regulates activity	0.426	Nek9 phosphorylates NEDD1 on Ser377 driving its recruitment and thereby that of γ-tubulin to the centrosome in mitotic cells.	SIGNOR-263016
P31749	P53004	1	phosphorylation	up-regulates activity	0.296	Site-directed mutagenesis, mass spectrometry, and kinetic analyses identified S(230) in hBVR (225)RNRYLSF sequence as the Akt1 target.	SIGNOR-275517
Q13418	Q96A00	1	phosphorylation	up-regulates activity	0.549	Phosphopeptide mapping, phospho amino acid analysis and immunoblotting using phospho-specific antibodies indicated that ilk predominantly phosphorylated the site critical for potent inhibition, i.e. Thr(38) of cpi-17	SIGNOR-90828
P02775	P35372	1	chemical inhibition	down-regulates activity	0.385	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-258413
Q92973	P49790	1	relocalization	up-regulates activity	0.499	TNPO1 only mediates the nuclear import of a subset of proteins.\|Among TNPO1 cargos, the most extensively characterized is the RNA binding protein heterogeneous nuclear ribonucleoprotein 1 (hnRNPA1) (27), which functions in several processes including mRNA biogenesis and promotion of transcription factor activity (28–30). NPC protein NUP153 is also a target for TNPO1-mediated nuclear import	SIGNOR-262100
P23443	Q9BPZ7	1	phosphorylation	down-regulates activity	0.565	Consistently, we detected in vivo Sin1 phosphorylation triggered by S6K1 and to a lesser extent, Akt1, but not other characterized AGC kinases (XREF_FIG and XREF_SUPPLEMENTARY).\|Here we report that phosphorylation of Sin1 at Thr 86 and Thr 398 suppresses mTORC2 kinase activity by dissociating Sin1 from mTORC2.	SIGNOR-279568
Q15424	P38398	0	ubiquitination	up-regulates quantity by stabilization	0.2	These results suggest that the BRCA1 and BARD1 heterodimer ubiquitinates SAFB and increases SAFB protein levels.	SIGNOR-278624
O75122	P06493	0	phosphorylation	up-regulates activity	0.569	Overall, these results support the idea that phosphorylation of CLASP2 on S1234 by Cdk1, but not phosphorylation of the CLASP2 C terminal by Plk1, is required to maintain mitotic spindle bipolarity.\|We propose that Cdk1 and Plk1 mediate a CLASP2 phospho-switch that is necessary to stabilize KT-MT attachments in human cells.	SIGNOR-278233
P06493	P00533	1	phosphorylation	down-regulates	0.426	Using a synthetic peptide corresponding to the sequence surrounding ser-1002, p34cdc2 was identified as a kinase capable of phosphorylating this serine residue. phosphorylation of the egf receptor by p34cdc2 was associated with a decrease in its tyrosine protein kinase activity.	SIGNOR-38313
Q13131	Q16576	1	phosphorylation	up-regulates activity	0.2	AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314\| interaction between RBBP7 and HAT1 is required for acetyltransferase activity	SIGNOR-264784
P17676	Q8NHY2	0	ubiquitination	down-regulates quantity by destabilization	0.2	We show expression of c/EBPβ in microglia is regulated post-translationally by the ubiquitin ligase COP1 (also called RFWD2). In the absence of COP1, c/EBPβ accumulates rapidly and drives a potent pro-inflammatory and neurodegeneration-related gene program, evidenced by increased neurotoxicity in microglia-neuronal co-cultures.	SIGNOR-261924
P11309	P46531	1	phosphorylation	up-regulates activity	0.27	Interestingly, Pim1 phosphorylated Notch1 and Notch3, but not Notch2 ICD (Figure xref ), which was in line with the observed Pearson correlations ( xref ).\|Our data indicate that endogenous Pim1 and Notch1 interact already in the cytoplasm, which supports the notion that Pim1 enhances nuclear localization and activity of Notch1.	SIGNOR-279643
P42771	O14920	0	phosphorylation	down-regulates	0.396	Ikkbeta specifically binds to p16 and phosphorylates ser8 of p16 phosphorylation at ser8 of p16 brings about a significant loss of its cyclin-dependent kinase (cdk) 4-inhibitory activity	SIGNOR-163801
Q9H6R0	Q9P275	0	deubiquitination	up-regulates quantity by stabilization	0.508	Loss of the deubiquitinase USP36 destabilizes the RNA helicase DHX33 and causes preimplantation lethality in mice.	SIGNOR-272289
P05771	Q05639	1	phosphorylation	up-regulates activity	0.2	PKCβI phosphorylates eEF1A at Ser53.our proteomics exploration of cPKC signaling in the nuclei of C2C12 cells demonstrated that the up-regulation of eEF1A intranuclear content, evoked by insulin, is associated with an increase in the phosphorylation of the Ser53 residue of the protein.	SIGNOR-263166
O60479	P17252	0	phosphorylation	down-regulates activity	0.307	Dlx3 is primarily phosphorylated by PKC alpha. By deletion and mutational analysis, we show that the serine residue S(138), located in the homeodomain of Dlx3 protein, was specifically phosphorylated by PKC. The phosphorylation of purified Dlx3 proteins by PKC partially inhibited formation of complexes between Dlx3 protein and DNA. These results suggest that Dlx3 protein can be directly phosphorylated by PKC and this affects the DNA binding activity of Dlx3.	SIGNOR-249096
P10721	P12931	0	phosphorylation	up-regulates activity	0.386	C-src phosphorylates tyr900 in the second part of the kinase domain of c-kit.	SIGNOR-103999
P60484	P53671	0	phosphorylation	down-regulates activity	0.274	LIMK2 inhibits PTEN phosphatase activity in vitro and in cells.\|PTEN phosphorylation and downregulation by LIMK2 promotes tumorigenesis and EMT in vivo.	SIGNOR-278363
P04626	P62993	1	relocalization	up-regulates	0.85	All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor	SIGNOR-121968
