GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
Q16539	Q99956	0	dephosphorylation	down-regulates	0.701	These properties define the ability of this enzyme to dephosphorylate and inactivate erk1/2 and p38a, but not jnk (c-jun n-terminal kinase) in vivo.	SIGNOR-87150
Q05655	Q9UQL6	1	phosphorylation	down-regulates activity	0.352	In this report, we show that VEGF stimulates PKD-dependent phosphorylation of HDAC5 at Ser259/498residues in ECs, which leads to HDAC5 nuclear exclusion and myocyte enhancer factor-2 (MEF2) transcriptional activation.	SIGNOR-260875
Q9UNE7	O00257	1	ubiquitination	down-regulates quantity by destabilization	0.2	The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα.	SIGNOR-277513
Q15022	P19784	0	phosphorylation	up-regulates activity	0.2	CK2 is the kinase for the phosphorylation of S583 of SUZ12.	SIGNOR-277797
P49916	P24941	0	phosphorylation	down-regulates	0.418	Dna ligase iii_ is specifically phosphorylated in replicating cells by the cell cycle kinase cdk2. However, in response to oxidative dna damage, dna ligase iii_ is dephosphorylated in a pathway that is dependent upon the dna damage-activated, phosphatidylinositol 3-phosphate (pi3)1-related kinase atm.	SIGNOR-150121
Q9H8V3	P41743	0	phosphorylation	up-regulates	0.474	Our data support a model in which pkc?-Mediated phosphorylation regulates ect2 binding to the oncogenic pkc?-Par6 complex thereby activating rac1 activity and driving transformed growth and invasion.	SIGNOR-170790
Q9ULB1	Q9NR48	0	transcriptional regulation	down-regulates quantity by repression	0.259	Our results reveal that a novel process of activity-dependent transcriptional repression exists in neurons and that Ash1L mediates the long-term repression of nrxn1α, thus implicating an important role for epigenetic modification in brain functioning.	SIGNOR-269056
P29474	Q05655	0	phosphorylation	down-regulates activity	0.568	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251631
P61587	Q13464	0	phosphorylation	up-regulates	0.707	We show that rock phosphorylates endogenous rhoe at serine 11 upon cell stimulation with platelet-derived growth factor. Phosphorylation has no effect on rhoe binding to rock i, but instead increases rhoe protein stability.	SIGNOR-134703
P19419	Q9UL54	0	phosphorylation	up-regulates activity	0.31	Transfection studies demonstrated that TAO2 stimulates phosphorylation of the TCF Elk1 on the major activating site, Ser383, and that TAO2 stimulates transactivation of Elk1 and the related TCF, Sap1.	SIGNOR-246638
Q8IZP0	P06493	0	phosphorylation	down-regulates activity	0.419	We identified serine 216 of Abi1 as a target of CDK1/cyclin B kinase that is phosphorylated in cells at the onset of mitosis.\|Bcr-Abl-induced actin polymerization requires the Abi1 pathway, as the blockade of the signal transduction from Bcr-Abl to Abi1 abolishes the F-actin assembly\|serine phosphorylation of Abi1 by CDK1/cyclin B serves as a cell cycle-dependent regulatory mechanism that inhibits actin assembly	SIGNOR-264421
O15399	P46934	0	ubiquitination	down-regulates activity	0.328	Nedd4 coexpression with GluN2D enhances GluN2D ubiquitination and reduces GluN1/GluN2D NMDA receptor responses.\|This suggests that Nedd4 association reduces GluN2D function, mostly likely by promoting GluN2D ubiquitination and internalization.	SIGNOR-278636
P09651	Q92973	0	relocalization	up-regulates activity	0.572	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-262099
O00139	P53350	0	phosphorylation	up-regulates activity	0.684	Taken together, KIF2A is phosphorylated at T554 by PLK1 in the subdistal appendages of the mother centriole, which enhances MT depolymerization to disassemble primary cilia in a growth-signal-dependent manner.\|Thus, PLK1 and APC/C mediated dual regulation connect the MT depolymerizing activity of KIF2A to a physiological primary cilia disassembly during the proliferative phase.	SIGNOR-278380
Q8TDX7	Q9HC35	1	phosphorylation	up-regulates activity	0.274	The mitotic kinases NEK6 and NEK7 phosphorylated the EML4 N-terminal domain at Ser144 and Ser146 in vitro, and depletion of these kinases in cells led to increased EML4 binding to microtubules in mitosis. An S144A-S146A double mutant not only bound inappropriately to mitotic microtubules but also increased their stability and interfered with chromosome congression. In addition, constitutive activation of NEK6 or NEK7 reduced the association of EML4 with interphase microtubules. Together, these data support a model in which NEK6- and NEK7-dependent phosphorylation promotes the dissociation of EML4 from microtubules in mitosis in a manner that is required for efficient chromosome congression.	SIGNOR-273884
O75144	P05771	0	phosphorylation	up-regulates activity	0.2	PKCα and PKCβ are required for phosphorylation of ICOSL and ICOSL-mediated cytokine induction	SIGNOR-273797
Q02548	P27361	0	phosphorylation	down-regulates activity	0.247	In this study, we demonstrated that PAX5 was phosphorylated by ERK1/2 in vitro and in vivo at serines 189 and 283. This phosphorylation attenuated the transcriptional repression of BLIMP1 by PAX5.	SIGNOR-269086
Q96EP0	Q14790	0	cleavage	down-regulates activity	0.315	We show that LUBAC interacted with caspase-1 via HOIP and modified its CARD domain with linear polyubiquitin and that depletion of HOIP or Sharpin resulted in heightened caspase-1 activation and cell death in response to inflammasome activation, unlike what is observed in macrophages. Reciprocally, caspase-1, as well as caspase-8, regulated LUBAC activity by proteolytically processing HOIP at Asp-348 and Asp-387 during the execution of cell death.	SIGNOR-272194
Q06124	Q9UQC2	1	dephosphorylation	down-regulates	0.742	Expression of the gab2 tyr-614-->phe (y614f) mutant, defective in shp-2 association, prevents erk (extracellular-signal-regulated kinase) activation and expression of a luciferase reporter plasmid driven by the c-fos sre (serum response element), indicating that interaction of shp-2 with gab2 is required for erk activation in response to il-2.	SIGNOR-124958
O14920	Q13148	1	phosphorylation	down-regulates quantity by destabilization	0.2	IκB kinase phosphorylates cytoplasmic TDP-43 and promotes its proteasome degradation. Furthermore, we identified IKKβ-induced phosphorylation sites of TDP-43 and found that phosphorylation at Thr8 and Ser92 is important for the reduction of TDP-43 by IKK.	SIGNOR-277860
Q13627	Q01130	1	phosphorylation	down-regulates activity	0.408	Dyrk1A inhibits SC35\u2032s activity to promote tau exon 10 inclusion.\|Dyrk1A interacts with and phosphorylates SC35 and inhibits its activity to promote tau exon 10 inclusion.	SIGNOR-278307
P20336	Q9UJD0	0	relocalization	up-regulates activity	0.282	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-264379
P49023	Q14289	0	phosphorylation	down-regulates quantity by destabilization	0.94	P130Cas and paxillin can be phosphorylated by Fak or Pyk2, and bind directly to these kinases.	SIGNOR-279272
P12931	P43403	1	phosphorylation	up-regulates activity	0.479	In the cluster, Zap70 will be rapidly phosphorylated by active Src and slowly phosphorylated by autoinhibited, inactive Src.\|We provide evidence that clusters harbor a positive feedback loop among Zap70, LAT, and Src-family kinases that binds phosphorylated LAT and further activates Zap70.	SIGNOR-279126
