GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P48048	P12931	0	phosphorylation	down-regulates	0.312	Inhibition of c-src with herbimycin a significantly decreased the tyrosine phosphorylation level of romk1... tyrosine dephosphorylation enhances the exocytosis of romk1	SIGNOR-97803
P06493	Q9HCH0	1	phosphorylation	down-regulates activity	0.2	Inhibiting Cdk1 with purvalanol A in nocodazole arrested cells increased fluorescent intensity of Cep169 at centrosomes relative to the value at the cytosol (2.36 +/- 0.12), while control cells indicated 1.13 +/- 0.03.\|Taken together, these results suggest that the Cdk1-dependent phosphorylation of Cep169 mediates the dissociation from centrosomes during mitosis.	SIGNOR-279144
P30305	O14965	0	phosphorylation	up-regulates	0.722	We show that bypass of the g2/m checkpoint by the chk1 kinase inhibitor ucn-01 results in the activation of aurora-a and phosphorylation of cdc25b on s353	SIGNOR-139396
P05067	P78536	0	cleavage	up-regulates activity	0.539	By the use of gene disruption (knockout), we now demonstrate that TACE (tumor necrosis factor alpha converting enzyme), a member of the ADAM family (a disintegrin and metalloprotease-family) of proteases, plays a central role in regulated alpha-cleavage of APP. Our data suggest that TACE may be the alpha-secretase responsible for the majority of regulated alpha-cleavage in cultured cells.	SIGNOR-262829
Q13315	Q99607	1	phosphorylation	down-regulates activity	0.349	Elf4 is phosphorylated by Atm after gamma irradiation, leading to its degradation.\|Thus, Atm promotes Elf4 protein degradation after gamma irradiation via phosphorylation at these sites.	SIGNOR-278466
Q99490	P06241	0	phosphorylation	up-regulates	0.467	We demonstrate that fyn is essential for phosphorylating pike-a and protects it from apoptotic cleavage. Active but not kinase-dead fyn interacts with pike-a and phosphorylates it on both y682 and y774 residues. Tyrosine phosphorylation in pike-a is required for its association with active fyn but not for akt. Mutation of d into a in pike-a protects it from caspase cleavage and promotes cell survival.	SIGNOR-147936
Q16539	P18031	0	dephosphorylation	down-regulates activity	0.443	Here, we show that PTP1B regulates CD40 and BAFF-R signaling and dephosphorylates the mitogen-activated protein kinase p38.\|Specifically, PTP1B counteracts p38 mitogen-activated protein kinase activation by directly dephosphorylating Tyr182 of this kinase.	SIGNOR-277167
P24821	P14921	0	transcriptional regulation	up-regulates quantity by expression	0.2	Sp1 and Ets1 are potent transactivators of the TN-C promoter.	SIGNOR-261599
P36871	Q13153	0	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
O00327	P31751	0	phosphorylation	down-regulates activity	0.358	Consistent with mass spectrometry results, constitutive active Akt2 (Akt2-CA) induced wild-type (WT) Bmal1 protein phosphorylation, which was abolished by a serine to alanine mutation at Ser42 residue (S42A) but not a S422A/S513A double mutation, as shown by immunoblot assay with phospho-Akt substrate antiserum ( xref ).\|In line with the in vivo results, overexpression of Akt2-CA strikingly lowered Bmal1 protein abundance in the nucleus in primary hepatocytes (XREF_FIG and XREF_SUPPLEMENTARY).	SIGNOR-280177
P43405	P12318	1	phosphorylation	up-regulates activity	0.673	To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and pointFyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation.	SIGNOR-247590
O60346	Q9Y243	1	dephosphorylation	down-regulates activity	0.648	The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.\|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells.	SIGNOR-248330
P08567	P17252	0	phosphorylation	up-regulates	0.28	To determine the role of pkc-dependent phosphorylation in pleckstrin function, we mapped the phosphorylation sites in vivo of wild-type and site-directed mutants of pleckstrin expressed in cos cells. Phosphorylation was found to occur almost exclusively on ser-113 and ser-117. Replacing all these sites with glycine decreased phosphorylation by > 90% and reduced pleckstrin's ability to inhibit phosphoinositide hydrolysis by as much as 80%.	SIGNOR-40048
Q6A1A2	O00141	1	phosphorylation	up-regulates	0.2	Our results are consistent with a model in which activation of sgk by igf-1 or hydrogen peroxide is initiated by a ptdins(3,4, 5)p3-dependent activation of pdk2, which phosphorylates ser422.	SIGNOR-66234
Q6UB99	Q9BR76	1	transcriptional regulation	up-regulates quantity by expression	0.2	Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons.	SIGNOR-266737
P17252	P29966	1	phosphorylation	down-regulates activity	0.73	Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin	SIGNOR-249650
P08069	P43250	0	phosphorylation	down-regulates quantity by destabilization	0.306	GRK2 and GRK6 coimmunoprecipitate with IGF-1R and increase IGF-1R serine phosphorylation, promoting β-arrestin1 association. Using immunoprecipitation, confocal microscopy, and FRET analysis, we demonstrated β-arrestin/IGF-1R association to be transient for GRK2 and stable for GRK6. Using bioinformatic studies we identified serines 1248 and 1291 as the major serine phosphorylation sites of the IGF-1R. Targeted mutation of S1248 recapitulates GRK2 modulation, whereas S1291 mutation resembles GRK6 effects on IGF-1R signaling/degradation	SIGNOR-276412
O95835	P46937	1	phosphorylation	down-regulates quantity by destabilization	0.84	We show that YAP is phosphorylated by Lats on Ser 381 in one of the HXRXXS motifs, and this phosphorylation provides the priming signal for CK1delta/epsilon to phosphorylate a phosphodegron in YAP. The phosphorylated phosphodegron recruits beta-TRCP, leading to YAP ubiquitination and degradation under conditions of elevated Hippo pathway activity, such as cell contact inhibition	SIGNOR-218034
P08559	Q9NTG7	0	deacetylation	down-regulates activity	0.48	SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells\|SIRT3 deacetylates PDHA1 lysine 321 (K321)	SIGNOR-267636
P53350	Q8N4N8	1	phosphorylation	up-regulates activity	0.66	We show that Plk1 directly phosphorylates Kif2b at threonine 125 (T125) and serine 204 (S204), and that these two sites differentially regulate Kif2b function. Phosphorylation of S204 is required for the kinetochore localization and activity of Kif2b in prometaphase, and phosphorylation of T125 is required for Kif2b activity in the correction of k-MT attachment errors.	SIGNOR-252049
O14965	P03372	1	phosphorylation	up-regulates activity	0.357	Based on these findings, we conclude that ER\u03b1-Ser167 and -Ser305 are phosphorylated by Aurora-A in vitro and in vivo .\|These data suggest that Aurora-A not only activates ER\u03b1 activity but also enhances E2 action and that Aurora-A-induced ER\u03b1 activation could not be inhibited by tamoxifen.	SIGNOR-278508