Q12906	P31749	0	phosphorylation	up-regulates activity	0.367	Upon T cell activation, NF90 translocates from the nucleus into the cytoplasm, where it binds to the AU-rich element-containing 3' untranslated regions of IL-2 mRNA and stabilizes it.\|Our previous work showed that CD28 costimulation of T cells activated AKT to phosphorylate NF90 at Ser647 and caused NF90 to undergo nuclear export and stabilize IL-2 mRNA.	SIGNOR-252512
P20336	Q92696	0	lipidation	up-regulates activity	0.569	Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional	SIGNOR-265574
Q96FA3	P53355	0	phosphorylation	down-regulates quantity by destabilization	0.2	DAPK1, which directly binds to and phosphorylates Pellino1 at Ser39, leading to Pellino1 poly-ubiquitination and turnover.	SIGNOR-277531
Q05513	Q9NPB6	1	phosphorylation	up-regulates quantity by stabilization	0.841	APKC associates and phosphorylates Par6 on S345. aPKC expression stabilizes Par6 protein levels. We show that the aPKC, PKCι, interacts with TGF-β receptors through Par6 and that these proteins localize to the leading edge of migrating cells. Furthermore, Par6 phosphorylation on serine 345 by TGF-β receptors is enhanced in the presence of aPKC. aPKC kinase activity, as well as an association with Par6, were found to be important for Par6 phosphorylation.	SIGNOR-276433
O95271	Q92530	1	ADP-ribosylation	down-regulates quantity by destabilization	0.501	We identify the ADP-ribosyltransferase tankyrase (TNKS) and the 19S assembly chaperones dp27 and dS5b as direct binding partners of the proteasome regulator PI31. TNKS-mediated ADP-ribosylation of PI31 drastically reduces its affinity for 20S proteasome alpha subunits to relieve 20S repression by PI31.	SIGNOR-263387
Q96PU5	P37088	1	ubiquitination	down-regulates quantity by destabilization	0.775	The serum and glucocorticoid inducible kinase 1 (SGK1) is induced in the aldosterone sensitive distal nephron (ASDN) where it may stimulate Na reabsorption, partly by inhibiting ubiquitin ligase Nedd4-2-mediated retrieval of epithelial Na+ channel ENaC from the luminal membrane.	SIGNOR-251948
P63000	Q8IZD9	0	guanine nucleotide exchange factor	up-regulates activity	0.656	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-260548
P10153	P11678	0	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
P17676	Q9UQM7	0	phosphorylation	up-regulates activity	0.326	These studies implicate Ser276 of CIEBPP as the major in vim phosphorylation site for CaMKII. \| Phosphorylation of serine at position 276 within the leucine zipper of C/EBP beta appeared to confer calcium-regulated transcriptional stimulation of a promoter that contained binding sites for C/EBP beta.	SIGNOR-250617
P09211	P05771	0	phosphorylation	up-regulates activity	0.2	Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently	SIGNOR-276023
P48730	P49810	1	phosphorylation	up-regulates activity	0.364	In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites.	SIGNOR-250802
P23528	Q8WYL5	0	dephosphorylation	up-regulates activity	0.786	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-248762
Q8WXE1	P24941	0	phosphorylation	up-regulates	0.579	Atrip is a cdk2 substrate, and cdk2-dependent phosphorylation of s224 regulates the ability of atr-atrip to promote cell cycle arrest in response to dna damage./ One possibility is s224 phosphorylation creates a binding site for another protein involved in the g2-m checkpoint response	SIGNOR-156928
Q00987	Q9H0A0	0	ubiquitination	down-regulates quantity by destabilization	0.33	NAT10 acetylates p53 at K120 and stabilizes p53 by counteracting Mdm2 action. In addition, NAT10 promotes Mdm2 degradation with its intrinsic E3 ligase activity.	SIGNOR-272405
Q49MG5	O14965	0	phosphorylation	up-regulates	0.326	Asap is a novel substrate of the oncogenic mitotic kinase aurora-a: phosphorylation on ser625 is essential to spindle formation and mitosis.	SIGNOR-158210
O43524	Q14164	0	phosphorylation	down-regulates	0.407	Ikbke phosphorylation and inhibition of foxo3a: a mechanism of ikbke oncogenic functionhere we report that ikbke regulates foxo3a through phosphorylation of foxo3a-ser644. The phosphorylation of foxo3a resulted in its degradation and nuclear-cytoplasmic translocation.	SIGNOR-202054
Q01094	P45983	0	phosphorylation	down-regulates activity	0.277	JNK1 phosphorylates E2F1 in vitro, and co-transfection of JNK1 reduces the DNA binding activity of E2F1	SIGNOR-279218
Q96BR1	Q14524	1	phosphorylation	up-regulates activity	0.275	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).\|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. \| Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275767
Q8TBB1	P56750	1	ubiquitination	down-regulates quantity by destabilization	0.294	We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.	SIGNOR-272900
Q01860	P28482	0	phosphorylation	down-regulates	0.38	We demonstrate that oct4a interacts with erk1/2 by using both in vitro gst pulldown and in vivo co-immunoprecipitation assays. Ms analysis identified phosphorylation of oct4a at ser-111. / serine 111 phosphorylation regulates oct4a protein subcellular distribution and degradation.	SIGNOR-192097
Q05925	O75398	0	transcriptional regulation	up-regulates quantity by expression	0.2	Deaf1 is the first transcription factor implicated in the regulation of En1, a critical determinant of eccrine fate, within keratinocytes.	SIGNOR-269062
Q96PN8	O15530	0	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
Q06609	P00519	0	phosphorylation	up-regulates activity	0.773	C-Abl phosphorylates Rad51 in vitro and in vivo. phosphorylation of Rad51 by c-Abl enhances complex formation between Rad51 and Rad52, which cooperates with Rad51 in recombination and repair. c-Abl phosphorylates Rad51 Tyr315	SIGNOR-251434
