GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P10636	P17655	0	cleavage	down-regulates activity	0.433	Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains	SIGNOR-251611
Q9BT81	Q9HCK8	0	transcriptional regulation	down-regulates quantity	0.2	Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells	SIGNOR-268922
P31749	Q8TDD2	1	phosphorylation	up-regulates	0.423	Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5	SIGNOR-252514
P51812	P31749	0	phosphorylation	down-regulates activity	0.265	Akt interacts with and phosphorylates RSK2 at S19.	SIGNOR-277548
P12931	Q14247	1	phosphorylation	down-regulates activity	0.801	Erk phosphorylation and a mimicking S405,418D double mutation enhanced cortactin binding and activation of N-WASP. In contrast, Src phosphorylation inhibited the ability of cortactin previously phosphorylated by Erk, and that of S405,418D double mutant cortactin, to bind and activate N-WASP. Furthermore, Y-->D mutation of three tyrosine residues targeted by Src (Y421, Y466, and Y482) inhibited the ability of S405,418D cortactin to activate N-WASP.	SIGNOR-246513
Q9NP31	P06239	0	phosphorylation	up-regulates activity	0.578	Here we mapped Lck phosphorylation and interaction sites on TSAd and evaluated their functional importance. The three C-terminal TSAd tyrosines Tyr(280), Tyr(290), and Tyr(305) were phosphorylated by Lck and functioned as docking sites for the Lck Src homology 2 (SH2) domain. Lck binds to TSAd prolines and phosphorylates and interacts with the three C-terminal TSAd tyrosines. We propose that through multivalent interactions with Lck, TSAd diverts Lck from phosphorylating other substrates, thus modulating its functional activity through substrate competition.	SIGNOR-262888
P09884	Q7L590	0	relocalization	up-regulates quantity by stabilization	0.862	Mcm10 is an essential eukaryotic protein required for the initiation and elongation phases of chromosomal replication. Specifically, Mcm10 is required for the association of several replication proteins, including DNA polymerase alpha (pol alpha), with chromatin.	SIGNOR-261271
P23443	O60331	1	phosphorylation	down-regulates quantity by destabilization	0.2	Here we show that p70S6K1 (S6K1), a downstream target of mechanistic target of rapamycin (mTOR), phosphorylates PIPKIγ90 at Thr-553 and Ser-555 and that S6K1-mediated PIPKIγ90 phosphorylation is essential for cell migration and invasion. These data suggest that S6K1-mediated PIPKIγ90 phosphorylation regulates cell migration and invasion by controlling PIPKIγ90 degradation.	SIGNOR-277283
Q96PE2	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.549	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-260542
P63104	P45983	0	phosphorylation	down-regulates	0.371	Jnk phosphorylated 14-3-3 at ser-184 and 14-3-3 at ser-186 both in vitro and in vivo, and such phosphorylation reduced the affinity of 14-3-3 proteins for bax	SIGNOR-124020
P12830	Q5T0T0	0	ubiquitination	down-regulates quantity by destabilization	0.2	Inhibiting proteasome activity with MG132 prevented CDH1 and beta2M degradation, indicating that MARCH8 might be targeting CDH1 and beta2M for proteasomal degradation.\|We demonstrated that MARCH8 interacts with and ubiquitinates CDH1 and beta2M.	SIGNOR-278820
P15056	P28482	0	phosphorylation	down-regulates activity	0.628	Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity.	SIGNOR-236388
Q96C90	Q05655	0	phosphorylation	up-regulates activity	0.2	Recombinant tagged PHI-1 was phosphorylated by protein kinase C at two sites, one a Ser and one a Thr; phosphorylation enhanced inhibitory potency 50-fold.	SIGNOR-265739
P53041	P04049	1	dephosphorylation	down-regulates activity	0.462	Protein phosphatase 5 (PP5) was identified as an inactivator that associates with Raf-1 on growth factor stimulation and selectively dephosphorylates an essential activating site, Ser 338. The PP5-mediated dephosphorylation of Ser 338 inhibited Raf-1 activity and downstream signalling to MEK	SIGNOR-248537
Q96R06	O14965	0	phosphorylation	up-regulates activity	0.511	We report here that Astrin acts as a mitotic phosphoprotein, and Aurora-A phosphorylates Astrin at Ser(115). The phosphorylation-deficient mutant Astrin S115A abnormally activates spindle assembly checkpoint and delays mitosis progression, decreases spindle stability, and induces chromosome misalignment. Mechanistic analyses reveal that Astrin phosphorylation mimicking mutant S115D, instead of S115A, binds and induces ubiquitination and degradation of securin, which sequentially activates Separase, an enzyme required for the separation of sister chromatids.	SIGNOR-276648
P78368	O14654	1	phosphorylation	down-regulates quantity by destabilization	0.2	IRS4 was phosphorylated at Ser859 by CK1γ2 in vitro and in vivo, which promoted the polyubiquitination and degradation of IRS4 through the ubiquitin/lysosome pathway by the carboxyl terminus of Hsc70-interacting protein(CHIP).	SIGNOR-277615
P54646	O14920	1	phosphorylation	up-regulates	0.257	These results demonstrate that the ikk is a direct substrate of ampk_2 and that its phosphorylation on ser177 and ser181no initiates the activation of the ampk_2 in endothelial cells which in turn phosphorylates and activates the _-subunit of the ikk. The latter also induces a higher rate of ikk auto-inactivation and thus attenuates the activation of nf_b and the expression of inflammatory genes	SIGNOR-174405
Q13418	P23528	1	phosphorylation	down-regulates	0.35	Actin (de)polymerization is regulated by cofilin, the ser(3) phosphorylation (ps(3)cofilin) of which inhibits its actin-severing activity. To determine how ilk regulates ps(3)cofilin, we examined the effects of ilk on ps(3)cofilin using normal rie1 cells.	SIGNOR-160756
P28328	P50542	1	ubiquitination	down-regulates quantity by destabilization	0.579	Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle.	SIGNOR-253021
Q5S007	O00429	1	phosphorylation	up-regulates activity	0.568	LRRK2 G2019S directly bound to and phosphorylated Drp1 at Threonine595, whereas P110 treatment abolished this phosphorylation.Threonine595 phosphorylation of Drp1 by LRRK2 G2019S is required for Drp1-mediated mitochondrial fragmentation and excessive autophagy	SIGNOR-276495
Q92888	O60674	0	phosphorylation	up-regulates	0.325	We found that angiotensin ii activates arhgef1 through a previously undescribed mechanism in which jak2 phosphorylates tyr738 of arhgef1	SIGNOR-163557
P19429	P05129	0	phosphorylation	down-regulates	0.2	Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction.	SIGNOR-134632
O43236	O15033	0	ubiquitination	down-regulates quantity by destabilization	0.2	Furthermore, the ubiquitination and degradation of SMAC, HtrA2, and ARTS were significantly enhanced in AREL1-expressing cells following apoptotic stimulation, indicating that AREL1 binds to and ubiquitinates cytosolic but not mitochondria-associated forms of IAP antagonists	SIGNOR-267670