P41225	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-268920
P48729	Q969R2	1	phosphorylation	up-regulates activity	0.2	CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.\|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes.	SIGNOR-264877
Q8NHY2	O00763	1	ubiquitination	down-regulates quantity by destabilization	0.2	TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1. Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D).	SIGNOR-271599
Q14332	Q9ULT6	0	ubiquitination	down-regulates	0.292	Znrf3 is associated with the wnt receptor complex, and inhibits wntby promoting the turnover of frizzled and lrp6.	SIGNOR-197417
Q14653	P03209	0	transcriptional regulation	down-regulates quantity by repression	0.2	EBV Rta selectively down-regulates the expression of IRF3 and IRF7, the main regulators of the Type I IFNs.	SIGNOR-266644
Q9UHF1	Q86V15	0	transcriptional regulation	up-regulates quantity	0.425	We have recently demonstrated that a novel transcriptional pathway involving activation of the Epidermal Growth Factor-like Domain 7 (Egfl7) gene by the transcription factor CASTOR (CASZ1) is required for blood vessel assembly and lumen morphogenesis.	SIGNOR-266858
P06241	P14923	1	phosphorylation	up-regulates activity	0.561	Phosphorylation of plakoglobin by Fer and Fyn kinases decreases plakoglobin-desmoplakin interaction and increases plakoglobin-α-catenin association. Fyn mainly phosphorylated Tyr549 and that it phosphorylated Tyr133 with a much lower activity	SIGNOR-251176
P45983	P05067	1	phosphorylation	up-regulates	0.71	Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in sh-sy5y neuroblastoma cells. We found that the threonine 668 within the abetapp intracellular domain (aid or elsewhere aicd) is indeed phosphorylated by jnk1	SIGNOR-117852
P24844	O43293	0	phosphorylation	up-regulates	0.487	More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above.	SIGNOR-188789
Q5BJH7	P08908	1	relocalization	up-regulates activity	0.399	Together, our results provide strong evidence that Yif1B is a member of the ER/Golgi trafficking machinery, which plays a key role in specific targeting of 5-HT(1A)R to the neuronal dendrites. This finding opens up new pathways for the study of 5-HT(1A)R regulation by partner proteins and for the development of novel antidepressant drugs.\|We confirmed 5-HT(1A)R-Yif1B interaction by glutathione S-transferase pull-down experiments using rat brain extracts and transfected cell lines.	SIGNOR-268299
Q6U7Q0	P48730	0	phosphorylation	down-regulates quantity by destabilization	0.2	CK1delta and GSK3beta kinases sequentially phosphorylate ZNF322A at serine-396 and then serine-391. Moreover, the doubly phosphorylated ZNF322A protein creates a destruction motif for the ubiquitin ligase FBXW7alpha leading to ZNF322A protein destruction.	SIGNOR-264892
Q14207	P24941	0	phosphorylation	up-regulates	0.447	Importantly, mutation of cdk2 phosphorylation sites to alanine abrogates the ability of p220 to activate the histone h2b promoter.	SIGNOR-82141
Q15139	O15264	0	phosphorylation	down-regulates	0.2	P38delta catalyzes an inhibitory phosphorylation of pkd1, thereby attenuating stimulated insulin secretion.	SIGNOR-183280
P84022	P28482	0	phosphorylation	down-regulates activity	0.746	Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3	SIGNOR-161613
O14965	Q8WV24	1	phosphorylation	down-regulates quantity by destabilization	0.447	Aurora A directly phosphorylates PHLDA1 leading to its degradation. Aurora A phosphorylates PHLDA1 at Ser 98.	SIGNOR-273545
P48454	O00429	1	dephosphorylation	up-regulates activity	0.262	When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis.	SIGNOR-248506
P35240	Q96PU5	0	ubiquitination	up-regulates activity	0.261	Merlin ubiquitination is mediated by the E3 ubiquitin ligase, NEDD4L, which requires a scaffold protein, AMOTL1, to approach Merlin. Several NF2-patient-derived Merlin mutations disrupt its binding to AMOTL1 and its regulation by the AMOTL1-NEDD4L apparatus. Lysine (K) 396 is the major ubiquitin conjugation residue. Disruption of Merlin ubiquitination by the K396R mutation or NEDD4L depletion diminishes its binding to Lats1 and inhibits Lats1 activation. These effects are also accompanied by loss of Merlin's anti-mitogenic and tumor suppressive properties. Thus, we propose that dephosphorylation and ubiquitination compose an intramolecular relay to activate Merlin functions in activating the Hippo pathway during growth control.	SIGNOR-263662
Q08289	Q13557	0	phosphorylation	up-regulates	0.412	We recently identified ca(v)1.2 beta(2a) residues critical for camkii phosphorylation (thr 498) beta(2a) thr 498 and leu 493 are required for ca(v)1.2 activation by camkii in native cells.	SIGNOR-164067
Q12899	Q14653	1	polyubiquitination	down-regulates quantity by destabilization	0.672	TRIM26 bound to IRF3 and promoted its K48-linked polyubiquitination and degradation in nucleus.	SIGNOR-272440
P42224	O15111	0	phosphorylation	up-regulates activity	0.331	In addition, IKK\u03b1 also phosphorylated STAT1 in a type I IFN-independent manner [Fig 8, a dashed line (B)].	SIGNOR-279732
Q9HAW9	P20823	0	transcriptional regulation	up-regulates quantity by expression	0.281	Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter.	SIGNOR-253972
P23588	Q15418	0	phosphorylation	up-regulates	0.529	S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function.	SIGNOR-123993
O96017	Q2M385	1	phosphorylation	up-regulates activity	0.2	Chk2 phosphorylates Mps1-T288 after DNA damage.\|In the present study, we show that Chk2 stabilizes Mps1 protein and phosphorylates Aurora B-B-serine 331 to prevent mitotic exit in vertebrate cells when the majority of kinetochores are unattached.	SIGNOR-279160
Q05655	O95466	1	phosphorylation	up-regulates activity	0.27	PKC\u03b4 induces FMNL1 phosphorylation.	SIGNOR-279261
Q13315	P67775	0	dephosphorylation	down-regulates activity	0.333	Ionizing radiation induces autophosphorylation of the ataxia-telangiectasia mutated (ATM) protein kinase on serine 1981; however, the precise mechanisms that regulate ATM activation are not fully understood. Here, we show that the protein phosphatase inhibitor okadaic acid (OA) induces autophosphorylation of ATM on serine 1981 in unirradiated cells at concentrations that inhibit protein phosphatase 2A-like activity in vitro.	SIGNOR-248644
Q15139	Q12809	1	phosphorylation	down-regulates activity	0.2	Based on LC-MS results from in vivo and HEK293 cell experiments we chose four KV11.1 mutant candidates for further functional analysis. Ablation of the putative PKD phosphorylation site in the mutant S284A increased the maximal current indicating S284 as a main PKD target in KV11.1.	SIGNOR-277612
Q9BYT3	P28482	1	phosphorylation	up-regulates activity	0.273	In vitro kinase assay results indicated that STK33 can phosphorylate ERK2.\|STK33 phosphorylated ERK2 and increased the activity of ERK2 and promote the tumorigenesis of colorectal cancer HCT15 cells.	SIGNOR-279351