Q8IZP0	P27361	0	phosphorylation	up-regulates	0.454	We show that erk colocalizes with the wrc at lamellipodial leading edges and directly phosphorylates two wrc components: wave2 and abi1.	SIGNOR-172881
Q9NRC1	P28370	0	transcriptional regulation	down-regulates quantity by repression	0.2	Human SWI/SNF-associated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes.	SIGNOR-268991
P49760	P18031	1	phosphorylation	up-regulates activity	0.322	The clk family kinases, clk1 and clk2, phosphorylate and activate the tyrosine phosphatase, ptp-1b.\|Phosphorylation of PTP-1B at Ser(50) by CLK1 or CLK2 is responsible for its enzymatic activation.	SIGNOR-70603
P49841	Q16555	1	phosphorylation	down-regulates activity	0.724	Here, we showed that glycogen synthase kinase-3beta (gsk-3beta) phosphorylated crmp-2 at thr-514 and inactivated it	SIGNOR-133255
O14654	P08069	0	phosphorylation	up-regulates	0.657	Insulin-like growth factor i acting through its receptor was as effective as insulin in eliciting tyrosine phosphorylation of irs-4.	SIGNOR-56604
P53350	O95239	1	phosphorylation	down-regulates activity	0.467	Moreover, phosphorylation of KIF4 and condensin I by Aurora B and polo like kinase 1 (Plk1) is important for KIF4 and condensin I localization to the chromosome.\|These results suggest that Plk1 negatively regulates the loading of both KIF4 and condensin to the chromosome.	SIGNOR-280069
P45984	P19793	1	phosphorylation	down-regulates activity	0.246	Under stress conditions, hyperphosphorylated by activated jnk on ser-56, ser-70, thr-82 and ser-260. These findings indicate that inflammation-mediated cell signaling leads to rapid and profound reductions in nuclear rxralpha levels, via a multistep, jnk-dependent mechanism involving ser260, nuclear export, and proteasomal degradation.	SIGNOR-145301
P35222	Q04912	0	phosphorylation	up-regulates activity	0.327	Ron and beta-catenin associate and Ron kinase activity leads to tyrosine phosphorylation of beta-catenin.\|We also show that tyrosine residues 654 and 670 of beta-catenin are important in mediating Ron induced beta-catenin transcriptional activation and cell growth.	SIGNOR-279376
P05141	Q9NQU5	0	phosphorylation	up-regulates quantity	0.2	In the present study, it was demonstrated that ANT2 was phosphorylated by PAK6 at T107.\|Moreover, PAK6 overexpression upregulated the protein expression of ANT2, while PAK6 knockdown led to opposing effects.	SIGNOR-279473
P10415	P67775	0	dephosphorylation	up-regulates activity	0.47	The phosphorylation of Bcl-2 resulted in a reduction in anti-apoptotic function, implying that dephosphorylation promoted the anti-apoptotic activity of Bcl-2 protein in human tumor cell lines. Thus, the present findings suggest that ERK and PP2A are physiological regulators of Bcl-2 phosphorylation, and these enzymes exert an influence on the anti-apoptotic function of Bcl-2.phosphorylation of Bcl2 at Ser70 is proposed to be a dynamic process regulated by the sequential action of an agonist-activated Bcl2 kinase and PP2A.	SIGNOR-248624
Q15797	O14595	0	dephosphorylation	down-regulates	0.5	In human cells, rnai-mediated depletion of scp1 and scp2 increases the extent and duration of smad1 phosphorylation in response to bmp, the transcriptional action of smad1, and the strength of endogenous bmp gene responses. The present identification of the scp family as smad c-terminal phosphatases sheds light on the events that attenuate smad signaling and reveals unexpected links to the essential phosphatases that control rna polymerase ii in eukaryotes.	SIGNOR-148434
P12830	P49841	0	phosphorylation	up-regulates activity	0.558	Phosphorylation of the E-cadherin Cytoplasmic Domain by CKII and GSK-3β Increases the Binding to β-catenin. pre-phosphorylation by CKII at Ser-855 and/or Ser-853 of E-cadherin is required before GSK-3β can phosphorylate at Ser-849.	SIGNOR-251225
Q13315	Q96GD4	0	phosphorylation	up-regulates	0.431	Aurora-b mediated atm serine 1403 phosphorylation is required for mitotic atm activation and the spindle checkpoint	SIGNOR-177280
Q16625	Q96J02	0	ubiquitination	down-regulates quantity by destabilization	0.348	Two mechanisms regarding junction protein turnover were illustrated in this process, that is, the Itch-induced occludin ubiquitination and proteasome degradation, and the caveolae-dependent endocytosis of junction proteins (JAM-A, N-cadherin, and \u03b2 -catenin), both of which led to the instability of junction apparatus between adjacent SCs and a subsequent damaged BTB.	SIGNOR-278756
P35637	Q16637	1	relocalization	up-regulates activity	0.37	Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.\|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 \|Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells	SIGNOR-262107
O43166	Q05086	0	polyubiquitination	down-regulates quantity by destabilization	0.365	the purified E6AP enhanced the ubiquitination and degradation of E6TP1 in the presence of E6 in vitro. Additionally, the expression of a dominant-negative E6AP mutant (C833A) in cells inhibited the E6-induced degradation of E6TP1. These findings demonstrate that the E6-induced decrease in the levels of E6TP1 protein involves the E6AP-mediated ubiquitination followed by proteasome-dependent degradation.	SIGNOR-272608
P00519	Q13233	1	phosphorylation	up-regulates activity	0.258	Moreover, c-Abl activates MEKK-1 in vitro and in response to DNA damage.\|The results demonstrate that the nuclear c-Abl binds to MEKK-1 and that c-Abl phosphorylates MEKK-1 in vitro and in vivo.	SIGNOR-279672