Q8IX03	P51812	0	phosphorylation	up-regulates	0.2	Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2.	SIGNOR-203302
P38936	Q13309	0	ubiquitination	down-regulates	0.772	Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase.	SIGNOR-138490
Q5TEC6	Q92831	0	acetylation	down-regulates activity	0.2	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269624
Q9UNS1	P04150	0	transcriptional regulation	up-regulates quantity by expression	0.252	GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription	SIGNOR-268052
Q00535	Q14194	1	phosphorylation	up-regulates	0.622	These findings suggest that sema3a-induced spine development is regulated by phosphorylation of crmp1 by cdk5. Introduction of crmp1-wt, but not crmp1-t509a/s522a, a crmp1 mutant that cannot be phosphorylated by cdk5, rescued the defect in sema3a responsiveness.	SIGNOR-159314
O43633	Q9UN37	0	cleavage	up-regulates activity	0.911	Here, we show, using high-speed atomic force microscopy and electron microscopy, that the AAA-type adenosine triphosphatase VPS4 constricts and cleaves ESCRT-III CHMP2A-CHMP3 helical filaments in vitro. Our results demonstrate that VPS4 actively constricts ESCRT-III filaments and cleaves them before their complete disassembly. We propose that the formation of ESCRT-III dome-like end caps by VPS4 within a membrane neck structure constricts the membrane to set the stage for membrane fission.	SIGNOR-260846
Q9UI47	P35222	1	relocalization	up-regulates quantity	0.753	Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14	SIGNOR-265493
Q16539	Q92993	1	phosphorylation	up-regulates activity	0.321	We found that phosphorylation of Tip60-T158 was increased by p38\u03b1 isolated from Dox- or \u03b3-radiation-treated cells over that from untreated cells (Figure xref ), indicating that DNA damage induces the protein kinase activity of p38\u03b1 towards Tip60-T158.	SIGNOR-278958
Q13976	Q01970	1	phosphorylation	down-regulates activity	0.539	PKG can directly phosphorylate PLC-beta2 and PLC-beta3 in vitro with purified proteins and in vivo with metabolic labeling. Phosphorylation of PLC-beta leads to the inhibition of G-protein-activated PLC-beta3 activity by 50-70% in COS-7 cell transfection assays. By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)). Mutation at these two sites (S26A and S1105A) of PLC-beta3 completely blocked the phosphorylation of PLC-beta3 protein catalyzed by PKG.	SIGNOR-249077
P47712	Q16539	0	phosphorylation	up-regulates activity	0.668	These results provide the first direct evidence that p38 kinase is responsible for cpla2 phosphorylation in sfllrn-stimulated platelets and is involved in the early phosphorylation of cpla2 in thrombin-stimulated platelets	SIGNOR-44673
P04637	P27361	0	phosphorylation	up-regulates	0.704	Mutant p53 is constitutively phosphorylated at serine 15 in uv-induced mouse skin tumors: involvement of erk1/2 map kinase.	SIGNOR-100270
O96017	Q08050	1	phosphorylation	up-regulates	0.721	Chk2 mediates stabilization of the foxm1 transcription factor to stimulate expression of dna repair genesthis phosphorylation of foxm1 on serine residue 361 caused increased stability of the foxm1 protein	SIGNOR-150746
Q9Y2Z0	P53350	0	phosphorylation	up-regulates activity	0.437	Plk1 phosphorylates Sgt1 at the kinetochores to promote timely kinetochore-microtubule attachment\|Plk1 is required for the kinetochore localization of Sgt1 and phosphorylates serine 331 of Sgt1 at the kinetochores. This phosphorylation event enhances the association of the Hsp90-Sgt1 chaperone	SIGNOR-265222
P41208	O14965	0	phosphorylation	up-regulates	0.516	Our studies show that aurora a phosphorylates centrin at serine 170 in vitro and that the serine 170 phosphorylation affects the stability of centrin by regulating its interaction with apc/c. finally we demonstrated that phosphorylation of centrin serine 170 is an absolute requirement for aurora a-mediated centriole amplification.	SIGNOR-174686
P63167	P61586	1	gtpase-activating protein	down-regulates activity	0.273	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-260501
O43175	O60260	0	ubiquitination	down-regulates quantity by destabilization	0.2	Parkin binds to PHGDH and degrades it through ubiquitination to inhibit serine synthesis, which contributes greatly to the tumor-suppressive function of Parkin.	SIGNOR-269075
Q86UZ6	P35558	1	transcriptional regulation	up-regulates quantity by expression	0.2	We identified LIF/ZBTB46 signalling as a key promoter of metabolic reprogramming and NE differentiation of PCa cells through interactions with PCK1. We showed that ZBTB46 directly upregulates the expression of PCK1 and NE marker gene through activation of LIF signalling.	SIGNOR-277987
P41594	Q05513	0	phosphorylation	up-regulates activity	0.37	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-249284
P49841	Q9GZV5	1	phosphorylation	down-regulates quantity by destabilization	0.2	GSK3 destabilizes TAZ. TAZS58A/S62A but not the TAZ S66A mutant diminished phos- phorylation by GSK3 , suggesting that Ser-58 and Ser-62 are important for GSK3 phosphorylation, whereas the Ser-66 is not (Fig. 4D).	SIGNOR-277646
Q9UBE8	Q8N122	1	phosphorylation	down-regulates activity	0.327	NLK inhibits mTORC1 lysosomal localization and thereby suppresses mTORC1 activation. Mechanistically, NLK phosphorylates Raptor on S863 to disrupt its interaction with the Rag GTPase, which is important for mTORC1 lysosomal recruitment.	SIGNOR-273908
P35241	Q5S007	0	phosphorylation	up-regulates activity	0.364	LRRK2 also phosphorylated ezrin and radixin, which are related to moesin, at the residue equivalent to Thr558, as well as a peptide (LRRKtide: RLGRDKYKTLRQIRQ) encompassing Thr558.	SIGNOR-279203
Q9UM73	Q14469	1	phosphorylation	up-regulates activity	0.266	NPM-ALK also directly phosphorylates HES1 protein.	SIGNOR-280181
P78527	P22415	1	phosphorylation	up-regulates	0.293	Feeding induces the recruitment of dna-pk to usf-1 and its phosphorylation, which then allows recruitment of p/caf, resulting in usf-1 acetylation and fas promoter activation.	SIGNOR-184849
P15918	P42345	1	relocalization	up-regulates	0.256	Rag gtpases, together with a multi-protein complex called ragulator, mediate amino acid-mediated mtor recruitment to the lysosome surface where mtor becomes activated.	SIGNOR-198242
P04150	Q16539	0	phosphorylation	up-regulates	0.511	We found serine 211 of the human gr to be a substrate for p38 mapk both in vitro and intracellularly. Mutation of this site to alanine greatly diminished gr-driven gene transcription and apoptosis.	SIGNOR-135198
P31749	O60858	0	polyubiquitination	down-regulates quantity by destabilization	0.353	Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT. We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro.	SIGNOR-271852
P68400	Q9UHH9	1	phosphorylation	down-regulates quantity by destabilization	0.255	CK2 physiologically phosphorylates IP6K2 at amino acid residues S347 and S356 contained within a PEST sequence, a consensus site for ubiquitination. HCT116 cells depleted of IP6K2 are resistant to cell death elicited by CK2 inhibitors. CK2 phosphorylation at the degradation motif of IP6K2 enhances its ubiquitination and subsequent degradation.	SIGNOR-273625