Q9Y4K3	P21580	0	deubiquitination	down-regulates activity	0.702	A20 is a deubiquitinating enzyme (dub) for lys63-linked polyubiquitinated signaling mediators such as traf6	SIGNOR-160223
P40763	P17706	0	dephosphorylation	down-regulates	0.735	The nuclear isoform of protein-tyrosine phosphatase tc-ptp regulates interleukin-6-mediated signaling pathway through stat3 dephosphorylation.	SIGNOR-90818
P23443	P23588	1	phosphorylation	up-regulates	0.776	S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function.	SIGNOR-123997
P68400	P06127	1	phosphorylation	up-regulates	0.342	In this study, we use jurkat t cell transfectants of cd5 cytoplasmic tail mutants to reveal phosphorylation sites relevant to signal transduction. Our results show that casein kinase ii (ckii) is responsible for the constitutive phosphorylation of cd5 molecules at a cluster of three serine residues located at the extreme c terminus (s458, s459, and s461)	SIGNOR-62311
O14920	Q9Y6Q9	1	phosphorylation	up-regulates activity	0.378	We demonstrated the in vitro phosphorylation of SRC-3 by the two catalytic subunits of the IKK complex, IKKα and IKKβ. IKK kinase activity is required for synergistic activation with SRC-3	SIGNOR-251298
O60674	Q9Y4C1	1	phosphorylation	up-regulates activity	0.2	KDM3A is tyrosine-phosphorylated by JAK2 in the nucleus and functions as a STAT3-dependent transcriptional coactivator. JAK2 phosphorylates KDM3A at tyrosine 1101 residue.	SIGNOR-277884
Q9BV40	Q86YJ5	0	ubiquitination	down-regulates quantity by destabilization	0.2	MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.	SIGNOR-271531
P09238	Q12948	0	transcriptional regulation	up-regulates quantity by expression	0.2	Therefore, FOXC1 is strongly suggested as a pro-metastatic gene in CRC by transcriptionally activating MMP10, SOX4 and SOX13\|MMP10 was demonstrated as the direct target and mediator of FOXC1.	SIGNOR-275915
Q12772	P04035	1	transcriptional regulation	up-regulates quantity by expression	0.492	The processed SREBP2, designated nuclear SREBP2 (nSREBP2), then enters the nucleus as a homodimer, binds to the sterol regulatory element (SRE) sequence in the promoters of target genes, including HMGCR and SQLE (encoding squalene monooxygenase), and upregulates their transcription	SIGNOR-265161
P53805	Q5S007	0	phosphorylation	up-regulates activity	0.371	LRRK2 Directly Phosphorylates RCAN1.	SIGNOR-278340
P31749	Q5S007	0	phosphorylation	up-regulates	0.379	Expression of wild-type LRRK2 promoted neuronal survival against apoptosis through activation of the downstream effector, Akt by phosphorylation of Ser473. Phosphorylated Akt in turn inhibited FOXO 1 signaling	SIGNOR-252598
P31751	P18031	1	phosphorylation	down-regulates activity	0.372	We conclude that ptp1b is a novel substrate for akt and that phosphorylation of ptp1b by akt at ser(50) may negatively modulate its phosphatase activity creating a positive feedback mechanism forinsulin signaling	SIGNOR-235491
P53004	P31749	0	phosphorylation	up-regulates activity	0.296	Site-directed mutagenesis, mass spectrometry, and kinetic analyses identified S(230) in hBVR (225)RNRYLSF sequence as the Akt1 target.	SIGNOR-275517
P17612	P16070	1	phosphorylation	up-regulates	0.2	Pka can phosphorylate ser316 directly cd44 s291a and s316a mutants may disrupt downstream signalling events by displacing endogenous cd44 from plasma membrane microdomains.	SIGNOR-147208
P00519	P07203	1	phosphorylation	up-regulates activity	0.459	GPx1 also functions as a substrate for c-Abl- and Arg-mediated phosphorylation on Tyr-96. The results further show that c-Abl and Arg stimulate GPx activity and that these kinases contribute to GPx-mediated protection of cells against oxidative stress.	SIGNOR-104324
Q12772	Q7KZF4	1	transcriptional regulation	up-regulates quantity by expression	0.342	These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression.	SIGNOR-259136
Q15672	P27361	0	phosphorylation	up-regulates	0.328	Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro	SIGNOR-173413
Q15078	P17655	0	cleavage	up-regulates activity	0.565	Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain	SIGNOR-251610
P61586	Q9NZN5	0	guanine nucleotide exchange factor	up-regulates activity	0.905	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-260539
Q14541	Q92819	1	transcriptional regulation	up-regulates quantity by expression	0.337	Transcription was activated by HNF4G in reporter assays using the promoter/enhancer region of the HAS2 gene. The endogenous expression of the HAS2 gene was suppressed by knockdown of HNF4G.	SIGNOR-261626
Q92974	Q13153	0	phosphorylation	down-regulates	0.353	We identify gef-h1 as a binding target and substrate for p21-activated kinase 1 (pak1), we show that phosphorylation of gef-h1 at ser(885) by pak1 induces 14-3-3 binding to the exchange factor and relocation of 14-3-3 to microtubules.	SIGNOR-187573
P06400	Q00532	0	phosphorylation	up-regulates activity	0.2	We also proved that as a downstream molecule of the P15 pathway, Rb is inhibited after CDKL1 knockdown. Rb is a well-known tumor suppressor in cell cycle regulation.28 Phosphorylation of Rb negatively regulates the cell cycle through E2F repression.29–31 However, Rb contains 13 conserved sites that are phosphorylated by the CDK–P15 complex in cycling cells and phosphorylation will cause site-specific and diverse conformational changes in the complex.32,33 Further studies need to be conducted to decipher the phosphorylated site of Rb related to CDKL1 knockdown.	SIGNOR-273863
P18031	P31751	0	phosphorylation	down-regulates activity	0.372	We conclude that ptp1b is a novel substrate for akt and that phosphorylation of ptp1b by akt at ser(50) may negatively modulate its phosphatase activity creating a positive feedback mechanism forinsulin signaling	SIGNOR-235491
Q99835	P23771	1	null	up-regulates activity	0.2	That GATA is a downstream effector of the hedgehog pathway.	SIGNOR-253527
P55957	Q9Y6C9	0	relocalization	up-regulates	0.303	Mtch2/mimp (mitochondrial carrier homologue 2/met-induced mitochondrial protein), a novel truncated bid (tbid)-interacting protein, is a surface-exposed outer mitochondrial membrane protein that facilitates the recruitment of tbid to mitochondria	SIGNOR-165081
P01100	P49675	1	transcriptional regulation	up-regulates quantity by expression	0.259	We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters.	SIGNOR-254878
P49841	Q14194	1	phosphorylation	up-regulates	0.47	Using in vitro kinase assays and pharmacological inhibition of gsk3 as described above for crmp2 and crmp4, it was found that thr509 (and presumably ser518 and thr514) of human crmp1 is phosphorylated by gsk3, following priming of ser522 by cdk5	SIGNOR-145999