P61586

O15085

0

guanine nucleotide exchange factor

up-regulates activity

0.903

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-260538

P05549

P54646

0

phosphorylation

up-regulates activity

0.307

Inhibition of AMPKalpha2 with either siRNA or compound C significantly suppressed the AngII- or nicotine enhanced AP-2alpha activity and the binding of AP-2alpha to DNA.|We report that nicotine, a major component of cigarette smoke, activates AMPK in VSMCs and that AMPKalpha2 phosphorylates AP-2alpha at serine 219 resulting in aberrant expression of MMP2 and consequent AAA formation.

SIGNOR-279648

O14965

P62136

0

dephosphorylation

down-regulates

0.436

Pp1 is shown to dephosphorylate active stk15 and abolish its activity in vitro.

SIGNOR-110411

Q15121

Q9UQM7

0

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

Q08050

O14757

0

phosphorylation

up-regulates activity

0.371

In addition, upon treatment with genotoxic agents, the checkpoint kinases Chk1 and Chk2 also phosphorylate and activate FOXM1.

SIGNOR-280224

P26651

P49137

0

phosphorylation

down-regulates activity

0.699

We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated.

SIGNOR-250153

Q9P1W9

P14618

1

phosphorylation

up-regulates quantity by stabilization

0.37

Here, we identified the protein-serine/threonine kinase PIM2, a known oncogene, as a novel binding partner of PKM2. The interaction between PIM2 and PKM2 was confirmed by multiple biochemical approaches in vitro and in cultured cells. Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. Compared with wild type, PKM2 with the phosphorylation-defective mutation displayed a reduced effect on glycolysis

SIGNOR-267472

Q96JA1

P21860

1

ubiquitination

down-regulates

0.434

We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation.

SIGNOR-139951

P04637

Q86UR1

1

transcriptional regulation

up-regulates quantity by expression

0.26

As a transcription factor, p53 induces several pro-apoptotic Bcl-2 members including Bax, Puma, Noxa and Bid, and represses the transcription of certain anti-apoptotic genes, including those encoding Bcl-2, Bcl-xL and survivin 3_and_5.

SIGNOR-209687

P21815

P15036

0

transcriptional regulation

up-regulates quantity by expression

0.2

Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin

SIGNOR-259873

Q92908

P49840

0

phosphorylation

down-regulates quantity by destabilization

0.265

Through bioinformatics and cell-based experiments, we identified the AKT-repressed signal as glycogen synthase kinase 3 (GSK3)-catalyzed phosphorylation of Ser(37) on the long form of the transcription factor GATA6. Phosphorylation of GATA6 on Ser(37) promoted its degradation, thereby preventing GATA6 from repressing transcripts that are induced by TNF and attenuated by insulin

SIGNOR-253156

Q14765

Q16539

0

phosphorylation

up-regulates

0.599

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

SIGNOR-154787

P02649

P02647

0

relocalization

up-regulates activity

0.738

ApoA-I stimulates apoE secretion in mature human adipocytes. The regulation of apoE secretion by apoA-I, is neither dependent upon an increase in gene transcription, nor upon increased release from the Golgi. It may therefore be assumed that, in macrophage models, apoE is stored mainly in the cytoplasm and/or on the cell surface, with apoA-I enabling secretion of this cytoplasmic pool

SIGNOR-252105

O00358

P07202

1

transcriptional regulation

up-regulates quantity by expression

0.382

TSH regulates TPO expression through the cAMP pathway and acts with thyroid-specific transcription factors such as TTF-1, TTF-2 and Pax-8

SIGNOR-267279

Q9UHP3

P43405

0

phosphorylation

down-regulates quantity

0.385

Altogether, these data strengthen our results that SYK specifically phosphorylates USP25 and suggest that Y740 is the most probable phosphorylated tyrosine on USP25.We also assessed whether the SYK mediated phosphorylation of USP25 alters its protease activity.|Preliminary data indicate that proteasome inhibition by MG132 treatment did not modify the SYK dependent decrease of USP25 levels in contrary to accumulation of USP25 protein by MG132 treatment in the absence of SYK overexpression.

SIGNOR-278458

P12931

P00519

1

phosphorylation

up-regulates activity

0.538

c-Src-induced c-Abl activation involves phosphorylation of Y245 and Y412, two residues required for c-Abl mitogenic function.

SIGNOR-246311

P29279

Q15561

0

transcriptional regulation

up-regulates quantity by expression

0.2

The multifunctional cytokine TGF-β has been identified as a potent inducer of CTGF expression, activating CTGF transcription through the canonical Smad signaling pathway. It is worth noting that TGF-β synergizes with Hippo–Yes-associated protein (YAP) signaling, a key regulator of tumorigenesis, to induce the expression of CTGF by the formation of a YAP-TEAD4-Smad3-p300 complex on the CTGF promoter

SIGNOR-277686

Q9P0J1

P24752

0

acetylation

down-regulates activity

0.34

We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1)

SIGNOR-267635

Q16539

Q9HBH9

1

phosphorylation

up-regulates

0.415

Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity

SIGNOR-48349

Q14012

Q9NXK8

0

ubiquitination

down-regulates quantity

0.475

Here, we show that a ubiquitin E3 ligase component, F-box protein Fbxl12, mediates CaMKI degradation via a proteasome-directed pathway leading to disruption of cyclin D1/cdk4 complex. Endogenous Fbxl12 and CaMKI interacted as demonstrated after Fbxl12 immuno-precipitation followed by immunoblot analysis with CaMKI antibodies assembly and resultantG1 arrest in lung epithelia. Fbxl12 targets CaMKI for ubiquitination.

SIGNOR-261193

P35222

P36888

0

phosphorylation

up-regulates activity

0.409

Endogenous beta-catenin co-immunoprecipitated with endogenous activated FLT3, and recombinant activated FLT3 directly phosphorylated recombinant beta-catenin. Finally, FLT3 inhibitor decreased tyrosine phosphorylation of beta-catenin in leukemia cells obtained from FLT3-ITD-positive AML patients. These data demonstrate that FLT3 activation induces beta-catenin tyrosine phosphorylation and nuclear localization, and thus suggest a mechanism for the association of FLT3 activation and beta-catenin oncogeneic signaling in AML.