P29803	Q16654	0	phosphorylation	down-regulates	0.547	Pyruvate dehydrogenase (pdh) activity (pdha) controls the entry of carbohydrate into the tricarboxylic cycle and is regulated by pdh kinase (pdk), which phosphorylates and inactivates the enzyme, and pdh phosphatase, which dephosphorylates the enzyme to the active form	SIGNOR-121936
O95271	Q9NTX7	0	ubiquitination	down-regulates quantity	0.723	We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation.	SIGNOR-260004
P06493	P04626	0	phosphorylation	down-regulates	0.274	Phosphorylation on tyrosine-15 of p34(cdc2) by erbb2 inhibits p34(cdc2) activation and is involved in resistance to taxol-induced apoptosis	SIGNOR-88671
Q13535	O15360	1	phosphorylation	up-regulates	0.598	The s1449a mutant failed to completely correct a variety of fa-associated phenotypes. The dna damage response is coordinated by phosphorylation events initiated by apical kinases atm (ataxia telangectasia mutated) and atr (atm and rad3-related), and atr is essential for proper fa pathway function. Serine 1449 is in a consensus atm/atr site	SIGNOR-182953
O14965	O95983	1	phosphorylation	up-regulates	0.286	These results suggest that the biochemical changes of mbd3 may be intimately related to the targeting of mbd3 to centrosomes. aurora-a phosphorylates mbd3	SIGNOR-93693
Q13017	P12931	0	phosphorylation	up-regulates activity	0.607	Phosphotyrosine (p-Tyr)-dependent and -independent mechanisms of p190 RhoGAP-p120 RasGAP interaction: Tyr 1105 of p190, a substrate for c-Src, is the sole p-Tyr mediator of complex formation. 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, indicating that Y1105 is a selective and preferential target of c-Src both in vitro and in vivo.	SIGNOR-276170
O43683	Q02224	1	relocalization	up-regulates activity	0.831	Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity	SIGNOR-252016
P10588	P22888	1	transcriptional regulation	down-regulates quantity by repression	0.302	Functional analysis showed that EAR2 and EAR3/COUP-TFI repressed the hLHR promoter activity, whereas TR4 activated hLHR gene transcription.	SIGNOR-266216
P17612	P48058	1	phosphorylation	up-regulates	0.429	We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus.	SIGNOR-97550
P01106	Q9NVW2	0	ubiquitination	down-regulates quantity by destabilization	0.37	This suggests that RLIM negatively regulates the transcriptional activity of c-Myc.\|We further showed that RLIM can promote polyubiquitination of c-Myc in cells.	SIGNOR-278551
P98066	P05412	0	transcriptional regulation	up-regulates quantity by expression	0.308	Tumor necrosis factor (TNF)-stimulated gene 6 (TSG-6) encodes a protein expressed during inflammation. We have previously shown that transcription factors of the NF-IL6 and AP-1 families cooperatively modulate activation of the TSG-6 gene by TNF or interleukin 1 (IL-1) through a promoter region that contains an NF-IL6 site (-106 to -114) and an AP-1 element	SIGNOR-254052
P54829	Q7L9L4	1	dephosphorylation	up-regulates activity	0.2	PTPN5 dephosphorylates\nMob1a at Y26 residue.	SIGNOR-277058
Q13490	P06730	1	ubiquitination	down-regulates quantity by destabilization	0.401	We found that endogenous eIF4E was ubiquitinated by cIAP1, and ubiquitinated eIF4E accumulated upon MG132 treatment.	SIGNOR-278741
Q8IUE6	Q14493	0	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265406
P09769	Q9Y6K9	1	phosphorylation	down-regulates activity	0.327	Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.	SIGNOR-276368
Q04206	P12644	1	transcriptional regulation	down-regulates quantity by repression	0.2	Co-transfection with pCMV4-RelA alone or in combination with pCMV4p50 repressed pSLA4.1 EX-Lux activity by approximately 75 percent in both H441 and A549 cells	SIGNOR-266087
P12931	P18206	1	phosphorylation	down-regulates activity	0.76	The phosphorylation of vinculin on tyrosine residues 100 and 1065, mediated by SRC kinases, affects cell spreadingWhen phosphorylated, the vinculin tail exhibited significantly less binding to the vinculin head domain than the unphosphorylated tail.	SIGNOR-247424
P31749	Q92945	1	phosphorylation	down-regulates activity	0.703	Beta-catenin transcript can be stabilized by either wnt or pi3k-akt signaling activation. Akt phosphorylates ksrp at a unique serine residue akt phosphorylates the mrna decay-promoting factor ksrp at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents ksrp interaction with the exoribonucleolytic complex exosome.	SIGNOR-252497
Q92544	Q16665	0	transcriptional regulation	down-regulates quantity by repression	0.2	Here, we investigated the impact of hypoxia on TM9SF4 expression in leukemic cells and identified TM9SF4 as a direct target of HIF-1α, downregulated in these cells by hypoxia. Then, we found that the hypoxia-mediated downregulation of TM9SF4 expression is associated with a decrease of cell adhesion of leukemic cells to fibronectin, thus demonstrating that human TM9SF4 is a new molecule involved in leukemic cell adhesion.	SIGNOR-266705
O94813	Q8NFU7	0	transcriptional regulation	up-regulates quantity by expression	0.2	Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9.	SIGNOR-259093
P13796	P17612	0	phosphorylation	up-regulates	0.327	Phosphorylation on ser5 increases the f-actin-binding activity of l-plastin and promotes its targeting to sites of actin assembly in cells. L-plastin phosphorylation require protein kinase a.	SIGNOR-146287
Q9Y6Q6	O75175	0	transcriptional regulation	down-regulates quantity by repression	0.2	Our results reveal that CNOT3 is a critical regulator of bone mass acting on bone resorption through posttranscriptional down-regulation of RANK mRNA stability, at least in part, even in aging-induced osteoporosis.	SIGNOR-261572
Q92793	P17252	0	phosphorylation	down-regulates	0.261	The action of metformin was shown to be mediated through activation of apkc?/?, Which phosphorylates cbp at ser436, and disrupts the transcriptionally active creb-cbp-crtc2 complex,	SIGNOR-166368
P07947	Q9GZV5	1	phosphorylation	up-regulates activity	0.317	Yes directly phosphorylates YAP and TAZ, resulting in their increased nuclear localization and transcriptional activity.Analysis by mass spectrometry identified Tyr391 and Tyr407 as the two phosphorylation sites of YAP, whereas Tyr305 was the sole phosphorylated residue of TAZ (Fig. 5F and fig. S4, A to C).	SIGNOR-277654
P16298	Q92934	1	dephosphorylation	up-regulates activity	0.364	Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD\|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis.	SIGNOR-248384
Q9BQI3	P05198	1	phosphorylation	down-regulates activity	0.89	HRI is an intracellular heme sensor that coordinates heme and globin synthesis in erythropoiesis by inhibiting protein synthesis of globins and heme biosynthetic enzymes during heme deficiency. HRI is a heme-regulated kinase that phosphorylates the α-subunit of eIF2 in heme deficiency, impairing another round of translational initiation and thereby inhibiting translation.	SIGNOR-251817
P38435	P08709	1	carboxylation	up-regulates activity	0.688	Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation.	SIGNOR-265919