P43405	P15311	1	phosphorylation	up-regulates activity	0.447	Phospho-SYK has also been shown to specifically activate ezrin upon CD81 engagement.\|We found that the activated SYK led to a time dependent phosphorylation of ezrin (pY354 and pThr567) and radixin (pThr564) (XREF_FIG).	SIGNOR-279129
P38435	P07225	1	carboxylation	up-regulates activity	0.613	Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z	SIGNOR-265924
P49841	P84022	1	phosphorylation	down-regulates quantity by destabilization	0.488	Mechanistically, axin facilitates gsk3-beta-mediated phosphorylation of smad3 at thr66, which triggers smad3 ubiquitination and degradation.	SIGNOR-160318
Q70Z35	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.406	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-260570
O15111	O15350	1	phosphorylation	up-regulates activity	0.336	IKK-alpha had an ability to stabilize p73 by inhibiting its polyubiquitination, and enhanced p73 mediated transcriptional activation as well as proapoptotic activity.\|In addition, IKK-alpha phosphorylated the NH 2 -terminal portion of p73 and a kinase deficient mutant form of IKK-alpha had undetectable effect on p73.	SIGNOR-279697
Q8IYK4	P02461	1	glycosylation	up-regulates activity	0.404	Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues.	SIGNOR-261158
P0DMV9	O15217	1	relocalization	up-regulates activity	0.2	Model showing Ser189/Thr193 protein kinase dependent phosphorylation of GST A4‐4 has increased affinity for chaperone Hsp70 which activates mitochondrial competent import signals for GSTA4‐4. \|Protein kinase A mediated phosphorylation of serine residues of CYPs increases the affinity of proteins for binding to cytoplasmic chaperones such as heat shock proteins (Hsp), Hsp70/Hsp90, resulting in increased mitochondrial translocation	SIGNOR-264800
Q9Y5X4	P03372	1	transcriptional regulation	up-regulates quantity by expression	0.251	NR2E3 directly regulates expression of ESR1 \| Furthermore, overexpression of exogenous NR2E3 further increased expression of ESR1 and its downstream targets as well as its transcriptional activity in MCF-7 cells (Fig S1 of Supporting Information), strongly demonstrating that NR2E3 regulates ESR1 expression and subsequent ESR1-mediated induction of target genes.	SIGNOR-266207
Q4G163	Q13555	0	phosphorylation	down-regulates activity	0.2	Activated CaMKII and polo-like kinase simultaneously phosphorylate and inactivate Emi2 [ xref , xref , xref , xref , xref ]).	SIGNOR-280200
Q15818	Q07812	1	relocalization	up-regulates activity	0.2	Immunofluorescence staining and subcellular fractionation analyses revealed increased mitochondrial translocation of Bad and Bax proteins from cytoplasm following OGD (4 h) and simultaneously increased release of Cyt C from mitochondria followed by activation of caspase-3. NP1 protein was immunoprecipitated with Bad and Bax proteins; OGD caused increased interactions of NP1 with Bad and Bax, thereby, facilitating their mitochondrial translocation and dissipation of mitochondrial membrane potential	SIGNOR-261439
Q16552	Q9BYH8	0	transcriptional regulation	up-regulates quantity by expression	0.381	In cooperation with RORγt and RORα, IκBζ enhances Il17a expression by binding directly to the regulatory region of the Il17a gene.	SIGNOR-266210
Q38SD2	P17252	0	phosphorylation	up-regulates activity	0.2	PKCα unexpectedly does not activate LRRK1 by phosphorylating the kinase domain, but instead phosphorylates a cluster of conserved residues (Ser1064, Ser1074 and Thr1075) located within a region of the CORB domain of the GTPase domain. we postulate that phosphorylation of Ser1064, Ser1074 and Thr1075 activates LRRK1 by promoting interaction and stabilization of the αC-helix on the kinase domain.	SIGNOR-276865
Q16539	Q96L92	1	phosphorylation	down-regulates activity	0.2	Altogether, our study suggests that MAPK11 and MAPK14 mediate the phosphorylation of SNX27 at Ser51 in vitro and in vivo.	SIGNOR-279069
P16220	Q00535	0	phosphorylation	up-regulates activity	0.374	CDK5 Activates the Self-Renewal Regulator CREB1 in GSCs.\|Our data indicate that CDK5, which has previously been shown to activate CREB1 through cAMP and PKA in dopamine neurons present in the ventral tegmental area, can directly bind with and phosphorylate CREB1 in a PKA and cAMP independent manner, at least in GSCs.	SIGNOR-279682
P49841	Q9UK32	0	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
P06241	Q14643	1	phosphorylation	up-regulates	0.487	We have identified tyrosine 353 (tyr353) in the ip3-binding domain of type 1 ip3r (ip3r1) as a phosphorylation site for fyntyrosine phosphorylation of ip3r1 increased ip3 binding at low ip3 concentrations (<10 nm).	SIGNOR-121795
Q07812	Q05513	0	phosphorylation	down-regulates activity	0.2	Protein kinase czeta abrogates the proapoptotic function of bax through phosphorylation. Overexpression of wild type or the constitutively active a119d but not the dominant negative k281w pkczeta mutant results in bax phosphorylation at serine 184.	SIGNOR-155111
Q13362	P18846	1	dephosphorylation	up-regulates	0.2	We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf5	SIGNOR-167564
P53990	Q6PHR2	0	phosphorylation	down-regulates activity	0.624	ULK3 phosphorylation of IST1 is required to sustain the abscission checkpoint and inhibits IST1 function in abscission.	SIGNOR-278205
P15941	P12931	0	phosphorylation	up-regulates	0.444	The c-src tyrosine kinase regulates signaling of the human df3/muc1 carcinoma-associated antigen with gsk3 beta and betBeta-catenin c-src phosphorylates the muc1 cytoplasmic domain at a yekv motif c-src-mediated phosphorylation of muc1 increases binding of muc1 and betBeta-catenin	SIGNOR-85938
P35222	P52333	0	phosphorylation	up-regulates activity	0.444	Jak3 phosphorylates Tyr 30, Tyr 64, and Tyr 86 of beta-catenin in intestinal epithelial cells.	SIGNOR-278180
P05787	Q16539	0	phosphorylation	up-regulates	0.592	Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif ((68)nqsllspl) and becomes phosphorylated in cultured cells and organs during mitosis, cell stress, and apoptosis. Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase.The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis.	SIGNOR-114079
P23769	Q8IX07	0	transcriptional regulation	down-regulates quantity by repression	0.746	GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1.	SIGNOR-256061
P08069	P12931	0	phosphorylation	up-regulates activity	0.582	The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain.	SIGNOR-247193
Q16665	Q00987	0	ubiquitination	down-regulates quantity by destabilization	0.643	We find that p53 promotes Mdm2-mediated ubiquitination and proteasomal degradation of the HIF-1alpha subunit of hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that regulates cellular energy metabolism and angiogenesis in response to oxygen deprivation.	SIGNOR-271385