P04275	P09958	0	cleavage	up-regulates activity	0.481	Like PACE,PACE4 was able to process pro-vWF to its mature form, and efficient cleavage required both the P4 arginine and the P2 lysine	SIGNOR-260368
P14866	Q16566	0	phosphorylation	up-regulates	0.379	Here we show that the regulation of the stress axis-regulated exon of the slo1 potassium channel transcripts by membrane depolarization requires a highly conserved camkiv target serine (ser-513) of the heterogeneous ribonucleoprotein l. Ser-513 phosphorylation within the rna recognition motif 4 enhanced heterogeneous ribonucleoprotein l interaction with the camkiv-responsive rna element 1 of stress axis-regulated exon and inhibited binding of the large subunit of the u2 auxiliary factor u2af65.	SIGNOR-197367
P20618	Q05086	0	ubiquitination	down-regulates quantity by destabilization	0.355	Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits.	SIGNOR-265131
P49593	O43318	1	dephosphorylation	down-regulates activity	0.395	However, our current work shows that POPX2 can downregulate TAK1 and affect the anti-apoptotic activities of TAK1, implying that silencing POPX2 could facilitate TAK1 activation and will lead to increased cell survival.\|We have also demonstrated that POPX2 can directly dephosphorylate TAK1 (XREF_FIG).	SIGNOR-277047
Q16539	O15519	1	phosphorylation	up-regulates	0.373	Here we demonstrate that m. tuberculosis?induced Tnf triggered reactive oxygen species?dependent Activation of ask1 and the tyrosine kinase c-abl (a000161) in mouse macrophages and that flips was phosphorylated on tyr211 and ser4 by c-abl and p38, respectively.	SIGNOR-187001
Q13158	O14965	0	phosphorylation	up-regulates	0.343	Here, we report that aur-a phosphorylates s203 of the fas associated with death domain protein (fadd)phosphorylation of s203 by aur-a serves to prime fadd for plk1-mediated phosphorylation at s194	SIGNOR-176739
P27361	P10828	1	phosphorylation	down-regulates activity	0.428	We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay.	SIGNOR-102224
O75969	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-272955
Q92905	O14920	0	phosphorylation	down-regulates activity	0.33	Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro.	SIGNOR-275519
Q15796	Q15759	0	phosphorylation	down-regulates	0.352	Smads can also be phosphorylated in the linker region most prominently by the action of mitogen-activated protein (map) kinaseslinker region phosphorylation can prevent nuclear translocation of smads and inhibit tgf-_ signalling, potentially leading to oncogenesis.	SIGNOR-167848
Q15797	O95257	1	transcriptional regulation	up-regulates quantity	0.2	Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation	SIGNOR-268937
P41252	Q2TAL8	0	transcriptional regulation	up-regulates quantity by expression	0.2	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269406
P07949	P28482	1	phosphorylation	up-regulates	0.423	We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1).	SIGNOR-140294
P00519	P22681	0	ubiquitination	down-regulates quantity by destabilization	0.614	We found that while c-cbl e3 ligase induced ubiquitin-dependent degradation of mature and phosphorylated bcr-abl proteins	SIGNOR-167194
Q09472	Q05655	0	phosphorylation	down-regulates	0.366	Inhibition of histone acetyltransferase function of p300 by pkcdeltawe found that pkcdelta but not classical pkc, specifically phosphorylates p300 at serine 89 in vitro and in vivo. This phosphorylation causes inhibition of p300 intrinsic hat activity.	SIGNOR-94263
Q13153	P36871	1	phosphorylation	up-regulates	0.343	The signaling kinase p21-activated kinase 1 (pak1) binds to, phosphorylates and enhances the enzymatic activity of phosphoglucomutase 1 (pgm),	SIGNOR-127135
P51636	P12931	0	phosphorylation	down-regulates	0.676	Here, we show that cav-2 is phosphorylated at both tyrosines 19 and 27. We reconstituted this phosphorylation event by recombinantly coexpressing c-src and cav-2.Further functional analysis revealed that tyrosine phosphorylation of cav-2 has no effect on its targeting to lipid rafts, but clearly disrupts the hetero-oligomerization of cav-2 with cav-1.	SIGNOR-129961
P19544	P15514	1	transcriptional regulation	up-regulates quantity by expression	0.396	The Wilms Tumor Suppressor WT1 Encodes a Transcriptional Activator of amphiregulin	SIGNOR-251745
P46527	Q13131	0	phosphorylation	up-regulates quantity by stabilization	0.267	P27Kip1-Mediated Cell Survival Is Dependent on AMPK-Specific Thr198 Phosphorylation\|AMPK-dependent phosphorylation of p27Kip1 on Thr198 promotes p27Kip1 protein stability, resulting in more autophagy and less apoptosis.	SIGNOR-259859
P35222	Q9UI47	0	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
Q05586	P17252	0	phosphorylation	up-regulates activity	0.417	Serines 890 and 896 of the NMDA receptor subunit NR1 are differentially phosphorylated by protein kinase C isoforms. The results show that PKC alpha phosphorylates preferentially S896 and PKC gamma preferentially S890.	SIGNOR-263177
Q9BZR9	O43318	1	polyubiquitination	up-regulates activity	0.343	These results suggest that TRIM8 could mediate K63-linked polyubiquitination of TAK1 at residue K158.These results suggest that TRIM8 is involved in TNFα- and IL-1β–induced NF-κB activation by mediating K63-linked TAK1 polyubiquitination and subsequent activation.	SIGNOR-271890
P46527	Q9Y463	0	phosphorylation	up-regulates	0.355	Mirk phosphorylates p27 at ser-10, thus stabilizing p27 and blocking its nuclear export and degradation	SIGNOR-235805
P46531	P49841	0	phosphorylation	up-regulates	0.463	Here, we observed that gsk3beta was able to bind and phosphorylate notch1ic in vitro, and attenuation of gsk3beta activity reduced phosphorylation of notchic in vivo.Functionally, ligand-activated signaling through the endogenous notch1 receptor was reduced in gsk3beta fibroblasts, implying a positive role for gsk3beta in mammalian notch signaling.	SIGNOR-90608
P00736	P68400	0	phosphorylation	down-regulates activity	0.307	We provide evidence that this kinase phosphorylates Clr at the level of Ser189. \| Accessibility of Ser189 was low in intact C1r, due in part to the presence of one of the oligosaccharides borne by the alpha region, further reduced in the presence of calcium, and abolished when C1r was incorporated into the C1s-C1r-C1r-C1s tetramer or the C1 complex.	SIGNOR-250833
O14579	Q96PM5	0	polyubiquitination	down-regulates quantity by destabilization	0.471	PIRH2 promotes the ubiquitylation of epsilon-COP in vitro and in vivo and consequently promotes the degradation of epsilon-COP.	SIGNOR-272630
Q13480	Q06124	0	dephosphorylation	down-regulates activity	0.952	These results suggest that Tyr(P)-627 and Tyr(P)-659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) that binds and activates SHP2.\|Thus, physical association of activated SHP2 with Gab1 is necessary and sufficient to mediate the ERK mitogen-activated protein kinase activation. Phosphopeptides derived from Gab1 were dephosphorylated by active SHP2 in vitro.	SIGNOR-248674