P38398	P11802	0	phosphorylation	down-regulates	0.665	In particular, we have identified ser 632 of brca1 as a cyclin d1/cdk4 phosphorylation site in vitro. Using chromatin immunoprecipitation assays, we observed that the inhibition of cyclin d1/cdk4 activity resulted in increased brca1 dna binding at particular promoters in vivo.	SIGNOR-153450
P14653	P32243	1	transcriptional regulation	up-regulates quantity by expression	0.274	Transactivation of the mouse OTX2 Luc constructs by the human HOXB1, HOXB2, and HOXB3 proteins. \| Likewise, the construct pOTX2LucΔ−710 showed an 8-, 12-, and 6-fold increase in transcriptional activity if co-transfected with pSG-HOXB1, -HOXB2, and -HOXB3, respectively	SIGNOR-261633
P46937	O15294	0	glycosylation	up-regulates activity	0.283	Mass spectrometry analysis showed that YAP was the effector protein modified by OGT. In details, YAP Ser109 O-GlcNAcylation promoted the malignant phenotypes in PTC cells by inducing YAP Ser127 dephosphorylation and activation.	SIGNOR-276942
Q9UK32	P49841	1	phosphorylation	down-regulates activity	0.2	Moreover, RSK4 stabilized Beta-catenin in the presence of GSK-3Beta WT but not RSK4 stabilizes Beta-catenin through phosphorylation of GSK-3Beta (Ser9) in ESCC cells\|GSK-3Beta S9A in ESCC cells, which was similar to overexpression of GSK3Beta S9D\|	SIGNOR-275801
Q7Z6G8	Q9UQM7	0	phosphorylation	down-regulates activity	0.257	CaMKII-mediated displacement of AIDA-1 out of the postsynaptic density core. The present study indicates that CaMKII activation is necessary for the NMDA-induced movement of AIDA-1 out of the PSD core.	SIGNOR-264231
P68400	Q02790	1	phosphorylation	down-regulates activity	0.343	Thr-143 in the hinge I region was identified as the major phosphorylation site for CK2. \| Most importantly, CK2-phosphorylated FKBP52 did not bind to HSP90	SIGNOR-250865
P53350	Q00613	1	phosphorylation	down-regulates	0.444	Hsf1 was phosphorylated by plk1 at ser(216) of the dsgxxs motif during the timing of mitosis and a phospho-defective mutant form of hsf1 inhibited mitotic progression. Phosphorylated hsf1 during spindle pole localization underwent ubiquitin degradation through the scf(beta-trcp) pathway.	SIGNOR-180915
P27361	Q12772	1	phosphorylation	up-regulates	0.392	Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity.	SIGNOR-123053
O14818	P00519	0	phosphorylation	up-regulates quantity by stabilization	0.397	PSMA7 degradation is suppressed by c-Abl-mediated tyrosine phosphorylation at Y106	SIGNOR-260937
P68400	Q8IVP5	1	phosphorylation	down-regulates activity	0.427	Here, we identify that the mitochondrially localized PGAM5 phosphatase interacts with and dephosphorylates FUNDC1 at serine 13 (Ser-13) upon hypoxia or carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) treatment. Dephosphorylation of FUNDC1 catalyzed by PGAM5 enhances its interaction with LC3, which is abrogated following knockdown of PGAM5 or the introduction of a cell-permeable unphosphorylated peptide encompassing the Ser-13 and LIR of FUNDC1. We further observed that CK2 phosphorylates FUNDC1 to reverse the effect of PGAM5 in mitophagy activation.	SIGNOR-273622
Q99743	P35398	0	transcriptional regulation	up-regulates quantity by expression	0.665	Direct Regulation of the NPAS2 Promoter by RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding.	SIGNOR-267980
Q14669	Q8N726	1	ubiquitination	down-regulates quantity by destabilization	0.582	ULF interacts with ARF both in vitro and in vivo and promotes the lysine-independent ubiquitylation and degradation of ARF.	SIGNOR-266781
Q13813	P42574	0	cleavage	down-regulates	0.675	Caspase-3 is required for alpha-fodrin cleavage but dispensable for cleavage of other death substrates in apoptosis.	SIGNOR-57891
P01241	P10415	1	transcriptional regulation	up-regulates quantity by expression	0.2	Autocrine hGH increased the transcription and subsequent mRNA level and protein expression of c-Myc, Cyclin D1, and Bcl-2 in human mammary epithelial cells	SIGNOR-261628
P63000	Q96JJ3	0	guanine nucleotide exchange factor	up-regulates activity	0.583	We found in this study that AUTS2 is involved in Rac1 activation via P-Rex1 and the Elmo2/Dock180 complex, but not STEF or Tiam1, for the lamellipodia formation in N1E-115 cells. However, the enhancement of neurite elongation in primary neurons by AUTS2 expression is specifically mediated by the Elmo2/Dock180 complex. These results suggested that several Rac-GEFs differentially or cooperatively participate in Rac1 activation to promote neuronal migration and neurite outgrowth.	SIGNOR-266821
P12931	P49407	1	phosphorylation	down-regulates	0.684	Using fluorescently tagged proteins combined with resonance energy transfer and image cross-correlation spectroscopy approaches, we show in live cells that beta2-adaptin phosphorylation is an important regulatory process for the dissociation of beta-arrestin-AP-2 complexes in CCPs. Finally, we show that beta2-adaptin phosphorylation is involved in the early steps of receptor internalization. Our findings not only unveil beta2-adaptin as a new Src target during AT1R internalization, but also support the role of receptor-mediated signaling in the control of clathrin-dependent endocytosis of receptors.	SIGNOR-154564
Q86U44	P27361	0	phosphorylation	up-regulates quantity by stabilization	0.271	Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex.	SIGNOR-265949
P63279	P35712	1	sumoylation	down-regulates activity	0.367	We show that SOX6 is modified in vitro and in vivo by small ubiquitin‐related modifier (SUMO) on two distinct sites. Mutation of both sites abolished SOX6 sumoylation and increased SOX6 transcriptional activity. SUMO dependent repression of SOX6 transcription was promoted by UBC9 whereas siRNA to UBC9, cotransfection of inactive UBC9 or a SUMO protease increased SOX6 transcriptional activity.	SIGNOR-256130
P03372	O60674	0	phosphorylation	down-regulates quantity	0.435	From these results, it can be concluded that JAK2 negatively regulates ERalpha protein level.We next analyzed by which mechanisms JAK2 could regulate ERalpha protein level.\|We investigated whether JAK2 phosphorylates ER\u03b1 resulting in its ubiquitination and proteasomal degradation.	SIGNOR-278949
P35251	P06493	0	phosphorylation	down-regulates activity	0.245	Phosphorylation of the PCNA binding domain of the large subunit of replication factor C on Thr506 by cyclin-dependent kinases regulates binding to PCNA\|Replication factor C (RF-C) complex binds to DNA primers and loads PCNA onto DNA, thereby increasing the processivity of DNA polymerases. \|Phosphorylation of either RF-Cp145 as a part of the RF-C complex or RF-Cp145 domain B by cdk-cyclin kinases inhibits their ability to bind PCNA.	SIGNOR-265504
P49841	O75122	1	phosphorylation	down-regulates activity	0.515	GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules.\| CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells	SIGNOR-264826
P11362	Q9Y2J4	1	phosphorylation	up-regulates activity	0.2	These data support an idea that Amotl2 Tyr-103 can be phosphorylated by FGF receptor tyrosine kinase activity. We then determined whether Amotl2 Tyr-103 is required for its interaction with c-Src. \|Amotl2 promotes MAPK/ERK activation via c-Src, which is dependent on phosphorylation of tyrosine residue at position 103 but independent of the C-terminal PDZ-binding domain.	SIGNOR-271869