SIGNOR-260124

Q14258

O95786

1

ubiquitination

up-regulates activity

0.803

Lys63 linked polyubiquitination of RIG-I at Lys 172 catalyzed by TRIM25 is an important step for RIG-I activation.

SIGNOR-278730

P43403

Q9UJU6

1

phosphorylation

up-regulates

0.64

We found an interaction between the tyrosine kinase zap-70 and hip-55, which was induced by tcr stimulation. Zap-70 phosphorylated hip-55 at tyr-334 and tyr-344, which were shown to be the tyrosine phosphorylation sites of hip-55 in stimulated t cells.Our results demonstrate for the first time that hip-55 is an important adaptor protein for the jnk kinase cascade in tcr signaling.

SIGNOR-118695

Q96E17

Q9UQ26

0

relocalization

up-regulates activity

0.558

N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle

SIGNOR-264378

P33076

P49841

0

phosphorylation

up-regulates

0.346

Here we report that CIITA represses collagen transcription through a phosphorylation-dependent interaction between its proline/serine/threonine domain and co-repressor molecules such as histone deacetylase (HDAC2) and Sin3B. Mutation of a serine (S373A) in CIITA, within a glycogen synthase kinase 3 (GSK3) consensus site, decreases repression of collagen transcription by blocking interaction with Sin3B

SIGNOR-158959

O60674

P16410

1

phosphorylation

up-regulates quantity by stabilization

0.445

Janus Kinase 2 (Jak2) was directly associated with a box 1-like motif in the cytoplasmic tail of CTLA-4 molecule. Jak2 phosphorylated Y-165 residue in the cytoplasmic region of CTLA-4. It has been reported that phosphorylation and dephosphorylation of tyrosine residue Y-165 in the cytoplasmic region of CTLA-4 play an important role in its negative signaling and cell surface expression. Some signaling molecules such as Src homology 2 protein tyrosine phosphatase 2 (SHP-2) and the p85 subunit of phosphatidylinositol 3 kinase (PI3 kinase) associate with phosphorylated tyrosine residue Y-165, through Src homology 2 (SH2) domains. On the other hand, the adapter complex proteins, AP-2 and AP-50 interact with the same tyrosine residue when unphosphorylated, resulting in clathrin-mediated endocytosis of CTLA-4 molecules.

SIGNOR-251346

O43734

Q14164

0

phosphorylation

up-regulates activity

0.416

IKKi was required for IL-17-induced phosphorylation of Act1 on Ser311, adjacent to a putative TRAF-binding motif. Substitution of the serine at position 311 with alanine impaired the IL-17-mediated Act1-TRAF2-TRAF5 interaction and gene expression. Thus, IKKi is a kinase newly identified as modulating IL-17 signaling through its effect on Act1 phosphorylation and consequent function.

SIGNOR-262883

P28482

P41162

1

phosphorylation

down-regulates activity

0.403

We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. Among the ERK2 substrates, we identified the E-twenty six (ETS) domain-containing protein ETV3. We determined that phosphorylation of this protein by ERK2 was functionally relevant, abrogating the DNA-binding activity of ETV3 at thousands of targets across the genome, thereby providing an additional mechanism for transcriptional regulation downstream of ERK2 activation.

SIGNOR-262758

Q5JQC9

Q9BYT3

0

phosphorylation

up-regulates quantity by stabilization

0.2

Differential phosphoproteomic analysis and in vitro kinase assay identified novel phosphorylation substrates of STK33, fibrous sheath components AKAP3 and AKAP4, whose expression levels decreased in testis after deletion of Stk33.

SIGNOR-272956

O14757

Q96AV8

1

phosphorylation

down-regulates activity

0.387

Chk1 inhibits the transcriptional repressor function of E2F7 and E2F8 to promote cell cycle progression and prevent apoptosis.|Here, we demonstrate that Chk1 phosphorylates both E2F7 and E2F8 in response to DNA damage.

SIGNOR-279692

P36507

O15530

0

phosphorylation

up-regulates

0.256

The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation.

SIGNOR-125176

P17252

Q86UX7

1

phosphorylation

up-regulates activity

0.2

PKC-induced phosphorylation events, as we have shown kindlin-3 to be a PKC phosphorylation target (Fig. 6C), are often followed by rapid activation of phosphatases (38).

SIGNOR-266415

P48729

P16220

1

phosphorylation

up-regulates

0.312

Ser108, ser111 and ser114, located in a region matching the consensus sequence for the casein kinase ii target, were required.These results strongly suggest that the casein kinase ii target region is involved in cell cycle-regulated phosphorylation of the creb protein and also in transcriptional enhancement.

SIGNOR-64258

P0C0L4

P48740

0

cleavage

up-regulates activity

0.606

The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots.

SIGNOR-263438

Q16816

P06737

1

phosphorylation

up-regulates activity

0.54

It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15

SIGNOR-267399

Q8NE35

O76050

0

ubiquitination

up-regulates activity

0.47

If Neurl1 interacts and modulates the activity of CPEB3 and increases the translation of GluA1 and GluA2 mRNAs, this effect would be blocked if we abolished the interaction between CPEB3 and Neurl1.|Neurl1 Interacts with and Ubiquitinates a Translational Regulator of GluA1 and GluA2 : the Cytoplasmic Polyadenylation Element Binding Protein 3.

SIGNOR-278588

Q14814

Q00535

0

phosphorylation

down-regulates activity

0.415

In this case, cdk5 phosphorylates MEF2D on Ser444 suppressing its transcriptional activity.

SIGNOR-279509

Q9UBF8

Q15208

0

phosphorylation

up-regulates activity

0.267

We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation.

SIGNOR-263033

P40337

P06493

0

phosphorylation

up-regulates activity

0.2

Mechanistically, CDK1 directly phosphorylates pVHL at Ser80, which primes the recognition of pVHL by PIN1.|PIN1 and CDK1 cooperatively modulate the protein turnover of pVHL, thereby conferring tumor growth, chemotherapeutic resistance and metastasis both in vitro and in vivo.