Q8IXL6	P10451	1	phosphorylation	down-regulates quantity	0.683	OPN phosphorylation by Fam20C decreased OPN secretion, and OPN neutralization reduced Fam20C-deficiency-induced osteoclast differentiation and bone metastasis.	SIGNOR-278936
Q08050	P53350	0	phosphorylation	up-regulates	0.705	It has been reported that plk1 could directly phosphorylate foxm1 at ser-715 and ser-724 for full activation and proper mitotic progression	SIGNOR-187892
P84022	P78368	0	phosphorylation	down-regulates	0.337	Cki?2 Directly phosphorylates smad3 at ser418, leading to the increased ubiquitination and proteasomal degradation of activated smad3 following tgf-? Treatment.	SIGNOR-181069
Q9UKV5	P11441	1	polyubiquitination	down-regulates activity	0.52	USP13 and gp78 control ubiquitination of Ubl4A.These data suggest that USP13 and gp78 play antagonizing roles in regulation of Ubl4A ubiquitination: While gp78 assembles ubiquitin chains on Ubl4A, USP13 antagonizes this activity to limit Ubl4A ubiquitination.Ubiquitination of Ubl4A preferentially occurs on Lys48. We identify the Bag6 cofactor Ubl4A as a shared substrate of gp78 and USP13. USP13 depletion is associated with hyper-ubiquitination of Ubl4A and altered interaction between the Bag6 complex and its co-chaperone SGTA. Because the interaction of Ubl4A with SGTA is mediated by positively-charged residues in Ubl4A including Lys48 (Chartron et al., 2012; Xu et al., 2012), which happens to be the major ubiquitination site, the simplest model to explain reduced Bag6-SGTA interaction in USP13 knockdown cells is that ubiquitin conjugates on Ubl4A sterically hinder SGTA binding.	SIGNOR-272856
O43318	P46937	1	phosphorylation	down-regulates activity	0.338	TAK1 inhibits YAP activity through beta-TRCP.\|Thus, our data indicate that TAK1 directly phosphorylates YAP at multiple sites.\|These observations prompted us to test whether TAK1 phosphorylates YAP at S127.	SIGNOR-278956
P17252	P22681	1	phosphorylation	down-regulates quantity	0.322	However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway.	SIGNOR-249056
P17612	P53396	1	phosphorylation	up-regulates activity	0.309	Phosphorylation of Recombinant Human ATP:Citrate Lyase by cAMP-Dependent Protein Kinase Abolishes Homotropic Allosteric Regulation of the Enzyme by Citrate and Increases the Enzyme Activity. Ser 454, which is phosphorylated by the catalytic subunit of cAMP-dependent protein kinase (PKA)	SIGNOR-250328
P00519	Q00987	1	phosphorylation	down-regulates activity	0.716	C-abl binds and phosphorylates mdm2 in vivo and in vitro;phosphorylation of mdm2 by c-abl impairs the inhibition of p53 by mdm2.	SIGNOR-90512
P25098	P05387	1	phosphorylation	up-regulates	0.2	The phosphorylation sites in grk2-phosphorylated p2 are identified (s102 and s105) and are identical to the sites known to regulate p2 activity.	SIGNOR-94254
Q8IW41	Q99497	1	phosphorylation	up-regulates activity	0.469	PRAK preferentially colocalizes with DJ-1 and leads to DJ-1 activation, which in turn facilitates DJ-1 to sequester Daxx in the nucleus, preventing oxidative stress induced cell death.\|These data clearly demonstrate a PRAK dependent phosphorylation of DJ-1.	SIGNOR-279746
Q14457	Q13043	0	phosphorylation	up-regulates activity	0.312	These results suggest that Mst1 directly stimulates interaction between Beclin1 and Bcl-2.\|We here demonstrate that Mst1-induced phosphorylation of Beclin1 in its BH3 domain at Thr 108 promotes binding of Beclin1 with Bcl-2/Bcl-xL.	SIGNOR-278502
P21860	Q9H4P4	0	polyubiquitination	down-regulates quantity by destabilization	0.691	Nrdp1/FLRF is a ubiquitin ligase promoting ubiquitination and degradation of the epidermal growth factor receptor family member, ErbB3	SIGNOR-272599
Q14680	Q99683	1	phosphorylation	up-regulates activity	0.271	MELK, as an upstream kinase of ASK1, phosphorylates threonine 838 in an activation loop of human ASK1, thereby stimulating ASK1 kinase activity.	SIGNOR-280039
Q00987	P41240	0	phosphorylation	up-regulates activity	0.2	Here we show that activated c-Src kinase phosphorylates Y281 and Y302 of Mdm2, resulting in an increase in Mdm2 stability and its association with Ubc12, the E2 enzyme of the neddylating complex.	SIGNOR-279163
Q13535	Q8N726	0	phosphorylation	up-regulates activity	0.391	Regulation of NF-kappaB and p53 through activation of ATR and Chk1 by the ARF tumour suppressorInduction of ATR activity in Hs68 E2F1ER cells by endogenous ARF.	SIGNOR-134781
P56524	P49841	0	phosphorylation	down-regulates	0.364	The double mutation of serines 298/302 into alanines, but also the sole mutation of serine 302, abolishes hdac4 phosphorylation by gsk3_we have shown that cells lacking gsk3_ are unable to degrade hdac4 after serum starvation	SIGNOR-170144
P62753	P23443	0	phosphorylation	up-regulates activity	0.937	A knockin mouse carrying mutations at all phosphorylation sites in the primary s6k substrate, ribosomal protein s6 (rps6), has provided insight into the physiological role of this protein phosphorylation event. Of the many known substrates of s6k1, it is rps6 that has been shown to be directly involved, via its phosphorylation, in controlling cell size.	SIGNOR-135176
P28482	P15056	1	phosphorylation	down-regulates activity	0.628	Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity.	SIGNOR-236388
P05771	P67775	0	dephosphorylation	down-regulates activity	0.446	Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme.	SIGNOR-248620
P36873	P05198	1	dephosphorylation	up-regulates activity	0.412	Dephosphorylation of eIF2Î± is central to ISR signal termination to restore protein synthesis and normal cell functioning. It is mediated by protein phosphatase 1 (PP1) complex that recruits a PP1 catalytic subunit (PP1c) and one of the two regulatory subunits. In mammals, phosphatase activity is regulated by either PPP1R15A (also known as growth arrest and DNA damageâ€inducible protein, GADD34), which is induced as part of the ISR. the GADD34â€“PP1 complex acts as an important negative feedback loop to restore protein synthesis once the ER stress has been resolved, and as such aids in cell survival	SIGNOR-254119
P17535	P28482	0	phosphorylation	up-regulates	0.529	Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase.	SIGNOR-196030
P53350	Q8TEP8	1	phosphorylation	up-regulates activity	0.608	In the presence of AurA binding, Plk1 preferentially phosphorylates and interacts with the T44 motif of Cep192 through the “self-priming and binding” mechanism	SIGNOR-266405
P53350	Q8NHV4	1	phosphorylation	up-regulates activity	0.619	Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation.	SIGNOR-272992
Q6ZN17	Q2Q1W2	0	polyubiquitination	down-regulates quantity by destabilization	0.527	In cells, TRIM71 negatively regulates Lin28B protein stability by catalyzing polyubiquitination.	SIGNOR-272054
Q9Y570	Q14012	0	phosphorylation	up-regulates activity	0.395	CaMKI Is the Upstream Kinase for Phosphorylation of PME-1/Ser15	SIGNOR-277827