P48048

P12931

0

phosphorylation

down-regulates

0.312

Inhibition of c-src with herbimycin a significantly decreased the tyrosine phosphorylation level of romk1... tyrosine dephosphorylation enhances the exocytosis of romk1

SIGNOR-97803

P06493

Q9HCH0

1

phosphorylation

down-regulates activity

0.2

Inhibiting Cdk1 with purvalanol A in nocodazole arrested cells increased fluorescent intensity of Cep169 at centrosomes relative to the value at the cytosol (2.36 +/- 0.12), while control cells indicated 1.13 +/- 0.03.|Taken together, these results suggest that the Cdk1-dependent phosphorylation of Cep169 mediates the dissociation from centrosomes during mitosis.

SIGNOR-279144

P30305

O14965

0

phosphorylation

up-regulates

0.722

We show that bypass of the g2/m checkpoint by the chk1 kinase inhibitor ucn-01 results in the activation of aurora-a and phosphorylation of cdc25b on s353

SIGNOR-139396

P05067

P78536

0

cleavage

up-regulates activity

0.539

By the use of gene disruption (knockout), we now demonstrate that TACE (tumor necrosis factor alpha converting enzyme), a member of the ADAM family (a disintegrin and metalloprotease-family) of proteases, plays a central role in regulated alpha-cleavage of APP. Our data suggest that TACE may be the alpha-secretase responsible for the majority of regulated alpha-cleavage in cultured cells.

SIGNOR-262829

Q13315

Q99607

1

phosphorylation

down-regulates activity

0.349

Elf4 is phosphorylated by Atm after gamma irradiation, leading to its degradation.|Thus, Atm promotes Elf4 protein degradation after gamma irradiation via phosphorylation at these sites.

SIGNOR-278466

Q99490

P06241

0

phosphorylation

up-regulates

0.467

We demonstrate that fyn is essential for phosphorylating pike-a and protects it from apoptotic cleavage. Active but not kinase-dead fyn interacts with pike-a and phosphorylates it on both y682 and y774 residues. Tyrosine phosphorylation in pike-a is required for its association with active fyn but not for akt. Mutation of d into a in pike-a protects it from caspase cleavage and promotes cell survival.

SIGNOR-147936

Q16539

P18031

0

dephosphorylation

down-regulates activity

0.443

Here, we show that PTP1B regulates CD40 and BAFF-R signaling and dephosphorylates the mitogen-activated protein kinase p38.|Specifically, PTP1B counteracts p38 mitogen-activated protein kinase activation by directly dephosphorylating Tyr182 of this kinase.

SIGNOR-277167

P24821

P14921

0

transcriptional regulation

up-regulates quantity by expression

0.2

Sp1 and Ets1 are potent transactivators of the TN-C promoter.

SIGNOR-261599

P36871

Q13153

0

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

O00327

P31751

0

phosphorylation

down-regulates activity

0.358

Consistent with mass spectrometry results, constitutive active Akt2 (Akt2-CA) induced wild-type (WT) Bmal1 protein phosphorylation, which was abolished by a serine to alanine mutation at Ser42 residue (S42A) but not a S422A/S513A double mutation, as shown by immunoblot assay with phospho-Akt substrate antiserum ( xref ).|In line with the in vivo results, overexpression of Akt2-CA strikingly lowered Bmal1 protein abundance in the nucleus in primary hepatocytes (XREF_FIG and XREF_SUPPLEMENTARY).

SIGNOR-280177

P43405

P12318

1

phosphorylation

up-regulates activity

0.673

To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and pointFyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation.

SIGNOR-247590

O60346

Q9Y243

1

dephosphorylation

down-regulates activity

0.648

The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells.

SIGNOR-248330

P08567

P17252

0

phosphorylation

up-regulates

0.28

To determine the role of pkc-dependent phosphorylation in pleckstrin function, we mapped the phosphorylation sites in vivo of wild-type and site-directed mutants of pleckstrin expressed in cos cells. Phosphorylation was found to occur almost exclusively on ser-113 and ser-117. Replacing all these sites with glycine decreased phosphorylation by > 90% and reduced pleckstrin's ability to inhibit phosphoinositide hydrolysis by as much as 80%.

SIGNOR-40048

Q6A1A2

O00141

1

phosphorylation

up-regulates

0.2

Our results are consistent with a model in which activation of sgk by igf-1 or hydrogen peroxide is initiated by a ptdins(3,4, 5)p3-dependent activation of pdk2, which phosphorylates ser422.

SIGNOR-66234

Q6UB99

Q9BR76

1

transcriptional regulation

up-regulates quantity by expression

0.2

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

SIGNOR-266737

P17252

P29966

1

phosphorylation

down-regulates activity

0.73

Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin

SIGNOR-249650

P08069

P43250

0

phosphorylation

down-regulates quantity by destabilization

0.306

GRK2 and GRK6 coimmunoprecipitate with IGF-1R and increase IGF-1R serine phosphorylation, promoting β-arrestin1 association. Using immunoprecipitation, confocal microscopy, and FRET analysis, we demonstrated β-arrestin/IGF-1R association to be transient for GRK2 and stable for GRK6. Using bioinformatic studies we identified serines 1248 and 1291 as the major serine phosphorylation sites of the IGF-1R. Targeted mutation of S1248 recapitulates GRK2 modulation, whereas S1291 mutation resembles GRK6 effects on IGF-1R signaling/degradation

SIGNOR-276412

O95835

P46937

1

phosphorylation

down-regulates quantity by destabilization

0.84

We show that YAP is phosphorylated by Lats on Ser 381 in one of the HXRXXS motifs, and this phosphorylation provides the priming signal for CK1delta/epsilon to phosphorylate a phosphodegron in YAP. The phosphorylated phosphodegron recruits beta-TRCP, leading to YAP ubiquitination and degradation under conditions of elevated Hippo pathway activity, such as cell contact inhibition

SIGNOR-218034

P08559

Q9NTG7

0

deacetylation

down-regulates activity

0.48

SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells|SIRT3 deacetylates PDHA1 lysine 321 (K321)

SIGNOR-267636

P53350

Q8N4N8

1

phosphorylation

up-regulates activity

0.66

We show that Plk1 directly phosphorylates Kif2b at threonine 125 (T125) and serine 204 (S204), and that these two sites differentially regulate Kif2b function. Phosphorylation of S204 is required for the kinetochore localization and activity of Kif2b in prometaphase, and phosphorylation of T125 is required for Kif2b activity in the correction of k-MT attachment errors.

SIGNOR-252049

O14965

P03372

1

phosphorylation

up-regulates activity

0.357

Based on these findings, we conclude that ER\u03b1-Ser167 and -Ser305 are phosphorylated by Aurora-A in vitro and in vivo .|These data suggest that Aurora-A not only activates ER\u03b1 activity but also enhances E2 action and that Aurora-A-induced ER\u03b1 activation could not be inhibited by tamoxifen.