Q16539

Q99956

0

dephosphorylation

down-regulates

0.701

These properties define the ability of this enzyme to dephosphorylate and inactivate erk1/2 and p38a, but not jnk (c-jun n-terminal kinase) in vivo.

SIGNOR-87150

Q05655

Q9UQL6

1

phosphorylation

down-regulates activity

0.352

In this report, we show that VEGF stimulates PKD-dependent phosphorylation of HDAC5 at Ser259/498residues in ECs, which leads to HDAC5 nuclear exclusion and myocyte enhancer factor-2 (MEF2) transcriptional activation.

SIGNOR-260875

Q9UNE7

O00257

1

ubiquitination

down-regulates quantity by destabilization

0.2

The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα.

SIGNOR-277513

Q15022

P19784

0

phosphorylation

up-regulates activity

0.2

CK2 is the kinase for the phosphorylation of S583 of SUZ12.

SIGNOR-277797

P49916

P24941

0

phosphorylation

down-regulates

0.418

Dna ligase iii_ is specifically phosphorylated in replicating cells by the cell cycle kinase cdk2. However, in response to oxidative dna damage, dna ligase iii_ is dephosphorylated in a pathway that is dependent upon the dna damage-activated, phosphatidylinositol 3-phosphate (pi3)1-related kinase atm.

SIGNOR-150121

Q9H8V3

P41743

0

phosphorylation

up-regulates

0.474

Our data support a model in which pkc?-Mediated phosphorylation regulates ect2 binding to the oncogenic pkc?-Par6 complex thereby activating rac1 activity and driving transformed growth and invasion.

SIGNOR-170790

Q9ULB1

Q9NR48

0

transcriptional regulation

down-regulates quantity by repression

0.259

Our results reveal that a novel process of activity-dependent transcriptional repression exists in neurons and that Ash1L mediates the long-term repression of nrxn1α, thus implicating an important role for epigenetic modification in brain functioning.

SIGNOR-269056

P29474

Q05655

0

phosphorylation

down-regulates activity

0.568

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

SIGNOR-251631

P61587

Q13464

0

phosphorylation

up-regulates

0.707

We show that rock phosphorylates endogenous rhoe at serine 11 upon cell stimulation with platelet-derived growth factor. Phosphorylation has no effect on rhoe binding to rock i, but instead increases rhoe protein stability.

SIGNOR-134703

P19419

Q9UL54

0

phosphorylation

up-regulates activity

0.31

Transfection studies demonstrated that TAO2 stimulates phosphorylation of the TCF Elk1 on the major activating site, Ser383, and that TAO2 stimulates transactivation of Elk1 and the related TCF, Sap1.

SIGNOR-246638

Q8IZP0

P06493

0

phosphorylation

down-regulates activity

0.419

We identified serine 216 of Abi1 as a target of CDK1/cyclin B kinase that is phosphorylated in cells at the onset of mitosis.|Bcr-Abl-induced actin polymerization requires the Abi1 pathway, as the blockade of the signal transduction from Bcr-Abl to Abi1 abolishes the F-actin assembly|serine phosphorylation of Abi1 by CDK1/cyclin B serves as a cell cycle-dependent regulatory mechanism that inhibits actin assembly

SIGNOR-264421

O15399

P46934

0

ubiquitination

down-regulates activity

0.328

Nedd4 coexpression with GluN2D enhances GluN2D ubiquitination and reduces GluN1/GluN2D NMDA receptor responses.|This suggests that Nedd4 association reduces GluN2D function, mostly likely by promoting GluN2D ubiquitination and internalization.

SIGNOR-278636

P09651

Q92973

0

relocalization

up-regulates activity

0.572

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-262099

O00139

P53350

0

phosphorylation

up-regulates activity

0.684

Taken together, KIF2A is phosphorylated at T554 by PLK1 in the subdistal appendages of the mother centriole, which enhances MT depolymerization to disassemble primary cilia in a growth-signal-dependent manner.|Thus, PLK1 and APC/C mediated dual regulation connect the MT depolymerizing activity of KIF2A to a physiological primary cilia disassembly during the proliferative phase.

SIGNOR-278380

Q8TDX7

Q9HC35

1

phosphorylation

up-regulates activity

0.274

The mitotic kinases NEK6 and NEK7 phosphorylated the EML4 N-terminal domain at Ser144 and Ser146 in vitro, and depletion of these kinases in cells led to increased EML4 binding to microtubules in mitosis. An S144A-S146A double mutant not only bound inappropriately to mitotic microtubules but also increased their stability and interfered with chromosome congression. In addition, constitutive activation of NEK6 or NEK7 reduced the association of EML4 with interphase microtubules. Together, these data support a model in which NEK6- and NEK7-dependent phosphorylation promotes the dissociation of EML4 from microtubules in mitosis in a manner that is required for efficient chromosome congression.

SIGNOR-273884

O75144

P05771

0

phosphorylation

up-regulates activity

0.2

PKCα and PKCβ are required for phosphorylation of ICOSL and ICOSL-mediated cytokine induction

SIGNOR-273797

Q02548

P27361

0

phosphorylation

down-regulates activity

0.247

In this study, we demonstrated that PAX5 was phosphorylated by ERK1/2 in vitro and in vivo at serines 189 and 283. This phosphorylation attenuated the transcriptional repression of BLIMP1 by PAX5.

SIGNOR-269086

Q96EP0

Q14790

0

cleavage

down-regulates activity

0.315

We show that LUBAC interacted with caspase-1 via HOIP and modified its CARD domain with linear polyubiquitin and that depletion of HOIP or Sharpin resulted in heightened caspase-1 activation and cell death in response to inflammasome activation, unlike what is observed in macrophages. Reciprocally, caspase-1, as well as caspase-8, regulated LUBAC activity by proteolytically processing HOIP at Asp-348 and Asp-387 during the execution of cell death.

SIGNOR-272194

Q06124

Q9UQC2

1

dephosphorylation

down-regulates

0.742

Expression of the gab2 tyr-614-->phe (y614f) mutant, defective in shp-2 association, prevents erk (extracellular-signal-regulated kinase) activation and expression of a luciferase reporter plasmid driven by the c-fos sre (serum response element), indicating that interaction of shp-2 with gab2 is required for erk activation in response to il-2.

SIGNOR-124958

O14920

Q13148

1

phosphorylation

down-regulates quantity by destabilization

0.2

IκB kinase phosphorylates cytoplasmic TDP-43 and promotes its proteasome degradation. Furthermore, we identified IKKβ-induced phosphorylation sites of TDP-43 and found that phosphorylation at Thr8 and Ser92 is important for the reduction of TDP-43 by IKK.

SIGNOR-277860

Q13627

Q01130

1

phosphorylation

down-regulates activity

0.408

Dyrk1A inhibits SC35\u2032s activity to promote tau exon 10 inclusion.|Dyrk1A interacts with and phosphorylates SC35 and inhibits its activity to promote tau exon 10 inclusion.

SIGNOR-278307

P20336

Q9UJD0

0

relocalization

up-regulates activity

0.282

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-264379

P49023

Q14289

0

phosphorylation

down-regulates quantity by destabilization

0.94

P130Cas and paxillin can be phosphorylated by Fak or Pyk2, and bind directly to these kinases.

SIGNOR-279272

P12931

P43403

1

phosphorylation

up-regulates activity

0.479

In the cluster, Zap70 will be rapidly phosphorylated by active Src and slowly phosphorylated by autoinhibited, inactive Src.|We provide evidence that clusters harbor a positive feedback loop among Zap70, LAT, and Src-family kinases that binds phosphorylated LAT and further activates Zap70.