P22681	P06239	1	polyubiquitination	down-regulates quantity by destabilization	0.711	Coexpression in 293T cells demonstrated that Lck kinase activity and Cbl ubiquitin ligase activity were essential for Lck ubiquitination and negative regulation of Lck-dependent serum response element-luciferase reporter activity. The Lck SH3 domain was pivotal for Cbl-Lck association and Cbl-mediated Lck degradation, with a smaller role for interactions mediated by the Cbl tyrosine kinase-binding domain.	SIGNOR-272614
P26358	Q01860	0	transcriptional regulation	up-regulates quantity by expression	0.437	Oct4 and Nanog upregulate Dnmt1 through direct binding to its promoter, thereby leading to the repressed expression of p16 and p21 and genes associated with development and lineage differentiation	SIGNOR-253158
Q01196	Q03014	1	transcriptional regulation	up-regulates quantity	0.271	We identified Hhex as a direct target of RUNX1 and FLT3-ITD stimulation and confirmed high HHEX expression in FLT3-ITD AMLs. HHEX could replace RUNX1 in cooperating with FLT3-ITD to induce AML.	SIGNOR-256305
Q00535	P48729	0	phosphorylation	up-regulates activity	0.297	We also show that casein kinase I, but not casein kinase II, can phosphorylate and activate cdk5 in vitro. Ser(159) in cdk5 is homologous to the regulatory Thr(160) in cdk2.	SIGNOR-275966
P28749	P11802	0	phosphorylation	up-regulates activity	0.807	Here we assessed the effects of alanine substitution at the individual or combined Cdk4(6)-specific sites in p130, compared with homologous sites in p107 (Thr(369)/Ser(650)/Ser(964)). In U-2-OS cells, the triple p107(DeltaCdk4)* mutant strongly inhibited E2F-4 activity and imposed a G(1) arrest resistant to cyclin D1 coexpression.	SIGNOR-250764
Q12923	Q9BUL8	1	dephosphorylation	down-regulates activity	0.567	In addition, our yeast two-hybrid analysis revealed that CCM3 also binds to the 270-kDa nonreceptor protein tyrosine phos- phatase FAP-1 in a region predicted to contain the C- terminal phosphatase domain [23]. We have shown that this catalytic domain is capable to dephosphorylate CCM3. By dephosphorylation, FAP-1 might therefore negatively reg- ulate CCM3 activity and downstream signaling.	SIGNOR-248714
P41235	Q13131	0	phosphorylation	down-regulates activity	0.285	Here we demonstrate that ampk directly phosphorylates hnf4 and represses its transcriptional activity. Ampk-mediated phosphorylation of hnf4 on serine 304 had a 2-fold effect	SIGNOR-101101
O14965	Q9Y448	1	phosphorylation	down-regulates activity	0.261	The protein astrin has been shown to remove Kif2b from kinetochores in metaphase through competitive binding of CLASP1 (Manning et al., 2010 blue right-pointing triangle). During prometaphase, Aurora B kinase activity prevents astrin from localizing to kinetochores (Manning et al., 2010 blue right-pointing triangle; Schmidt et al., 2010 blue right-pointing triangle). This permits Kif2b to localize to kinetochores to destabilize k-MT attachments to execute error correction through Plk1-dependent recruitment and activation.	SIGNOR-252052
O60825	P23443	0	phosphorylation	up-regulates activity	0.247	Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b.	SIGNOR-49371
Q14934	Q08209	0	dephosphorylation	up-regulates	0.566	Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat.	SIGNOR-176379
P30307	P27348	0	relocalization	down-regulates	0.575	Cdc25c: nuclear exclusion/cytoplasmic sequestration via binding to 14-3-3 proteins.	SIGNOR-163237
O15350	P00519	0	phosphorylation	up-regulates	0.754	C-abl phosphorylates p73 on a tyrosine residue at position 99 both in vitro and in cells that have been exposed to ionizing radiation. Our results show that c-abl stimulates p73-mediated transactivation and apoptosis.	SIGNOR-68931
Q93073	O14965	0	phosphorylation	up-regulates quantity	0.2	To explore the underlying mechanisms, we found that SLAN, a potential tumor suppressor, served as a substrate of Aurora-A and knockdown of SLAN induced immature cytokinesis. Aurora-A phosphorylates SLAN at T573 under the help of the scaffold protein 14-3-3η. Intriguingly, SLAN T573D or T573E inactivated and T573A activated the key cytokinesis regulator RhoA.	SIGNOR-273547
P04637	Q92570	1	transcriptional regulation	up-regulates quantity by expression	0.264	We showed that p53 directly bound the promoter of NR4A3 gene and induced its transcription. p53 transactivates the NR4A3 promoter in H1299 cells.	SIGNOR-256200
Q5JUK2	P21754	1	transcriptional regulation	up-regulates quantity by expression	0.378	Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters.	SIGNOR-266078
P43403	P06239	0	phosphorylation	up-regulates activity	0.619	We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck	SIGNOR-249375
P36956	P49841	0	phosphorylation	down-regulates quantity by destabilization	0.485	Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1.	SIGNOR-236667
Q06609	O14757	0	phosphorylation	up-regulates	0.843	We demonstrate that chk1 interacts with rad51, and that rad51 is phosphorylated on thr 309 in a chk1-dependent manner	SIGNOR-133375
P62136	Q9GZV5	1	dephosphorylation	up-regulates activity	0.542	PP1A dephosphorylates TAZ at Ser-89 and Ser-311, promotes TAZ nuclear translocation, and stabilizes TAZ by disrupting the binding to the SCF E3 ubiquitin ligase.	SIGNOR-277116
P06400	Q00987	0	ubiquitination	down-regulates quantity by destabilization	0.667	In this study, we found that Mdm2, a ubiquitin ligase for p53, promoted ubiquitin-dependent degradation of pRB	SIGNOR-278530
Q06413	P12882	1	transcriptional regulation	up-regulates quantity by expression	0.383	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238754
Q9UQK1	O95278	0	dephosphorylation	up-regulates quantity by stabilization	0.749	We have recently described that the activity of R5/PTG is down-regulated by the laforin-malin complex, composed of a dual specificity phosphatase (laforin) and an E3-ubiquitin ligase (malin). We now demonstrate that phosphorylation of R5/PTG at Ser-8 by AMPK accelerates its laforin/malin-dependent ubiquitination and subsequent proteasomal degradation, which results in a decrease of its glycogenic activity.	SIGNOR-276239
Q9NRD5	P78348	1	relocalization	up-regulates activity	0.537	we found that the PDZ domain-containing protein PICK1 (protein interacting with C kinase) interacts specifically with the C-termini of BNC1 and ASIC. Our studies showing association of recombinant PICK1 with ASIC and BNC1, and the presence of both PICK1 and ASIC in the synaptosomal fraction	SIGNOR-223417
Q92945	P31751	0	phosphorylation	down-regulates	0.343	AKT phosphorylates the mRNA decay-promoting factor KSRP at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents KSRP interaction with the exoribonucleolytic complex exosome. This impairs KSRPs ability to promote rapid mRNA decay.	SIGNOR-151220
P04637	P62140	0	dephosphorylation	down-regulates activity	0.286	Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities\|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.	SIGNOR-248572