SIGNOR-278508

P41225

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-268920

P48729

Q969R2

1

phosphorylation

up-regulates activity

0.2

CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes.

SIGNOR-264877

Q8NHY2

O00763

1

ubiquitination

down-regulates quantity by destabilization

0.2

TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1. Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D).

SIGNOR-271599

Q14332

Q9ULT6

0

ubiquitination

down-regulates

0.292

Znrf3 is associated with the wnt receptor complex, and inhibits wntby promoting the turnover of frizzled and lrp6.

SIGNOR-197417

Q14653

P03209

0

transcriptional regulation

down-regulates quantity by repression

0.2

EBV Rta selectively down-regulates the expression of IRF3 and IRF7, the main regulators of the Type I IFNs.

SIGNOR-266644

Q9UHF1

Q86V15

0

transcriptional regulation

up-regulates quantity

0.425

We have recently demonstrated that a novel transcriptional pathway involving activation of the Epidermal Growth Factor-like Domain 7 (Egfl7) gene by the transcription factor CASTOR (CASZ1) is required for blood vessel assembly and lumen morphogenesis.

SIGNOR-266858

P06241

P14923

1

phosphorylation

up-regulates activity

0.561

Phosphorylation of plakoglobin by Fer and Fyn kinases decreases plakoglobin-desmoplakin interaction and increases plakoglobin-α-catenin association. Fyn mainly phosphorylated Tyr549 and that it phosphorylated Tyr133 with a much lower activity

SIGNOR-251176

P45983

P05067

1

phosphorylation

up-regulates

0.71

Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in sh-sy5y neuroblastoma cells. We found that the threonine 668 within the abetapp intracellular domain (aid or elsewhere aicd) is indeed phosphorylated by jnk1

SIGNOR-117852

P24844

O43293

0

phosphorylation

up-regulates

0.487

More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above.

SIGNOR-188789

Q5BJH7

P08908

1

relocalization

up-regulates activity

0.399

Together, our results provide strong evidence that Yif1B is a member of the ER/Golgi trafficking machinery, which plays a key role in specific targeting of 5-HT(1A)R to the neuronal dendrites. This finding opens up new pathways for the study of 5-HT(1A)R regulation by partner proteins and for the development of novel antidepressant drugs.|We confirmed 5-HT(1A)R-Yif1B interaction by glutathione S-transferase pull-down experiments using rat brain extracts and transfected cell lines.

SIGNOR-268299

Q6U7Q0

P48730

0

phosphorylation

down-regulates quantity by destabilization

0.2

CK1delta and GSK3beta kinases sequentially phosphorylate ZNF322A at serine-396 and then serine-391. Moreover, the doubly phosphorylated ZNF322A protein creates a destruction motif for the ubiquitin ligase FBXW7alpha leading to ZNF322A protein destruction.

SIGNOR-264892

Q14207

P24941

0

phosphorylation

up-regulates

0.447

Importantly, mutation of cdk2 phosphorylation sites to alanine abrogates the ability of p220 to activate the histone h2b promoter.

SIGNOR-82141

Q15139

O15264

0

phosphorylation

down-regulates

0.2

P38delta catalyzes an inhibitory phosphorylation of pkd1, thereby attenuating stimulated insulin secretion.

SIGNOR-183280

P84022

P28482

0

phosphorylation

down-regulates activity

0.746

Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3

SIGNOR-161613

O14965

Q8WV24

1

phosphorylation

down-regulates quantity by destabilization

0.447

Aurora A directly phosphorylates PHLDA1 leading to its degradation. Aurora A phosphorylates PHLDA1 at Ser 98.

SIGNOR-273545

P48454

O00429

1

dephosphorylation

up-regulates activity

0.262

When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis.

SIGNOR-248506

P35240

Q96PU5

0

ubiquitination

up-regulates activity

0.261

Merlin ubiquitination is mediated by the E3 ubiquitin ligase, NEDD4L, which requires a scaffold protein, AMOTL1, to approach Merlin. Several NF2-patient-derived Merlin mutations disrupt its binding to AMOTL1 and its regulation by the AMOTL1-NEDD4L apparatus. Lysine (K) 396 is the major ubiquitin conjugation residue. Disruption of Merlin ubiquitination by the K396R mutation or NEDD4L depletion diminishes its binding to Lats1 and inhibits Lats1 activation. These effects are also accompanied by loss of Merlin's anti-mitogenic and tumor suppressive properties. Thus, we propose that dephosphorylation and ubiquitination compose an intramolecular relay to activate Merlin functions in activating the Hippo pathway during growth control.

SIGNOR-263662

Q08289

Q13557

0

phosphorylation

up-regulates

0.412

We recently identified ca(v)1.2 beta(2a) residues critical for camkii phosphorylation (thr 498) beta(2a) thr 498 and leu 493 are required for ca(v)1.2 activation by camkii in native cells.

SIGNOR-164067

Q12899

Q14653

1

polyubiquitination

down-regulates quantity by destabilization

0.672

TRIM26 bound to IRF3 and promoted its K48-linked polyubiquitination and degradation in nucleus.

SIGNOR-272440

P42224

O15111

0

phosphorylation

up-regulates activity

0.331

In addition, IKK\u03b1 also phosphorylated STAT1 in a type I IFN-independent manner [Fig 8, a dashed line (B)].

SIGNOR-279732

Q9HAW9

P20823

0

transcriptional regulation

up-regulates quantity by expression

0.281

Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter.

SIGNOR-253972

P23588

Q15418

0

phosphorylation

up-regulates

0.529

S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function.

SIGNOR-123993

O96017

Q2M385

1

phosphorylation

up-regulates activity

0.2

Chk2 phosphorylates Mps1-T288 after DNA damage.|In the present study, we show that Chk2 stabilizes Mps1 protein and phosphorylates Aurora B-B-serine 331 to prevent mitotic exit in vertebrate cells when the majority of kinetochores are unattached.

SIGNOR-279160

Q05655

O95466

1

phosphorylation

up-regulates activity

0.27

PKC\u03b4 induces FMNL1 phosphorylation.

SIGNOR-279261

Q13315

P67775

0

dephosphorylation

down-regulates activity

0.333

Ionizing radiation induces autophosphorylation of the ataxia-telangiectasia mutated (ATM) protein kinase on serine 1981; however, the precise mechanisms that regulate ATM activation are not fully understood. Here, we show that the protein phosphatase inhibitor okadaic acid (OA) induces autophosphorylation of ATM on serine 1981 in unirradiated cells at concentrations that inhibit protein phosphatase 2A-like activity in vitro.

SIGNOR-248644

Q15139

Q12809

1

phosphorylation

down-regulates activity

0.2

Based on LC-MS results from in vivo and HEK293 cell experiments we chose four KV11.1 mutant candidates for further functional analysis. Ablation of the putative PKD phosphorylation site in the mutant S284A increased the maximal current indicating S284 as a main PKD target in KV11.1.