SIGNOR-280207

P23246

P49841

0

phosphorylation

down-regulates

0.345

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

SIGNOR-168392

Q00535

P04150

1

phosphorylation

down-regulates activity

0.481

Cdk5 phosphorylated gr at multiple serines, including ser203 and ser211 of its n-terminal domain, and suppressed the transcriptional activity of this receptor on glucocorticoid-responsive promoters by attenuating attraction of transcriptional cofactors to dna.| the effect of CDK5 on GR-induced transcriptional activity is specific to gene promoter, and possibly, to tissue

SIGNOR-154405

Q8NHV4

Q8TD19

0

phosphorylation

up-regulates activity

0.426

Nek9 phosphorylates NEDD1 on Ser377 driving its recruitment and thereby that of γ-tubulin to the centrosome in mitotic cells.

SIGNOR-263016

P31749

P53004

1

phosphorylation

up-regulates activity

0.296

Site-directed mutagenesis, mass spectrometry, and kinetic analyses identified S(230) in hBVR (225)RNRYLSF sequence as the Akt1 target.

SIGNOR-275517

Q13418

Q96A00

1

phosphorylation

up-regulates activity

0.549

Phosphopeptide mapping, phospho amino acid analysis and immunoblotting using phospho-specific antibodies indicated that ilk predominantly phosphorylated the site critical for potent inhibition, i.e. Thr(38) of cpi-17

SIGNOR-90828

P02775

P35372

1

chemical inhibition

down-regulates activity

0.385

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-258413

Q92973

P49790

1

relocalization

up-regulates activity

0.499

TNPO1 only mediates the nuclear import of a subset of proteins.|Among TNPO1 cargos, the most extensively characterized is the RNA binding protein heterogeneous nuclear ribonucleoprotein 1 (hnRNPA1) (27), which functions in several processes including mRNA biogenesis and promotion of transcription factor activity (28–30). NPC protein NUP153 is also a target for TNPO1-mediated nuclear import

SIGNOR-262100

P23443

Q9BPZ7

1

phosphorylation

down-regulates activity

0.565

Consistently, we detected in vivo Sin1 phosphorylation triggered by S6K1 and to a lesser extent, Akt1, but not other characterized AGC kinases (XREF_FIG and XREF_SUPPLEMENTARY).|Here we report that phosphorylation of Sin1 at Thr 86 and Thr 398 suppresses mTORC2 kinase activity by dissociating Sin1 from mTORC2.

SIGNOR-279568

Q15424

P38398

0

ubiquitination

up-regulates quantity by stabilization

0.2

These results suggest that the BRCA1 and BARD1 heterodimer ubiquitinates SAFB and increases SAFB protein levels.

SIGNOR-278624

O75122

P06493

0

phosphorylation

up-regulates activity

0.569

Overall, these results support the idea that phosphorylation of CLASP2 on S1234 by Cdk1, but not phosphorylation of the CLASP2 C terminal by Plk1, is required to maintain mitotic spindle bipolarity.|We propose that Cdk1 and Plk1 mediate a CLASP2 phospho-switch that is necessary to stabilize KT-MT attachments in human cells.

SIGNOR-278233

P06493

P00533

1

phosphorylation

down-regulates

0.426

Using a synthetic peptide corresponding to the sequence surrounding ser-1002, p34cdc2 was identified as a kinase capable of phosphorylating this serine residue. phosphorylation of the egf receptor by p34cdc2 was associated with a decrease in its tyrosine protein kinase activity.

SIGNOR-38313

Q13131

Q16576

1

phosphorylation

up-regulates activity

0.2

AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314| interaction between RBBP7 and HAT1 is required for acetyltransferase activity

SIGNOR-264784

P17676

Q8NHY2

0

ubiquitination

down-regulates quantity by destabilization

0.2

We show expression of c/EBPβ in microglia is regulated post-translationally by the ubiquitin ligase COP1 (also called RFWD2). In the absence of COP1, c/EBPβ accumulates rapidly and drives a potent pro-inflammatory and neurodegeneration-related gene program, evidenced by increased neurotoxicity in microglia-neuronal co-cultures.

SIGNOR-261924

P11309

P46531

1

phosphorylation

up-regulates activity

0.27

Interestingly, Pim1 phosphorylated Notch1 and Notch3, but not Notch2 ICD (Figure xref ), which was in line with the observed Pearson correlations ( xref ).|Our data indicate that endogenous Pim1 and Notch1 interact already in the cytoplasm, which supports the notion that Pim1 enhances nuclear localization and activity of Notch1.

SIGNOR-279643

P42771

O14920

0

phosphorylation

down-regulates

0.396

Ikkbeta specifically binds to p16 and phosphorylates ser8 of p16 phosphorylation at ser8 of p16 brings about a significant loss of its cyclin-dependent kinase (cdk) 4-inhibitory activity

SIGNOR-163801

Q9H6R0

Q9P275

0

deubiquitination

up-regulates quantity by stabilization

0.508

Loss of the deubiquitinase USP36 destabilizes the RNA helicase DHX33 and causes preimplantation lethality in mice.

SIGNOR-272289

P05771

Q05639

1

phosphorylation

up-regulates activity

0.2

PKCβI phosphorylates eEF1A at Ser53.our proteomics exploration of cPKC signaling in the nuclei of C2C12 cells demonstrated that the up-regulation of eEF1A intranuclear content, evoked by insulin, is associated with an increase in the phosphorylation of the Ser53 residue of the protein.

SIGNOR-263166

O60479

P17252

0

phosphorylation

down-regulates activity

0.307

Dlx3 is primarily phosphorylated by PKC alpha. By deletion and mutational analysis, we show that the serine residue S(138), located in the homeodomain of Dlx3 protein, was specifically phosphorylated by PKC. The phosphorylation of purified Dlx3 proteins by PKC partially inhibited formation of complexes between Dlx3 protein and DNA. These results suggest that Dlx3 protein can be directly phosphorylated by PKC and this affects the DNA binding activity of Dlx3.