P10636

P17655

0

cleavage

down-regulates activity

0.433

Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains

SIGNOR-251611

Q9BT81

Q9HCK8

0

transcriptional regulation

down-regulates quantity

0.2

Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells

SIGNOR-268922

P31749

Q8TDD2

1

phosphorylation

up-regulates

0.423

Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5

SIGNOR-252514

P51812

P31749

0

phosphorylation

down-regulates activity

0.265

Akt interacts with and phosphorylates RSK2 at S19.

SIGNOR-277548

P12931

Q14247

1

phosphorylation

down-regulates activity

0.801

Erk phosphorylation and a mimicking S405,418D double mutation enhanced cortactin binding and activation of N-WASP. In contrast, Src phosphorylation inhibited the ability of cortactin previously phosphorylated by Erk, and that of S405,418D double mutant cortactin, to bind and activate N-WASP. Furthermore, Y-->D mutation of three tyrosine residues targeted by Src (Y421, Y466, and Y482) inhibited the ability of S405,418D cortactin to activate N-WASP.

SIGNOR-246513

Q9NP31

P06239

0

phosphorylation

up-regulates activity

0.578

Here we mapped Lck phosphorylation and interaction sites on TSAd and evaluated their functional importance. The three C-terminal TSAd tyrosines Tyr(280), Tyr(290), and Tyr(305) were phosphorylated by Lck and functioned as docking sites for the Lck Src homology 2 (SH2) domain. Lck binds to TSAd prolines and phosphorylates and interacts with the three C-terminal TSAd tyrosines. We propose that through multivalent interactions with Lck, TSAd diverts Lck from phosphorylating other substrates, thus modulating its functional activity through substrate competition.

SIGNOR-262888

P09884

Q7L590

0

relocalization

up-regulates quantity by stabilization

0.862

Mcm10 is an essential eukaryotic protein required for the initiation and elongation phases of chromosomal replication. Specifically, Mcm10 is required for the association of several replication proteins, including DNA polymerase alpha (pol alpha), with chromatin.

SIGNOR-261271

P23443

O60331

1

phosphorylation

down-regulates quantity by destabilization

0.2

Here we show that p70S6K1 (S6K1), a downstream target of mechanistic target of rapamycin (mTOR), phosphorylates PIPKIγ90 at Thr-553 and Ser-555 and that S6K1-mediated PIPKIγ90 phosphorylation is essential for cell migration and invasion. These data suggest that S6K1-mediated PIPKIγ90 phosphorylation regulates cell migration and invasion by controlling PIPKIγ90 degradation.

SIGNOR-277283

Q96PE2

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.549

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-260542

P63104

P45983

0

phosphorylation

down-regulates

0.371

Jnk phosphorylated 14-3-3 at ser-184 and 14-3-3 at ser-186 both in vitro and in vivo, and such phosphorylation reduced the affinity of 14-3-3 proteins for bax

SIGNOR-124020

P12830

Q5T0T0

0

ubiquitination

down-regulates quantity by destabilization

0.2

Inhibiting proteasome activity with MG132 prevented CDH1 and beta2M degradation, indicating that MARCH8 might be targeting CDH1 and beta2M for proteasomal degradation.|We demonstrated that MARCH8 interacts with and ubiquitinates CDH1 and beta2M.

SIGNOR-278820

P15056

P28482

0

phosphorylation

down-regulates activity

0.628

Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity.

SIGNOR-236388

Q96C90

Q05655

0

phosphorylation

up-regulates activity

0.2

Recombinant tagged PHI-1 was phosphorylated by protein kinase C at two sites, one a Ser and one a Thr; phosphorylation enhanced inhibitory potency 50-fold.

SIGNOR-265739

P53041

P04049

1

dephosphorylation

down-regulates activity

0.462

Protein phosphatase 5 (PP5) was identified as an inactivator that associates with Raf-1 on growth factor stimulation and selectively dephosphorylates an essential activating site, Ser 338. The PP5-mediated dephosphorylation of Ser 338 inhibited Raf-1 activity and downstream signalling to MEK

SIGNOR-248537

Q96R06

O14965

0

phosphorylation

up-regulates activity

0.511

We report here that Astrin acts as a mitotic phosphoprotein, and Aurora-A phosphorylates Astrin at Ser(115). The phosphorylation-deficient mutant Astrin S115A abnormally activates spindle assembly checkpoint and delays mitosis progression, decreases spindle stability, and induces chromosome misalignment. Mechanistic analyses reveal that Astrin phosphorylation mimicking mutant S115D, instead of S115A, binds and induces ubiquitination and degradation of securin, which sequentially activates Separase, an enzyme required for the separation of sister chromatids.

SIGNOR-276648

P78368

O14654

1

phosphorylation

down-regulates quantity by destabilization

0.2

IRS4 was phosphorylated at Ser859 by CK1γ2 in vitro and in vivo, which promoted the polyubiquitination and degradation of IRS4 through the ubiquitin/lysosome pathway by the carboxyl terminus of Hsc70-interacting protein(CHIP).

SIGNOR-277615

P54646

O14920

1

phosphorylation

up-regulates

0.257

These results demonstrate that the ikk is a direct substrate of ampk_2 and that its phosphorylation on ser177 and ser181no initiates the activation of the ampk_2 in endothelial cells which in turn phosphorylates and activates the _-subunit of the ikk. The latter also induces a higher rate of ikk auto-inactivation and thus attenuates the activation of nf_b and the expression of inflammatory genes

SIGNOR-174405

Q13418

P23528

1

phosphorylation

down-regulates

0.35

Actin (de)polymerization is regulated by cofilin, the ser(3) phosphorylation (ps(3)cofilin) of which inhibits its actin-severing activity. To determine how ilk regulates ps(3)cofilin, we examined the effects of ilk on ps(3)cofilin using normal rie1 cells.

SIGNOR-160756

P28328

P50542

1

ubiquitination

down-regulates quantity by destabilization

0.579

Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle.