SIGNOR-277612

Q9BYT3

P28482

1

phosphorylation

up-regulates activity

0.273

In vitro kinase assay results indicated that STK33 can phosphorylate ERK2.|STK33 phosphorylated ERK2 and increased the activity of ERK2 and promote the tumorigenesis of colorectal cancer HCT15 cells.

SIGNOR-279351

Q9Y4K3

P21580

0

deubiquitination

down-regulates activity

0.702

A20 is a deubiquitinating enzyme (dub) for lys63-linked polyubiquitinated signaling mediators such as traf6

SIGNOR-160223

P40763

P17706

0

dephosphorylation

down-regulates

0.735

The nuclear isoform of protein-tyrosine phosphatase tc-ptp regulates interleukin-6-mediated signaling pathway through stat3 dephosphorylation.

SIGNOR-90818

P23443

P23588

1

phosphorylation

up-regulates

0.776

S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function.

SIGNOR-123997

P68400

P06127

1

phosphorylation

up-regulates

0.342

In this study, we use jurkat t cell transfectants of cd5 cytoplasmic tail mutants to reveal phosphorylation sites relevant to signal transduction. Our results show that casein kinase ii (ckii) is responsible for the constitutive phosphorylation of cd5 molecules at a cluster of three serine residues located at the extreme c terminus (s458, s459, and s461)

SIGNOR-62311

O14920

Q9Y6Q9

1

phosphorylation

up-regulates activity

0.378

We demonstrated the in vitro phosphorylation of SRC-3 by the two catalytic subunits of the IKK complex, IKKα and IKKβ. IKK kinase activity is required for synergistic activation with SRC-3

SIGNOR-251298

O60674

Q9Y4C1

1

phosphorylation

up-regulates activity

0.2

KDM3A is tyrosine-phosphorylated by JAK2 in the nucleus and functions as a STAT3-dependent transcriptional coactivator. JAK2 phosphorylates KDM3A at tyrosine 1101 residue.

SIGNOR-277884

Q9BV40

Q86YJ5

0

ubiquitination

down-regulates quantity by destabilization

0.2

MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.

SIGNOR-271531

P09238

Q12948

0

transcriptional regulation

up-regulates quantity by expression

0.2

Therefore, FOXC1 is strongly suggested as a pro-metastatic gene in CRC by transcriptionally activating MMP10, SOX4 and SOX13|MMP10 was demonstrated as the direct target and mediator of FOXC1.

SIGNOR-275915

Q12772

P04035

1

transcriptional regulation

up-regulates quantity by expression

0.492

The processed SREBP2, designated nuclear SREBP2 (nSREBP2), then enters the nucleus as a homodimer, binds to the sterol regulatory element (SRE) sequence in the promoters of target genes, including HMGCR and SQLE (encoding squalene monooxygenase), and upregulates their transcription

SIGNOR-265161

P53805

Q5S007

0

phosphorylation

up-regulates activity

0.371

LRRK2 Directly Phosphorylates RCAN1.

SIGNOR-278340

P31749

Q5S007

0

phosphorylation

up-regulates

0.379

Expression of wild-type LRRK2 promoted neuronal survival against apoptosis through activation of the downstream effector, Akt by phosphorylation of Ser473. Phosphorylated Akt in turn inhibited FOXO 1 signaling

SIGNOR-252598

P31751

P18031

1

phosphorylation

down-regulates activity

0.372

We conclude that ptp1b is a novel substrate for akt and that phosphorylation of ptp1b by akt at ser(50) may negatively modulate its phosphatase activity creating a positive feedback mechanism forinsulin signaling

SIGNOR-235491

P53004

P31749

0

phosphorylation

up-regulates activity

0.296

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

SIGNOR-275517

P17612

P16070

1

phosphorylation

up-regulates

0.2

Pka can phosphorylate ser316 directly cd44 s291a and s316a mutants may disrupt downstream signalling events by displacing endogenous cd44 from plasma membrane microdomains.

SIGNOR-147208

P00519

P07203

1

phosphorylation

up-regulates activity

0.459

GPx1 also functions as a substrate for c-Abl- and Arg-mediated phosphorylation on Tyr-96. The results further show that c-Abl and Arg stimulate GPx activity and that these kinases contribute to GPx-mediated protection of cells against oxidative stress.

SIGNOR-104324

Q12772

Q7KZF4

1

transcriptional regulation

up-regulates quantity by expression

0.342

These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression.

SIGNOR-259136

Q15672

P27361

0

phosphorylation

up-regulates

0.328

Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro

SIGNOR-173413

Q15078

P17655

0

cleavage

up-regulates activity

0.565

Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain

SIGNOR-251610

P61586

Q9NZN5

0

guanine nucleotide exchange factor

up-regulates activity

0.905

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-260539

Q14541

Q92819

1

transcriptional regulation

up-regulates quantity by expression

0.337

Transcription was activated by HNF4G in reporter assays using the promoter/enhancer region of the HAS2 gene. The endogenous expression of the HAS2 gene was suppressed by knockdown of HNF4G.

SIGNOR-261626

Q92974

Q13153

0

phosphorylation

down-regulates

0.353

We identify gef-h1 as a binding target and substrate for p21-activated kinase 1 (pak1), we show that phosphorylation of gef-h1 at ser(885) by pak1 induces 14-3-3 binding to the exchange factor and relocation of 14-3-3 to microtubules.

SIGNOR-187573

P06400

Q00532

0

phosphorylation

up-regulates activity

0.2

We also proved that as a downstream molecule of the P15 pathway, Rb is inhibited after CDKL1 knockdown. Rb is a well-known tumor suppressor in cell cycle regulation.28 Phosphorylation of Rb negatively regulates the cell cycle through E2F repression.29–31 However, Rb contains 13 conserved sites that are phosphorylated by the CDK–P15 complex in cycling cells and phosphorylation will cause site-specific and diverse conformational changes in the complex.32,33 Further studies need to be conducted to decipher the phosphorylated site of Rb related to CDKL1 knockdown.

SIGNOR-273863

P18031

P31751

0

phosphorylation

down-regulates activity

0.372

We conclude that ptp1b is a novel substrate for akt and that phosphorylation of ptp1b by akt at ser(50) may negatively modulate its phosphatase activity creating a positive feedback mechanism forinsulin signaling

SIGNOR-235491

Q99835

P23771

1

null

up-regulates activity

0.2

That GATA is a downstream effector of the hedgehog pathway.

SIGNOR-253527

P55957

Q9Y6C9

0

relocalization

up-regulates

0.303

Mtch2/mimp (mitochondrial carrier homologue 2/met-induced mitochondrial protein), a novel truncated bid (tbid)-interacting protein, is a surface-exposed outer mitochondrial membrane protein that facilitates the recruitment of tbid to mitochondria

SIGNOR-165081

P01100

P49675

1

transcriptional regulation

up-regulates quantity by expression

0.259

We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters.