SIGNOR-279126

Q8IX03

P51812

0

phosphorylation

up-regulates

0.2

Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2.

SIGNOR-203302

P38936

Q13309

0

ubiquitination

down-regulates

0.772

Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase.

SIGNOR-138490

Q5TEC6

Q92831

0

acetylation

down-regulates activity

0.2

The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.

SIGNOR-269624

Q9UNS1

P04150

0

transcriptional regulation

up-regulates quantity by expression

0.252

GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription

SIGNOR-268052

Q00535

Q14194

1

phosphorylation

up-regulates

0.622

These findings suggest that sema3a-induced spine development is regulated by phosphorylation of crmp1 by cdk5. Introduction of crmp1-wt, but not crmp1-t509a/s522a, a crmp1 mutant that cannot be phosphorylated by cdk5, rescued the defect in sema3a responsiveness.

SIGNOR-159314

O43633

Q9UN37

0

cleavage

up-regulates activity

0.911

Here, we show, using high-speed atomic force microscopy and electron microscopy, that the AAA-type adenosine triphosphatase VPS4 constricts and cleaves ESCRT-III CHMP2A-CHMP3 helical filaments in vitro. Our results demonstrate that VPS4 actively constricts ESCRT-III filaments and cleaves them before their complete disassembly. We propose that the formation of ESCRT-III dome-like end caps by VPS4 within a membrane neck structure constricts the membrane to set the stage for membrane fission.

SIGNOR-260846

Q9UI47

P35222

1

relocalization

up-regulates quantity

0.753

Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14

SIGNOR-265493

Q16539

Q92993

1

phosphorylation

up-regulates activity

0.321

We found that phosphorylation of Tip60-T158 was increased by p38\u03b1 isolated from Dox- or \u03b3-radiation-treated cells over that from untreated cells (Figure xref ), indicating that DNA damage induces the protein kinase activity of p38\u03b1 towards Tip60-T158.

SIGNOR-278958

Q13976

Q01970

1

phosphorylation

down-regulates activity

0.539

PKG can directly phosphorylate PLC-beta2 and PLC-beta3 in vitro with purified proteins and in vivo with metabolic labeling. Phosphorylation of PLC-beta leads to the inhibition of G-protein-activated PLC-beta3 activity by 50-70% in COS-7 cell transfection assays. By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)). Mutation at these two sites (S26A and S1105A) of PLC-beta3 completely blocked the phosphorylation of PLC-beta3 protein catalyzed by PKG.

SIGNOR-249077

P47712

Q16539

0

phosphorylation

up-regulates activity

0.668

These results provide the first direct evidence that p38 kinase is responsible for cpla2 phosphorylation in sfllrn-stimulated platelets and is involved in the early phosphorylation of cpla2 in thrombin-stimulated platelets

SIGNOR-44673

P04637

P27361

0

phosphorylation

up-regulates

0.704

Mutant p53 is constitutively phosphorylated at serine 15 in uv-induced mouse skin tumors: involvement of erk1/2 map kinase.

SIGNOR-100270

O96017

Q08050

1

phosphorylation

up-regulates

0.721

Chk2 mediates stabilization of the foxm1 transcription factor to stimulate expression of dna repair genesthis phosphorylation of foxm1 on serine residue 361 caused increased stability of the foxm1 protein

SIGNOR-150746

Q9Y2Z0

P53350

0

phosphorylation

up-regulates activity

0.437

Plk1 phosphorylates Sgt1 at the kinetochores to promote timely kinetochore-microtubule attachment|Plk1 is required for the kinetochore localization of Sgt1 and phosphorylates serine 331 of Sgt1 at the kinetochores. This phosphorylation event enhances the association of the Hsp90-Sgt1 chaperone

SIGNOR-265222

P41208

O14965

0

phosphorylation

up-regulates

0.516

Our studies show that aurora a phosphorylates centrin at serine 170 in vitro and that the serine 170 phosphorylation affects the stability of centrin by regulating its interaction with apc/c. finally we demonstrated that phosphorylation of centrin serine 170 is an absolute requirement for aurora a-mediated centriole amplification.

SIGNOR-174686

P63167

P61586

1

gtpase-activating protein

down-regulates activity

0.273

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-260501

O43175

O60260

0

ubiquitination

down-regulates quantity by destabilization

0.2

Parkin binds to PHGDH and degrades it through ubiquitination to inhibit serine synthesis, which contributes greatly to the tumor-suppressive function of Parkin.

SIGNOR-269075

Q86UZ6

P35558

1

transcriptional regulation

up-regulates quantity by expression

0.2

We identified LIF/ZBTB46 signalling as a key promoter of metabolic reprogramming and NE differentiation of PCa cells through interactions with PCK1. We showed that ZBTB46 directly upregulates the expression of PCK1 and NE marker gene through activation of LIF signalling.

SIGNOR-277987

P41594

Q05513

0

phosphorylation

up-regulates activity

0.37

Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.

SIGNOR-249284

P49841

Q9GZV5

1

phosphorylation

down-regulates quantity by destabilization

0.2

GSK3 destabilizes TAZ. TAZS58A/S62A but not the TAZ S66A mutant diminished phos- phorylation by GSK3 , suggesting that Ser-58 and Ser-62 are important for GSK3 phosphorylation, whereas the Ser-66 is not (Fig. 4D).

SIGNOR-277646

Q9UBE8

Q8N122

1

phosphorylation

down-regulates activity

0.327

NLK inhibits mTORC1 lysosomal localization and thereby suppresses mTORC1 activation. Mechanistically, NLK phosphorylates Raptor on S863 to disrupt its interaction with the Rag GTPase, which is important for mTORC1 lysosomal recruitment.

SIGNOR-273908

P35241

Q5S007

0

phosphorylation

up-regulates activity

0.364

LRRK2 also phosphorylated ezrin and radixin, which are related to moesin, at the residue equivalent to Thr558, as well as a peptide (LRRKtide: RLGRDKYKTLRQIRQ) encompassing Thr558.

SIGNOR-279203

Q9UM73

Q14469

1

phosphorylation

up-regulates activity

0.266

NPM-ALK also directly phosphorylates HES1 protein.

SIGNOR-280181

P78527

P22415

1

phosphorylation

up-regulates

0.293

Feeding induces the recruitment of dna-pk to usf-1 and its phosphorylation, which then allows recruitment of p/caf, resulting in usf-1 acetylation and fas promoter activation.

SIGNOR-184849

P15918

P42345

1

relocalization

up-regulates

0.256

Rag gtpases, together with a multi-protein complex called ragulator, mediate amino acid-mediated mtor recruitment to the lysosome surface where mtor becomes activated.

SIGNOR-198242

P04150

Q16539

0

phosphorylation

up-regulates

0.511

We found serine 211 of the human gr to be a substrate for p38 mapk both in vitro and intracellularly. Mutation of this site to alanine greatly diminished gr-driven gene transcription and apoptosis.

SIGNOR-135198

P31749

O60858

0

polyubiquitination

down-regulates quantity by destabilization

0.353

Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT. We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro.

SIGNOR-271852

P68400

Q9UHH9

1

phosphorylation

down-regulates quantity by destabilization

0.255

CK2 physiologically phosphorylates IP6K2 at amino acid residues S347 and S356 contained within a PEST sequence, a consensus site for ubiquitination. HCT116 cells depleted of IP6K2 are resistant to cell death elicited by CK2 inhibitors. CK2 phosphorylation at the degradation motif of IP6K2 enhances its ubiquitination and subsequent degradation.