SIGNOR-253021

Q5S007

O00429

1

phosphorylation

up-regulates activity

0.568

LRRK2 G2019S directly bound to and phosphorylated Drp1 at Threonine595, whereas P110 treatment abolished this phosphorylation.Threonine595 phosphorylation of Drp1 by LRRK2 G2019S is required for Drp1-mediated mitochondrial fragmentation and excessive autophagy

SIGNOR-276495

Q92888

O60674

0

phosphorylation

up-regulates

0.325

We found that angiotensin ii activates arhgef1 through a previously undescribed mechanism in which jak2 phosphorylates tyr738 of arhgef1

SIGNOR-163557

P19429

P05129

0

phosphorylation

down-regulates

0.2

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

SIGNOR-134632

O43236

O15033

0

ubiquitination

down-regulates quantity by destabilization

0.2

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

SIGNOR-267670

P04275

P09958

0

cleavage

up-regulates activity

0.481

Like PACE,PACE4 was able to process pro-vWF to its mature form, and efficient cleavage required both the P4 arginine and the P2 lysine

SIGNOR-260368

P14866

Q16566

0

phosphorylation

up-regulates

0.379

Here we show that the regulation of the stress axis-regulated exon of the slo1 potassium channel transcripts by membrane depolarization requires a highly conserved camkiv target serine (ser-513) of the heterogeneous ribonucleoprotein l. Ser-513 phosphorylation within the rna recognition motif 4 enhanced heterogeneous ribonucleoprotein l interaction with the camkiv-responsive rna element 1 of stress axis-regulated exon and inhibited binding of the large subunit of the u2 auxiliary factor u2af65.

SIGNOR-197367

P20618

Q05086

0

ubiquitination

down-regulates quantity by destabilization

0.355

Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits.

SIGNOR-265131

P49593

O43318

1

dephosphorylation

down-regulates activity

0.395

However, our current work shows that POPX2 can downregulate TAK1 and affect the anti-apoptotic activities of TAK1, implying that silencing POPX2 could facilitate TAK1 activation and will lead to increased cell survival.|We have also demonstrated that POPX2 can directly dephosphorylate TAK1 (XREF_FIG).

SIGNOR-277047

Q16539

O15519

1

phosphorylation

up-regulates

0.373

Here we demonstrate that m. tuberculosis?induced Tnf triggered reactive oxygen species?dependent Activation of ask1 and the tyrosine kinase c-abl (a000161) in mouse macrophages and that flips was phosphorylated on tyr211 and ser4 by c-abl and p38, respectively.

SIGNOR-187001

Q13158

O14965

0

phosphorylation

up-regulates

0.343

Here, we report that aur-a phosphorylates s203 of the fas associated with death domain protein (fadd)phosphorylation of s203 by aur-a serves to prime fadd for plk1-mediated phosphorylation at s194

SIGNOR-176739

P27361

P10828

1

phosphorylation

down-regulates activity

0.428

We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay.

SIGNOR-102224

O75969

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-272955

Q92905

O14920

0

phosphorylation

down-regulates activity

0.33

Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro.

SIGNOR-275519

Q15796

Q15759

0

phosphorylation

down-regulates

0.352

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

SIGNOR-167848

Q15797

O95257

1

transcriptional regulation

up-regulates quantity

0.2

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

SIGNOR-268937

P41252

Q2TAL8

0

transcriptional regulation

up-regulates quantity by expression

0.2

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

SIGNOR-269406

P07949

P28482

1

phosphorylation

up-regulates

0.423

We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1).

SIGNOR-140294

P00519

P22681

0

ubiquitination

down-regulates quantity by destabilization

0.614

We found that while c-cbl e3 ligase induced ubiquitin-dependent degradation of mature and phosphorylated bcr-abl proteins

SIGNOR-167194

Q09472

Q05655

0

phosphorylation

down-regulates

0.366

Inhibition of histone acetyltransferase function of p300 by pkcdeltawe found that pkcdelta but not classical pkc, specifically phosphorylates p300 at serine 89 in vitro and in vivo. This phosphorylation causes inhibition of p300 intrinsic hat activity.

SIGNOR-94263

Q13153

P36871

1

phosphorylation

up-regulates

0.343

The signaling kinase p21-activated kinase 1 (pak1) binds to, phosphorylates and enhances the enzymatic activity of phosphoglucomutase 1 (pgm),

SIGNOR-127135

P51636

P12931

0

phosphorylation

down-regulates

0.676

Here, we show that cav-2 is phosphorylated at both tyrosines 19 and 27. We reconstituted this phosphorylation event by recombinantly coexpressing c-src and cav-2.Further functional analysis revealed that tyrosine phosphorylation of cav-2 has no effect on its targeting to lipid rafts, but clearly disrupts the hetero-oligomerization of cav-2 with cav-1.

SIGNOR-129961

P19544

P15514

1

transcriptional regulation

up-regulates quantity by expression

0.396

The Wilms Tumor Suppressor WT1 Encodes a Transcriptional Activator of amphiregulin

SIGNOR-251745

P46527

Q13131

0

phosphorylation

up-regulates quantity by stabilization

0.267

P27Kip1-Mediated Cell Survival Is Dependent on AMPK-Specific Thr198 Phosphorylation|AMPK-dependent phosphorylation of p27Kip1 on Thr198 promotes p27Kip1 protein stability, resulting in more autophagy and less apoptosis.

SIGNOR-259859

P35222

Q9UI47

0

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

Q05586

P17252

0

phosphorylation

up-regulates activity

0.417

Serines 890 and 896 of the NMDA receptor subunit NR1 are differentially phosphorylated by protein kinase C isoforms. The results show that PKC alpha phosphorylates preferentially S896 and PKC gamma preferentially S890.

SIGNOR-263177

Q9BZR9

O43318

1

polyubiquitination

up-regulates activity

0.343

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

SIGNOR-271890

P46527

Q9Y463

0

phosphorylation

up-regulates

0.355

Mirk phosphorylates p27 at ser-10, thus stabilizing p27 and blocking its nuclear export and degradation

SIGNOR-235805

P46531

P49841

0

phosphorylation

up-regulates

0.463

Here, we observed that gsk3beta was able to bind and phosphorylate notch1ic in vitro, and attenuation of gsk3beta activity reduced phosphorylation of notchic in vivo.Functionally, ligand-activated signaling through the endogenous notch1 receptor was reduced in gsk3beta fibroblasts, implying a positive role for gsk3beta in mammalian notch signaling.

SIGNOR-90608

P00736

P68400

0

phosphorylation

down-regulates activity

0.307

We provide evidence that this kinase phosphorylates Clr at the level of Ser189. | Accessibility of Ser189 was low in intact C1r, due in part to the presence of one of the oligosaccharides borne by the alpha region, further reduced in the presence of calcium, and abolished when C1r was incorporated into the C1s-C1r-C1r-C1s tetramer or the C1 complex.

SIGNOR-250833

O14579

Q96PM5

0

polyubiquitination

down-regulates quantity by destabilization

0.471

PIRH2 promotes the ubiquitylation of epsilon-COP in vitro and in vivo and consequently promotes the degradation of epsilon-COP.

SIGNOR-272630

Q13480

Q06124

0

dephosphorylation

down-regulates activity

0.952

These results suggest that Tyr(P)-627 and Tyr(P)-659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) that binds and activates SHP2.|Thus, physical association of activated SHP2 with Gab1 is necessary and sufficient to mediate the ERK mitogen-activated protein kinase activation. Phosphopeptides derived from Gab1 were dephosphorylated by active SHP2 in vitro.