SIGNOR-249096

P10721

P12931

0

phosphorylation

up-regulates activity

0.386

C-src phosphorylates tyr900 in the second part of the kinase domain of c-kit.

SIGNOR-103999

P60484

P53671

0

phosphorylation

down-regulates activity

0.274

LIMK2 inhibits PTEN phosphatase activity in vitro and in cells.|PTEN phosphorylation and downregulation by LIMK2 promotes tumorigenesis and EMT in vivo.

SIGNOR-278363

P04626

P62993

1

relocalization

up-regulates

0.85

All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor

SIGNOR-121968

Q12906

P31749

0

phosphorylation

up-regulates activity

0.367

Upon T cell activation, NF90 translocates from the nucleus into the cytoplasm, where it binds to the AU-rich element-containing 3' untranslated regions of IL-2 mRNA and stabilizes it.|Our previous work showed that CD28 costimulation of T cells activated AKT to phosphorylate NF90 at Ser647 and caused NF90 to undergo nuclear export and stabilize IL-2 mRNA.

SIGNOR-252512

P20336

Q92696

0

lipidation

up-regulates activity

0.569

Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional

SIGNOR-265574

Q96FA3

P53355

0

phosphorylation

down-regulates quantity by destabilization

0.2

DAPK1, which directly binds to and phosphorylates Pellino1 at Ser39, leading to Pellino1 poly-ubiquitination and turnover.

SIGNOR-277531

Q05513

Q9NPB6

1

phosphorylation

up-regulates quantity by stabilization

0.841

APKC associates and phosphorylates Par6 on S345. aPKC expression stabilizes Par6 protein levels. We show that the aPKC, PKCι, interacts with TGF-β receptors through Par6 and that these proteins localize to the leading edge of migrating cells. Furthermore, Par6 phosphorylation on serine 345 by TGF-β receptors is enhanced in the presence of aPKC. aPKC kinase activity, as well as an association with Par6, were found to be important for Par6 phosphorylation.

SIGNOR-276433

O95271

Q92530

1

ADP-ribosylation

down-regulates quantity by destabilization

0.501

We identify the ADP-ribosyltransferase tankyrase (TNKS) and the 19S assembly chaperones dp27 and dS5b as direct binding partners of the proteasome regulator PI31. TNKS-mediated ADP-ribosylation of PI31 drastically reduces its affinity for 20S proteasome alpha subunits to relieve 20S repression by PI31.

SIGNOR-263387

Q96PU5

P37088

1

ubiquitination

down-regulates quantity by destabilization

0.775

The serum and glucocorticoid inducible kinase 1 (SGK1) is induced in the aldosterone sensitive distal nephron (ASDN) where it may stimulate Na reabsorption, partly by inhibiting ubiquitin ligase Nedd4-2-mediated retrieval of epithelial Na+ channel ENaC from the luminal membrane.

SIGNOR-251948

P63000

Q8IZD9

0

guanine nucleotide exchange factor

up-regulates activity

0.656

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-260548

P10153

P11678

0

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

P17676

Q9UQM7

0

phosphorylation

up-regulates activity

0.326

These studies implicate Ser276 of CIEBPP as the major in vim phosphorylation site for CaMKII. | Phosphorylation of serine at position 276 within the leucine zipper of C/EBP beta appeared to confer calcium-regulated transcriptional stimulation of a promoter that contained binding sites for C/EBP beta.

SIGNOR-250617

P09211

P05771

0

phosphorylation

up-regulates activity

0.2

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

SIGNOR-276023

P48730

P49810

1

phosphorylation

up-regulates activity

0.364

In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites.

SIGNOR-250802

P23528

Q8WYL5

0

dephosphorylation

up-regulates activity

0.786

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-248762

Q8WXE1

P24941

0

phosphorylation

up-regulates

0.579

Atrip is a cdk2 substrate, and cdk2-dependent phosphorylation of s224 regulates the ability of atr-atrip to promote cell cycle arrest in response to dna damage./ One possibility is s224 phosphorylation creates a binding site for another protein involved in the g2-m checkpoint response

SIGNOR-156928

Q00987

Q9H0A0

0

ubiquitination

down-regulates quantity by destabilization

0.33

NAT10 acetylates p53 at K120 and stabilizes p53 by counteracting Mdm2 action. In addition, NAT10 promotes Mdm2 degradation with its intrinsic E3 ligase activity.

SIGNOR-272405

Q49MG5

O14965

0

phosphorylation

up-regulates

0.326

Asap is a novel substrate of the oncogenic mitotic kinase aurora-a: phosphorylation on ser625 is essential to spindle formation and mitosis.

SIGNOR-158210

O43524

Q14164

0

phosphorylation

down-regulates

0.407

Ikbke phosphorylation and inhibition of foxo3a: a mechanism of ikbke oncogenic functionhere we report that ikbke regulates foxo3a through phosphorylation of foxo3a-ser644. The phosphorylation of foxo3a resulted in its degradation and nuclear-cytoplasmic translocation.

SIGNOR-202054

Q01094

P45983

0

phosphorylation

down-regulates activity

0.277

JNK1 phosphorylates E2F1 in vitro, and co-transfection of JNK1 reduces the DNA binding activity of E2F1

SIGNOR-279218

Q96BR1

Q14524

1

phosphorylation

up-regulates activity

0.275

Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5

SIGNOR-275767

Q8TBB1

P56750

1

ubiquitination

down-regulates quantity by destabilization

0.294

We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.

SIGNOR-272900

Q01860

P28482

0

phosphorylation

down-regulates

0.38

We demonstrate that oct4a interacts with erk1/2 by using both in vitro gst pulldown and in vivo co-immunoprecipitation assays. Ms analysis identified phosphorylation of oct4a at ser-111. / serine 111 phosphorylation regulates oct4a protein subcellular distribution and degradation.

SIGNOR-192097

Q05925

O75398

0

transcriptional regulation

up-regulates quantity by expression

0.2

Deaf1 is the first transcription factor implicated in the regulation of En1, a critical determinant of eccrine fate, within keratinocytes.