SIGNOR-273625

P29803

Q16654

0

phosphorylation

down-regulates

0.547

Pyruvate dehydrogenase (pdh) activity (pdha) controls the entry of carbohydrate into the tricarboxylic cycle and is regulated by pdh kinase (pdk), which phosphorylates and inactivates the enzyme, and pdh phosphatase, which dephosphorylates the enzyme to the active form

SIGNOR-121936

O95271

Q9NTX7

0

ubiquitination

down-regulates quantity

0.723

We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation.

SIGNOR-260004

P06493

P04626

0

phosphorylation

down-regulates

0.274

Phosphorylation on tyrosine-15 of p34(cdc2) by erbb2 inhibits p34(cdc2) activation and is involved in resistance to taxol-induced apoptosis

SIGNOR-88671

Q13535

O15360

1

phosphorylation

up-regulates

0.598

The s1449a mutant failed to completely correct a variety of fa-associated phenotypes. The dna damage response is coordinated by phosphorylation events initiated by apical kinases atm (ataxia telangectasia mutated) and atr (atm and rad3-related), and atr is essential for proper fa pathway function. Serine 1449 is in a consensus atm/atr site

SIGNOR-182953

O14965

O95983

1

phosphorylation

up-regulates

0.286

These results suggest that the biochemical changes of mbd3 may be intimately related to the targeting of mbd3 to centrosomes. aurora-a phosphorylates mbd3

SIGNOR-93693

Q13017

P12931

0

phosphorylation

up-regulates activity

0.607

Phosphotyrosine (p-Tyr)-dependent and -independent mechanisms of p190 RhoGAP-p120 RasGAP interaction: Tyr 1105 of p190, a substrate for c-Src, is the sole p-Tyr mediator of complex formation. 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, indicating that Y1105 is a selective and preferential target of c-Src both in vitro and in vivo.

SIGNOR-276170

O43683

Q02224

1

relocalization

up-regulates activity

0.831

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

SIGNOR-252016

P10588

P22888

1

transcriptional regulation

down-regulates quantity by repression

0.302

Functional analysis showed that EAR2 and EAR3/COUP-TFI repressed the hLHR promoter activity, whereas TR4 activated hLHR gene transcription.

SIGNOR-266216

P17612

P48058

1

phosphorylation

up-regulates

0.429

We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus.

SIGNOR-97550

P01106

Q9NVW2

0

ubiquitination

down-regulates quantity by destabilization

0.37

This suggests that RLIM negatively regulates the transcriptional activity of c-Myc.|We further showed that RLIM can promote polyubiquitination of c-Myc in cells.

SIGNOR-278551

P98066

P05412

0

transcriptional regulation

up-regulates quantity by expression

0.308

Tumor necrosis factor (TNF)-stimulated gene 6 (TSG-6) encodes a protein expressed during inflammation. We have previously shown that transcription factors of the NF-IL6 and AP-1 families cooperatively modulate activation of the TSG-6 gene by TNF or interleukin 1 (IL-1) through a promoter region that contains an NF-IL6 site (-106 to -114) and an AP-1 element

SIGNOR-254052

P54829

Q7L9L4

1

dephosphorylation

up-regulates activity

0.2

PTPN5 dephosphorylates\nMob1a at Y26 residue.

SIGNOR-277058

Q13490

P06730

1

ubiquitination

down-regulates quantity by destabilization

0.401

We found that endogenous eIF4E was ubiquitinated by cIAP1, and ubiquitinated eIF4E accumulated upon MG132 treatment.

SIGNOR-278741

Q8IUE6

Q14493

0

translation regulation

up-regulates quantity by expression

0.2

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

SIGNOR-265406

P09769

Q9Y6K9

1

phosphorylation

down-regulates activity

0.327

Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.

SIGNOR-276368

Q04206

P12644

1

transcriptional regulation

down-regulates quantity by repression

0.2

Co-transfection with pCMV4-RelA alone or in combination with pCMV4p50 repressed pSLA4.1 EX-Lux activity by approximately 75 percent in both H441 and A549 cells

SIGNOR-266087

P12931

P18206

1

phosphorylation

down-regulates activity

0.76

The phosphorylation of vinculin on tyrosine residues 100 and 1065, mediated by SRC kinases, affects cell spreadingWhen phosphorylated, the vinculin tail exhibited significantly less binding to the vinculin head domain than the unphosphorylated tail.

SIGNOR-247424

P31749

Q92945

1

phosphorylation

down-regulates activity

0.703

Beta-catenin transcript can be stabilized by either wnt or pi3k-akt signaling activation. Akt phosphorylates ksrp at a unique serine residue akt phosphorylates the mrna decay-promoting factor ksrp at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents ksrp interaction with the exoribonucleolytic complex exosome.

SIGNOR-252497

Q92544

Q16665

0

transcriptional regulation

down-regulates quantity by repression

0.2

Here, we investigated the impact of hypoxia on TM9SF4 expression in leukemic cells and identified TM9SF4 as a direct target of HIF-1α, downregulated in these cells by hypoxia. Then, we found that the hypoxia-mediated downregulation of TM9SF4 expression is associated with a decrease of cell adhesion of leukemic cells to fibronectin, thus demonstrating that human TM9SF4 is a new molecule involved in leukemic cell adhesion.

SIGNOR-266705

O94813

Q8NFU7

0

transcriptional regulation

up-regulates quantity by expression

0.2

Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9.

SIGNOR-259093

P13796

P17612

0

phosphorylation

up-regulates

0.327

Phosphorylation on ser5 increases the f-actin-binding activity of l-plastin and promotes its targeting to sites of actin assembly in cells. L-plastin phosphorylation require protein kinase a.

SIGNOR-146287

Q9Y6Q6

O75175

0

transcriptional regulation

down-regulates quantity by repression

0.2

Our results reveal that CNOT3 is a critical regulator of bone mass acting on bone resorption through posttranscriptional down-regulation of RANK mRNA stability, at least in part, even in aging-induced osteoporosis.

SIGNOR-261572

Q92793

P17252

0

phosphorylation

down-regulates

0.261

The action of metformin was shown to be mediated through activation of apkc?/?, Which phosphorylates cbp at ser436, and disrupts the transcriptionally active creb-cbp-crtc2 complex,

SIGNOR-166368

P07947

Q9GZV5

1

phosphorylation

up-regulates activity

0.317

Yes directly phosphorylates YAP and TAZ, resulting in their increased nuclear localization and transcriptional activity.Analysis by mass spectrometry identified Tyr391 and Tyr407 as the two phosphorylation sites of YAP, whereas Tyr305 was the sole phosphorylated residue of TAZ (Fig. 5F and fig. S4, A to C).

SIGNOR-277654

P16298

Q92934

1

dephosphorylation

up-regulates activity

0.364

Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis.

SIGNOR-248384

Q9BQI3

P05198

1

phosphorylation

down-regulates activity

0.89

HRI is an intracellular heme sensor that coordinates heme and globin synthesis in erythropoiesis by inhibiting protein synthesis of globins and heme biosynthetic enzymes during heme deficiency. HRI is a heme-regulated kinase that phosphorylates the α-subunit of eIF2 in heme deficiency, impairing another round of translational initiation and thereby inhibiting translation.

SIGNOR-251817

P38435

P08709

1

carboxylation

up-regulates activity

0.688

Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation.

SIGNOR-265919

P38398

P11802

0

phosphorylation

down-regulates

0.665

In particular, we have identified ser 632 of brca1 as a cyclin d1/cdk4 phosphorylation site in vitro. Using chromatin immunoprecipitation assays, we observed that the inhibition of cyclin d1/cdk4 activity resulted in increased brca1 dna binding at particular promoters in vivo.