SIGNOR-248674

Q8IXL6

P10451

1

phosphorylation

down-regulates quantity

0.683

OPN phosphorylation by Fam20C decreased OPN secretion, and OPN neutralization reduced Fam20C-deficiency-induced osteoclast differentiation and bone metastasis.

SIGNOR-278936

Q08050

P53350

0

phosphorylation

up-regulates

0.705

It has been reported that plk1 could directly phosphorylate foxm1 at ser-715 and ser-724 for full activation and proper mitotic progression

SIGNOR-187892

P84022

P78368

0

phosphorylation

down-regulates

0.337

Cki?2 Directly phosphorylates smad3 at ser418, leading to the increased ubiquitination and proteasomal degradation of activated smad3 following tgf-? Treatment.

SIGNOR-181069

Q9UKV5

P11441

1

polyubiquitination

down-regulates activity

0.52

USP13 and gp78 control ubiquitination of Ubl4A.These data suggest that USP13 and gp78 play antagonizing roles in regulation of Ubl4A ubiquitination: While gp78 assembles ubiquitin chains on Ubl4A, USP13 antagonizes this activity to limit Ubl4A ubiquitination.Ubiquitination of Ubl4A preferentially occurs on Lys48. We identify the Bag6 cofactor Ubl4A as a shared substrate of gp78 and USP13. USP13 depletion is associated with hyper-ubiquitination of Ubl4A and altered interaction between the Bag6 complex and its co-chaperone SGTA. Because the interaction of Ubl4A with SGTA is mediated by positively-charged residues in Ubl4A including Lys48 (Chartron et al., 2012; Xu et al., 2012), which happens to be the major ubiquitination site, the simplest model to explain reduced Bag6-SGTA interaction in USP13 knockdown cells is that ubiquitin conjugates on Ubl4A sterically hinder SGTA binding.

SIGNOR-272856

O43318

P46937

1

phosphorylation

down-regulates activity

0.338

TAK1 inhibits YAP activity through beta-TRCP.|Thus, our data indicate that TAK1 directly phosphorylates YAP at multiple sites.|These observations prompted us to test whether TAK1 phosphorylates YAP at S127.

SIGNOR-278956

P17252

P22681

1

phosphorylation

down-regulates quantity

0.322

However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway.

SIGNOR-249056

P17612

P53396

1

phosphorylation

up-regulates activity

0.309

Phosphorylation of Recombinant Human ATP:Citrate Lyase by cAMP-Dependent Protein Kinase Abolishes Homotropic Allosteric Regulation of the Enzyme by Citrate and Increases the Enzyme Activity. Ser 454, which is phosphorylated by the catalytic subunit of cAMP-dependent protein kinase (PKA)

SIGNOR-250328

P00519

Q00987

1

phosphorylation

down-regulates activity

0.716

C-abl binds and phosphorylates mdm2 in vivo and in vitro;phosphorylation of mdm2 by c-abl impairs the inhibition of p53 by mdm2.

SIGNOR-90512

P25098

P05387

1

phosphorylation

up-regulates

0.2

The phosphorylation sites in grk2-phosphorylated p2 are identified (s102 and s105) and are identical to the sites known to regulate p2 activity.

SIGNOR-94254

Q8IW41

Q99497

1

phosphorylation

up-regulates activity

0.469

PRAK preferentially colocalizes with DJ-1 and leads to DJ-1 activation, which in turn facilitates DJ-1 to sequester Daxx in the nucleus, preventing oxidative stress induced cell death.|These data clearly demonstrate a PRAK dependent phosphorylation of DJ-1.

SIGNOR-279746

Q14457

Q13043

0

phosphorylation

up-regulates activity

0.312

These results suggest that Mst1 directly stimulates interaction between Beclin1 and Bcl-2.|We here demonstrate that Mst1-induced phosphorylation of Beclin1 in its BH3 domain at Thr 108 promotes binding of Beclin1 with Bcl-2/Bcl-xL.

SIGNOR-278502

P21860

Q9H4P4

0

polyubiquitination

down-regulates quantity by destabilization

0.691

Nrdp1/FLRF is a ubiquitin ligase promoting ubiquitination and degradation of the epidermal growth factor receptor family member, ErbB3

SIGNOR-272599

Q14680

Q99683

1

phosphorylation

up-regulates activity

0.271

MELK, as an upstream kinase of ASK1, phosphorylates threonine 838 in an activation loop of human ASK1, thereby stimulating ASK1 kinase activity.

SIGNOR-280039

Q00987

P41240

0

phosphorylation

up-regulates activity

0.2

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

SIGNOR-279163

Q13535

Q8N726

0

phosphorylation

up-regulates activity

0.391

Regulation of NF-kappaB and p53 through activation of ATR and Chk1 by the ARF tumour suppressorInduction of ATR activity in Hs68 E2F1ER cells by endogenous ARF.

SIGNOR-134781

P56524

P49841

0

phosphorylation

down-regulates

0.364

The double mutation of serines 298/302 into alanines, but also the sole mutation of serine 302, abolishes hdac4 phosphorylation by gsk3_we have shown that cells lacking gsk3_ are unable to degrade hdac4 after serum starvation

SIGNOR-170144

P62753

P23443

0

phosphorylation

up-regulates activity

0.937

A knockin mouse carrying mutations at all phosphorylation sites in the primary s6k substrate, ribosomal protein s6 (rps6), has provided insight into the physiological role of this protein phosphorylation event. Of the many known substrates of s6k1, it is rps6 that has been shown to be directly involved, via its phosphorylation, in controlling cell size.

SIGNOR-135176

P28482

P15056

1

phosphorylation

down-regulates activity

0.628

Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity.

SIGNOR-236388

P05771

P67775

0

dephosphorylation

down-regulates activity

0.446

Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme.

SIGNOR-248620

P36873

P05198

1

dephosphorylation

up-regulates activity

0.412

Dephosphorylation of eIF2Î± is central to ISR signal termination to restore protein synthesis and normal cell functioning. It is mediated by protein phosphatase 1 (PP1) complex that recruits a PP1 catalytic subunit (PP1c) and one of the two regulatory subunits. In mammals, phosphatase activity is regulated by either PPP1R15A (also known as growth arrest and DNA damageâ€inducible protein, GADD34), which is induced as part of the ISR. the GADD34â€“PP1 complex acts as an important negative feedback loop to restore protein synthesis once the ER stress has been resolved, and as such aids in cell survival

SIGNOR-254119

P17535

P28482

0

phosphorylation

up-regulates

0.529

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

SIGNOR-196030

P53350

Q8TEP8

1

phosphorylation

up-regulates activity

0.608

In the presence of AurA binding, Plk1 preferentially phosphorylates and interacts with the T44 motif of Cep192 through the “self-priming and binding” mechanism

SIGNOR-266405

P53350

Q8NHV4

1

phosphorylation

up-regulates activity

0.619

Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation.

SIGNOR-272992

Q6ZN17

Q2Q1W2

0

polyubiquitination

down-regulates quantity by destabilization

0.527

In cells, TRIM71 negatively regulates Lin28B protein stability by catalyzing polyubiquitination.