SIGNOR-254878

P49841

Q14194

1

phosphorylation

up-regulates

0.47

Using in vitro kinase assays and pharmacological inhibition of gsk3 as described above for crmp2 and crmp4, it was found that thr509 (and presumably ser518 and thr514) of human crmp1 is phosphorylated by gsk3, following priming of ser522 by cdk5

SIGNOR-145999

P43405

P15311

1

phosphorylation

up-regulates activity

0.447

Phospho-SYK has also been shown to specifically activate ezrin upon CD81 engagement.|We found that the activated SYK led to a time dependent phosphorylation of ezrin (pY354 and pThr567) and radixin (pThr564) (XREF_FIG).

SIGNOR-279129

P38435

P07225

1

carboxylation

up-regulates activity

0.613

Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z

SIGNOR-265924

P49841

P84022

1

phosphorylation

down-regulates quantity by destabilization

0.488

Mechanistically, axin facilitates gsk3-beta-mediated phosphorylation of smad3 at thr66, which triggers smad3 ubiquitination and degradation.

SIGNOR-160318

Q70Z35

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.406

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-260570

O15111

O15350

1

phosphorylation

up-regulates activity

0.336

IKK-alpha had an ability to stabilize p73 by inhibiting its polyubiquitination, and enhanced p73 mediated transcriptional activation as well as proapoptotic activity.|In addition, IKK-alpha phosphorylated the NH 2 -terminal portion of p73 and a kinase deficient mutant form of IKK-alpha had undetectable effect on p73.

SIGNOR-279697

Q8IYK4

P02461

1

glycosylation

up-regulates activity

0.404

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

SIGNOR-261158

P0DMV9

O15217

1

relocalization

up-regulates activity

0.2

Model showing Ser189/Thr193 protein kinase dependent phosphorylation of GST A4‐4 has increased affinity for chaperone Hsp70 which activates mitochondrial competent import signals for GSTA4‐4. |Protein kinase A mediated phosphorylation of serine residues of CYPs increases the affinity of proteins for binding to cytoplasmic chaperones such as heat shock proteins (Hsp), Hsp70/Hsp90, resulting in increased mitochondrial translocation

SIGNOR-264800

Q9Y5X4

P03372

1

transcriptional regulation

up-regulates quantity by expression

0.251

NR2E3 directly regulates expression of ESR1 | Furthermore, overexpression of exogenous NR2E3 further increased expression of ESR1 and its downstream targets as well as its transcriptional activity in MCF-7 cells (Fig S1 of Supporting Information), strongly demonstrating that NR2E3 regulates ESR1 expression and subsequent ESR1-mediated induction of target genes.

SIGNOR-266207

Q4G163

Q13555

0

phosphorylation

down-regulates activity

0.2

Activated CaMKII and polo-like kinase simultaneously phosphorylate and inactivate Emi2 [ xref , xref , xref , xref , xref ]).

SIGNOR-280200

Q15818

Q07812

1

relocalization

up-regulates activity

0.2

Immunofluorescence staining and subcellular fractionation analyses revealed increased mitochondrial translocation of Bad and Bax proteins from cytoplasm following OGD (4 h) and simultaneously increased release of Cyt C from mitochondria followed by activation of caspase-3. NP1 protein was immunoprecipitated with Bad and Bax proteins; OGD caused increased interactions of NP1 with Bad and Bax, thereby, facilitating their mitochondrial translocation and dissipation of mitochondrial membrane potential

SIGNOR-261439

Q16552

Q9BYH8

0

transcriptional regulation

up-regulates quantity by expression

0.381

In cooperation with RORγt and RORα, IκBζ enhances Il17a expression by binding directly to the regulatory region of the Il17a gene.

SIGNOR-266210

Q38SD2

P17252

0

phosphorylation

up-regulates activity

0.2

PKCα unexpectedly does not activate LRRK1 by phosphorylating the kinase domain, but instead phosphorylates a cluster of conserved residues (Ser1064, Ser1074 and Thr1075) located within a region of the CORB domain of the GTPase domain. we postulate that phosphorylation of Ser1064, Ser1074 and Thr1075 activates LRRK1 by promoting interaction and stabilization of the αC-helix on the kinase domain.

SIGNOR-276865

Q16539

Q96L92

1

phosphorylation

down-regulates activity

0.2

Altogether, our study suggests that MAPK11 and MAPK14 mediate the phosphorylation of SNX27 at Ser51 in vitro and in vivo.

SIGNOR-279069

P16220

Q00535

0

phosphorylation

up-regulates activity

0.374

CDK5 Activates the Self-Renewal Regulator CREB1 in GSCs.|Our data indicate that CDK5, which has previously been shown to activate CREB1 through cAMP and PKA in dopamine neurons present in the ventral tegmental area, can directly bind with and phosphorylate CREB1 in a PKA and cAMP independent manner, at least in GSCs.

SIGNOR-279682

P49841

Q9UK32

0

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

P06241

Q14643

1

phosphorylation

up-regulates

0.487

We have identified tyrosine 353 (tyr353) in the ip3-binding domain of type 1 ip3r (ip3r1) as a phosphorylation site for fyntyrosine phosphorylation of ip3r1 increased ip3 binding at low ip3 concentrations (<10 nm).

SIGNOR-121795

Q07812

Q05513

0

phosphorylation

down-regulates activity

0.2

Protein kinase czeta abrogates the proapoptotic function of bax through phosphorylation. Overexpression of wild type or the constitutively active a119d but not the dominant negative k281w pkczeta mutant results in bax phosphorylation at serine 184.

SIGNOR-155111

Q13362

P18846

1

dephosphorylation

up-regulates

0.2

We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf5

SIGNOR-167564

P53990

Q6PHR2

0

phosphorylation

down-regulates activity

0.624

ULK3 phosphorylation of IST1 is required to sustain the abscission checkpoint and inhibits IST1 function in abscission.

SIGNOR-278205

P15941

P12931

0

phosphorylation

up-regulates

0.444

The c-src tyrosine kinase regulates signaling of the human df3/muc1 carcinoma-associated antigen with gsk3 beta and betBeta-catenin c-src phosphorylates the muc1 cytoplasmic domain at a yekv motif c-src-mediated phosphorylation of muc1 increases binding of muc1 and betBeta-catenin

SIGNOR-85938

P35222

P52333

0

phosphorylation

up-regulates activity

0.444

Jak3 phosphorylates Tyr 30, Tyr 64, and Tyr 86 of beta-catenin in intestinal epithelial cells.

SIGNOR-278180

P05787

Q16539

0

phosphorylation

up-regulates

0.592

Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif ((68)nqsllspl) and becomes phosphorylated in cultured cells and organs during mitosis, cell stress, and apoptosis. Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase.The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis.

SIGNOR-114079

P23769

Q8IX07

0

transcriptional regulation

down-regulates quantity by repression

0.746

GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1.

SIGNOR-256061

P08069

P12931

0

phosphorylation

up-regulates activity

0.582

The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain.

SIGNOR-247193

Q16665

Q00987

0

ubiquitination

down-regulates quantity by destabilization

0.643

We find that p53 promotes Mdm2-mediated ubiquitination and proteasomal degradation of the HIF-1alpha subunit of hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that regulates cellular energy metabolism and angiogenesis in response to oxygen deprivation.

SIGNOR-271385