SIGNOR-269062

Q96PN8

O15530

0

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

Q06609

P00519

0

phosphorylation

up-regulates activity

0.773

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

SIGNOR-251434

Q8IZP0

P27361

0

phosphorylation

up-regulates

0.454

We show that erk colocalizes with the wrc at lamellipodial leading edges and directly phosphorylates two wrc components: wave2 and abi1.

SIGNOR-172881

Q9NRC1

P28370

0

transcriptional regulation

down-regulates quantity by repression

0.2

Human SWI/SNF-associated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes.

SIGNOR-268991

P49760

P18031

1

phosphorylation

up-regulates activity

0.322

The clk family kinases, clk1 and clk2, phosphorylate and activate the tyrosine phosphatase, ptp-1b.|Phosphorylation of PTP-1B at Ser(50) by CLK1 or CLK2 is responsible for its enzymatic activation.

SIGNOR-70603

P49841

Q16555

1

phosphorylation

down-regulates activity

0.724

Here, we showed that glycogen synthase kinase-3beta (gsk-3beta) phosphorylated crmp-2 at thr-514 and inactivated it

SIGNOR-133255

O14654

P08069

0

phosphorylation

up-regulates

0.657

Insulin-like growth factor i acting through its receptor was as effective as insulin in eliciting tyrosine phosphorylation of irs-4.

SIGNOR-56604

P53350

O95239

1

phosphorylation

down-regulates activity

0.467

Moreover, phosphorylation of KIF4 and condensin I by Aurora B and polo like kinase 1 (Plk1) is important for KIF4 and condensin I localization to the chromosome.|These results suggest that Plk1 negatively regulates the loading of both KIF4 and condensin to the chromosome.

SIGNOR-280069

P45984

P19793

1

phosphorylation

down-regulates activity

0.246

Under stress conditions, hyperphosphorylated by activated jnk on ser-56, ser-70, thr-82 and ser-260. These findings indicate that inflammation-mediated cell signaling leads to rapid and profound reductions in nuclear rxralpha levels, via a multistep, jnk-dependent mechanism involving ser260, nuclear export, and proteasomal degradation.

SIGNOR-145301

P35222

Q04912

0

phosphorylation

up-regulates activity

0.327

Ron and beta-catenin associate and Ron kinase activity leads to tyrosine phosphorylation of beta-catenin.|We also show that tyrosine residues 654 and 670 of beta-catenin are important in mediating Ron induced beta-catenin transcriptional activation and cell growth.

SIGNOR-279376

P05141

Q9NQU5

0

phosphorylation

up-regulates quantity

0.2

In the present study, it was demonstrated that ANT2 was phosphorylated by PAK6 at T107.|Moreover, PAK6 overexpression upregulated the protein expression of ANT2, while PAK6 knockdown led to opposing effects.

SIGNOR-279473

P10415

P67775

0

dephosphorylation

up-regulates activity

0.47

The phosphorylation of Bcl-2 resulted in a reduction in anti-apoptotic function, implying that dephosphorylation promoted the anti-apoptotic activity of Bcl-2 protein in human tumor cell lines. Thus, the present findings suggest that ERK and PP2A are physiological regulators of Bcl-2 phosphorylation, and these enzymes exert an influence on the anti-apoptotic function of Bcl-2.phosphorylation of Bcl2 at Ser70 is proposed to be a dynamic process regulated by the sequential action of an agonist-activated Bcl2 kinase and PP2A.

SIGNOR-248624

Q15797

O14595

0

dephosphorylation

down-regulates

0.5

In human cells, rnai-mediated depletion of scp1 and scp2 increases the extent and duration of smad1 phosphorylation in response to bmp, the transcriptional action of smad1, and the strength of endogenous bmp gene responses. The present identification of the scp family as smad c-terminal phosphatases sheds light on the events that attenuate smad signaling and reveals unexpected links to the essential phosphatases that control rna polymerase ii in eukaryotes.

SIGNOR-148434

P12830

P49841

0

phosphorylation

up-regulates activity

0.558

Phosphorylation of the E-cadherin Cytoplasmic Domain by CKII and GSK-3β Increases the Binding to β-catenin. pre-phosphorylation by CKII at Ser-855 and/or Ser-853 of E-cadherin is required before GSK-3β can phosphorylate at Ser-849.

SIGNOR-251225

Q13315

Q96GD4

0

phosphorylation

up-regulates

0.431

Aurora-b mediated atm serine 1403 phosphorylation is required for mitotic atm activation and the spindle checkpoint

SIGNOR-177280

Q16625

Q96J02

0

ubiquitination

down-regulates quantity by destabilization

0.348

Two mechanisms regarding junction protein turnover were illustrated in this process, that is, the Itch-induced occludin ubiquitination and proteasome degradation, and the caveolae-dependent endocytosis of junction proteins (JAM-A, N-cadherin, and \u03b2 -catenin), both of which led to the instability of junction apparatus between adjacent SCs and a subsequent damaged BTB.

SIGNOR-278756

P35637

Q16637

1

relocalization

up-regulates activity

0.37

Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 |Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells

SIGNOR-262107

O43166

Q05086

0

polyubiquitination

down-regulates quantity by destabilization

0.365

the purified E6AP enhanced the ubiquitination and degradation of E6TP1 in the presence of E6 in vitro. Additionally, the expression of a dominant-negative E6AP mutant (C833A) in cells inhibited the E6-induced degradation of E6TP1. These findings demonstrate that the E6-induced decrease in the levels of E6TP1 protein involves the E6AP-mediated ubiquitination followed by proteasome-dependent degradation.

SIGNOR-272608

P00519

Q13233

1

phosphorylation

up-regulates activity

0.258

Moreover, c-Abl activates MEKK-1 in vitro and in response to DNA damage.|The results demonstrate that the nuclear c-Abl binds to MEKK-1 and that c-Abl phosphorylates MEKK-1 in vitro and in vivo.

SIGNOR-279672