SIGNOR-272054

Q9Y570

Q14012

0

phosphorylation

up-regulates activity

0.395

CaMKI Is the Upstream Kinase for Phosphorylation of PME-1/Ser15

SIGNOR-277827

P22681

P06239

1

polyubiquitination

down-regulates quantity by destabilization

0.711

Coexpression in 293T cells demonstrated that Lck kinase activity and Cbl ubiquitin ligase activity were essential for Lck ubiquitination and negative regulation of Lck-dependent serum response element-luciferase reporter activity. The Lck SH3 domain was pivotal for Cbl-Lck association and Cbl-mediated Lck degradation, with a smaller role for interactions mediated by the Cbl tyrosine kinase-binding domain.

SIGNOR-272614

P26358

Q01860

0

transcriptional regulation

up-regulates quantity by expression

0.437

Oct4 and Nanog upregulate Dnmt1 through direct binding to its promoter, thereby leading to the repressed expression of p16 and p21 and genes associated with development and lineage differentiation

SIGNOR-253158

Q01196

Q03014

1

transcriptional regulation

up-regulates quantity

0.271

We identified Hhex as a direct target of RUNX1 and FLT3-ITD stimulation and confirmed high HHEX expression in FLT3-ITD AMLs. HHEX could replace RUNX1 in cooperating with FLT3-ITD to induce AML.

SIGNOR-256305

Q00535

P48729

0

phosphorylation

up-regulates activity

0.297

We also show that casein kinase I, but not casein kinase II, can phosphorylate and activate cdk5 in vitro. Ser(159) in cdk5 is homologous to the regulatory Thr(160) in cdk2.

SIGNOR-275966

P28749

P11802

0

phosphorylation

up-regulates activity

0.807

Here we assessed the effects of alanine substitution at the individual or combined Cdk4(6)-specific sites in p130, compared with homologous sites in p107 (Thr(369)/Ser(650)/Ser(964)). In U-2-OS cells, the triple p107(DeltaCdk4)* mutant strongly inhibited E2F-4 activity and imposed a G(1) arrest resistant to cyclin D1 coexpression.

SIGNOR-250764

Q12923

Q9BUL8

1

dephosphorylation

down-regulates activity

0.567

In addition, our yeast two-hybrid analysis revealed that CCM3 also binds to the 270-kDa nonreceptor protein tyrosine phos- phatase FAP-1 in a region predicted to contain the C- terminal phosphatase domain [23]. We have shown that this catalytic domain is capable to dephosphorylate CCM3. By dephosphorylation, FAP-1 might therefore negatively reg- ulate CCM3 activity and downstream signaling.

SIGNOR-248714

P41235

Q13131

0

phosphorylation

down-regulates activity

0.285

Here we demonstrate that ampk directly phosphorylates hnf4 and represses its transcriptional activity. Ampk-mediated phosphorylation of hnf4 on serine 304 had a 2-fold effect

SIGNOR-101101

O14965

Q9Y448

1

phosphorylation

down-regulates activity

0.261

The protein astrin has been shown to remove Kif2b from kinetochores in metaphase through competitive binding of CLASP1 (Manning et al., 2010 blue right-pointing triangle). During prometaphase, Aurora B kinase activity prevents astrin from localizing to kinetochores (Manning et al., 2010 blue right-pointing triangle; Schmidt et al., 2010 blue right-pointing triangle). This permits Kif2b to localize to kinetochores to destabilize k-MT attachments to execute error correction through Plk1-dependent recruitment and activation.

SIGNOR-252052

O60825

P23443

0

phosphorylation

up-regulates activity

0.247

Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b.

SIGNOR-49371

Q14934

Q08209

0

dephosphorylation

up-regulates

0.566

Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat.

SIGNOR-176379

P30307

P27348

0

relocalization

down-regulates

0.575

Cdc25c: nuclear exclusion/cytoplasmic sequestration via binding to 14-3-3 proteins.

SIGNOR-163237

O15350

P00519

0

phosphorylation

up-regulates

0.754

C-abl phosphorylates p73 on a tyrosine residue at position 99 both in vitro and in cells that have been exposed to ionizing radiation. Our results show that c-abl stimulates p73-mediated transactivation and apoptosis.

SIGNOR-68931

Q93073

O14965

0

phosphorylation

up-regulates quantity

0.2

To explore the underlying mechanisms, we found that SLAN, a potential tumor suppressor, served as a substrate of Aurora-A and knockdown of SLAN induced immature cytokinesis. Aurora-A phosphorylates SLAN at T573 under the help of the scaffold protein 14-3-3η. Intriguingly, SLAN T573D or T573E inactivated and T573A activated the key cytokinesis regulator RhoA.

SIGNOR-273547

P04637

Q92570

1

transcriptional regulation

up-regulates quantity by expression

0.264

We showed that p53 directly bound the promoter of NR4A3 gene and induced its transcription. p53 transactivates the NR4A3 promoter in H1299 cells.

SIGNOR-256200

Q5JUK2

P21754

1

transcriptional regulation

up-regulates quantity by expression

0.378

Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters.

SIGNOR-266078

P43403

P06239

0

phosphorylation

up-regulates activity

0.619

We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck

SIGNOR-249375

P36956

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.485

Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1.

SIGNOR-236667

Q06609

O14757

0

phosphorylation

up-regulates

0.843

We demonstrate that chk1 interacts with rad51, and that rad51 is phosphorylated on thr 309 in a chk1-dependent manner

SIGNOR-133375

P62136

Q9GZV5

1

dephosphorylation

up-regulates activity

0.542

PP1A dephosphorylates TAZ at Ser-89 and Ser-311, promotes TAZ nuclear translocation, and stabilizes TAZ by disrupting the binding to the SCF E3 ubiquitin ligase.

SIGNOR-277116

P06400

Q00987

0

ubiquitination

down-regulates quantity by destabilization

0.667

In this study, we found that Mdm2, a ubiquitin ligase for p53, promoted ubiquitin-dependent degradation of pRB

SIGNOR-278530

Q06413

P12882

1

transcriptional regulation

up-regulates quantity by expression

0.383

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

SIGNOR-238754

Q9UQK1

O95278

0

dephosphorylation

up-regulates quantity by stabilization

0.749

We have recently described that the activity of R5/PTG is down-regulated by the laforin-malin complex, composed of a dual specificity phosphatase (laforin) and an E3-ubiquitin ligase (malin). We now demonstrate that phosphorylation of R5/PTG at Ser-8 by AMPK accelerates its laforin/malin-dependent ubiquitination and subsequent proteasomal degradation, which results in a decrease of its glycogenic activity.

SIGNOR-276239

Q9NRD5

P78348

1

relocalization

up-regulates activity

0.537

we found that the PDZ domain-containing protein PICK1 (protein interacting with C kinase) interacts specifically with the C-termini of BNC1 and ASIC. Our studies showing association of recombinant PICK1 with ASIC and BNC1, and the presence of both PICK1 and ASIC in the synaptosomal fraction

SIGNOR-223417

Q92945

P31751

0

phosphorylation

down-regulates

0.343

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

SIGNOR-151220

P04637

P62140

0

dephosphorylation

down-regulates activity

0.286

Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.

SIGNOR-248572