SIGNOR-153450

P14653

P32243

1

transcriptional regulation

up-regulates quantity by expression

0.274

Transactivation of the mouse OTX2 Luc constructs by the human HOXB1, HOXB2, and HOXB3 proteins. | Likewise, the construct pOTX2LucΔ−710 showed an 8-, 12-, and 6-fold increase in transcriptional activity if co-transfected with pSG-HOXB1, -HOXB2, and -HOXB3, respectively

SIGNOR-261633

P46937

O15294

0

glycosylation

up-regulates activity

0.283

Mass spectrometry analysis showed that YAP was the effector protein modified by OGT. In details, YAP Ser109 O-GlcNAcylation promoted the malignant phenotypes in PTC cells by inducing YAP Ser127 dephosphorylation and activation.

SIGNOR-276942

Q9UK32

P49841

1

phosphorylation

down-regulates activity

0.2

Moreover, RSK4 stabilized Beta-catenin in the presence of GSK-3Beta WT but not RSK4 stabilizes Beta-catenin through phosphorylation of GSK-3Beta (Ser9) in ESCC cells|GSK-3Beta S9A in ESCC cells, which was similar to overexpression of GSK3Beta S9D|

SIGNOR-275801

Q7Z6G8

Q9UQM7

0

phosphorylation

down-regulates activity

0.257

CaMKII-mediated displacement of AIDA-1 out of the postsynaptic density core. The present study indicates that CaMKII activation is necessary for the NMDA-induced movement of AIDA-1 out of the PSD core.

SIGNOR-264231

P68400

Q02790

1

phosphorylation

down-regulates activity

0.343

Thr-143 in the hinge I region was identified as the major phosphorylation site for CK2. | Most importantly, CK2-phosphorylated FKBP52 did not bind to HSP90

SIGNOR-250865

P53350

Q00613

1

phosphorylation

down-regulates

0.444

Hsf1 was phosphorylated by plk1 at ser(216) of the dsgxxs motif during the timing of mitosis and a phospho-defective mutant form of hsf1 inhibited mitotic progression. Phosphorylated hsf1 during spindle pole localization underwent ubiquitin degradation through the scf(beta-trcp) pathway.

SIGNOR-180915

P27361

Q12772

1

phosphorylation

up-regulates

0.392

Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity.

SIGNOR-123053

O14818

P00519

0

phosphorylation

up-regulates quantity by stabilization

0.397

PSMA7 degradation is suppressed by c-Abl-mediated tyrosine phosphorylation at Y106

SIGNOR-260937

P68400

Q8IVP5

1

phosphorylation

down-regulates activity

0.427

Here, we identify that the mitochondrially localized PGAM5 phosphatase interacts with and dephosphorylates FUNDC1 at serine 13 (Ser-13) upon hypoxia or carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) treatment. Dephosphorylation of FUNDC1 catalyzed by PGAM5 enhances its interaction with LC3, which is abrogated following knockdown of PGAM5 or the introduction of a cell-permeable unphosphorylated peptide encompassing the Ser-13 and LIR of FUNDC1. We further observed that CK2 phosphorylates FUNDC1 to reverse the effect of PGAM5 in mitophagy activation.

SIGNOR-273622

Q99743

P35398

0

transcriptional regulation

up-regulates quantity by expression

0.665

Direct Regulation of the NPAS2 Promoter by RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding.

SIGNOR-267980

Q14669

Q8N726

1

ubiquitination

down-regulates quantity by destabilization

0.582

ULF interacts with ARF both in vitro and in vivo and promotes the lysine-independent ubiquitylation and degradation of ARF.

SIGNOR-266781

Q13813

P42574

0

cleavage

down-regulates

0.675

Caspase-3 is required for alpha-fodrin cleavage but dispensable for cleavage of other death substrates in apoptosis.

SIGNOR-57891

P01241

P10415

1

transcriptional regulation

up-regulates quantity by expression

0.2

Autocrine hGH increased the transcription and subsequent mRNA level and protein expression of c-Myc, Cyclin D1, and Bcl-2 in human mammary epithelial cells

SIGNOR-261628

P63000

Q96JJ3

0

guanine nucleotide exchange factor

up-regulates activity

0.583

We found in this study that AUTS2 is involved in Rac1 activation via P-Rex1 and the Elmo2/Dock180 complex, but not STEF or Tiam1, for the lamellipodia formation in N1E-115 cells. However, the enhancement of neurite elongation in primary neurons by AUTS2 expression is specifically mediated by the Elmo2/Dock180 complex. These results suggested that several Rac-GEFs differentially or cooperatively participate in Rac1 activation to promote neuronal migration and neurite outgrowth.

SIGNOR-266821

P12931

P49407

1

phosphorylation

down-regulates

0.684

Using fluorescently tagged proteins combined with resonance energy transfer and image cross-correlation spectroscopy approaches, we show in live cells that beta2-adaptin phosphorylation is an important regulatory process for the dissociation of beta-arrestin-AP-2 complexes in CCPs. Finally, we show that beta2-adaptin phosphorylation is involved in the early steps of receptor internalization. Our findings not only unveil beta2-adaptin as a new Src target during AT1R internalization, but also support the role of receptor-mediated signaling in the control of clathrin-dependent endocytosis of receptors.

SIGNOR-154564

Q86U44

P27361

0

phosphorylation

up-regulates quantity by stabilization

0.271

Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex.

SIGNOR-265949

P63279

P35712

1

sumoylation

down-regulates activity

0.367

We show that SOX6 is modified in vitro and in vivo by small ubiquitin‐related modifier (SUMO) on two distinct sites. Mutation of both sites abolished SOX6 sumoylation and increased SOX6 transcriptional activity. SUMO dependent repression of SOX6 transcription was promoted by UBC9 whereas siRNA to UBC9, cotransfection of inactive UBC9 or a SUMO protease increased SOX6 transcriptional activity.

SIGNOR-256130

P03372

O60674

0

phosphorylation

down-regulates quantity

0.435

From these results, it can be concluded that JAK2 negatively regulates ERalpha protein level.We next analyzed by which mechanisms JAK2 could regulate ERalpha protein level.|We investigated whether JAK2 phosphorylates ER\u03b1 resulting in its ubiquitination and proteasomal degradation.

SIGNOR-278949

P35251

P06493

0

phosphorylation

down-regulates activity

0.245

Phosphorylation of the PCNA binding domain of the large subunit of replication factor C on Thr506 by cyclin-dependent kinases regulates binding to PCNA|Replication factor C (RF-C) complex binds to DNA primers and loads PCNA onto DNA, thereby increasing the processivity of DNA polymerases. |Phosphorylation of either RF-Cp145 as a part of the RF-C complex or RF-Cp145 domain B by cdk-cyclin kinases inhibits their ability to bind PCNA.

SIGNOR-265504

P49841

O75122

1

phosphorylation

down-regulates activity

0.515

GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules.| CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells

SIGNOR-264826

P11362

Q9Y2J4

1

phosphorylation

up-regulates activity

0.2

These data support an idea that Amotl2 Tyr-103 can be phosphorylated by FGF receptor tyrosine kinase activity. We then determined whether Amotl2 Tyr-103 is required for its interaction with c-Src. |Amotl2 promotes MAPK/ERK activation via c-Src, which is dependent on phosphorylation of tyrosine residue at position 103 but independent of the C-terminal PDZ-binding domain.

SIGNOR-271869