GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
P35222	O96013	phosphorylation	up-regulates	0.286	Pak4 interacts with and phosphorylates _-catenin on ser675, which promotes the tcf/lef transcriptional activity and stabilizes _-catenin through inhibition of its degradation.	SIGNOR-191557
P51809	P12931	phosphorylation	up-regulates activity	0.286	We found that TI-VAMP is phosphorylated in vitro by c-Src kinase on tyrosine 45 of the Longin domain.Mimicking tyrosine 45 phosphorylation activates both t-SNARE binding and exocytosis of TI-VAMP.	SIGNOR-273819
Q9BSA4	Q96PU5	polyubiquitination	down-regulates quantity by destabilization	0.286	Our data indicate that Nedd4-2 binds to two family members, TTYH2 and TTYH3, which contain consensus PY ((L/P)PXY) binding sites for HECT type E3 ubiquitin ligases, but not to TTYH1, which lacks this motif. Consistently, Nedd4-2 ubiquitinates both TTYH2 and TTYH3. Importantly, we have shown that endogenous TTYH2 and Nedd4-2 are binding partners and demonstrated that the TTYH2 PY motif is essential for these interactions. We have also shown that Nedd4-2-mediated ubiquitination of TTYH2 is a critical regulator of cell surface and total cellular levels of this protein.	SIGNOR-272632
P68366	Q8NG68	tyrosination	down-regulates	0.286	Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization	SIGNOR-176927
P35222	P35790	phosphorylation	down-regulates activity	0.286	The data suggest that CKI phosphorylates and destabilizes the beta-catenin degradation complex, likely through the dissociation of PP2A, providing a mechanism by which CKI stabilizes beta-catenin and propagates the Wnt signal.	SIGNOR-279161
P13640	Q16236	transcriptional regulation	up-regulates quantity by expression	0.286	NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification. The expression of MT1G during ferroptosis is regulated by the NFE2L2 signaling pathway. In the context of cancer, particularly HCC, the upregulation of MT1G has been linked to resistance against sorafenib, a kinase inhibitor commonly used in cancer therapy	SIGNOR-279866
P55957	P68400	phosphorylation	up-regulates activity	0.286	Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. \| These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.	SIGNOR-250831
O43602	P45983	phosphorylation	up-regulates activity	0.286	DCX phosphorylation by JNK1 is required for glioma suppression.	SIGNOR-279217
Q96CF2	Q6PHR2	phosphorylation	down-regulates activity	0.286	CHMP4C was phosphorylated by recombinant ULK3 in these experiments, whereas CHMP4A and CHMP4B were not (Figure 7\u2014figure supplement 1A).	SIGNOR-279771
Q96QZ7	Q15418	phosphorylation	up-regulates activity	0.286	We report herein that p90RSK associates with MAGI1 in ECs and executes 2 independently regulated PTMs of MAGI1: S741 phosphorylation and K931 deSUMOylation. MAGI1-S741 phosphorylation is vital for Rap1 activation.	SIGNOR-273837
P40763	Q07912	phosphorylation	up-regulates activity	0.286	Since STAT1 and STAT3 are structurally related [3], we also assessed if ACK1 could induce the phosphorylation of STAT3 at residue Y705 (p-STAT3).\|Our work demonstrates that catalytically active ACK1 can promote the activation of STAT1 and STAT3.\|Here we demonstrate that catalytically active ACK1 induces the tyrosine phosphorylation of STAT1 and STAT3.	SIGNOR-279312
Q92769	P00519	phosphorylation	up-regulates quantity by stabilization	0.285	C-Abl stabilizes HDAC2 levels by tyrosine phosphorylation repressing neuronal gene expression in Alzheimer's disease.	SIGNOR-260928
Q9BZS1	P49841	phosphorylation	down-regulates quantity by destabilization	0.285	Our previous study showed, by mass spectrometry analysis, that GSK-3β phosphorylates Foxp3 at Ser270 and Ser275	SIGNOR-277245
Q8TEA8	P68400	phosphorylation	up-regulates activity	0.285	Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D).	SIGNOR-273970
P41235	Q13131	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
P09429	Q16566	phosphorylation	up-regulates activity	0.285	Collectively, our results demonstrate that CaMKIV promotes the nucleocytoplasmic shuttling of HMGB1 and suggest that the process may be mediated through CaMKIV-dependent serine phosphorylation of HMGB1.	SIGNOR-278510
P49841	P17655	cleavage	up-regulates activity	0.285	Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase	SIGNOR-251613
O15379	P49841	phosphorylation	up-regulates activity	0.285	Given that pharmacological inhibition of GSK3beta inhibits HDAC3 neurotoxicity, we explored the possibility that HDAC3 was directly phosphorylated by GSK3beta.\|HDAC3 is directly phosphorylated by GSK3\u03b2, suggesting that the neuronal death-promoting action of GSK3\u03b2 could be mediated through HDAC3 phosphorylation.	SIGNOR-278400
Q9UJD0	Q9UFD9	binding	down-regulates activity	0.285	SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.	SIGNOR-264370
P06213	P23469	dephosphorylation	down-regulates activity	0.285	In this study, we showed that receptor-type PTPepsilon (PTP epsilonM) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163\| These results suggest that PTPepsilonM is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver.	SIGNOR-248444
P04004	P05129	phosphorylation	up-regulates quantity by stabilization	0.285	Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin.	SIGNOR-248964
Q99986	Q05655	phosphorylation	down-regulates activity	0.285	PKC\u03b4 phosphorylates VRK1 on Ser-355 in vitro.\|PKCdelta negatively regulates VRK1 kinase activity in vitro.	SIGNOR-278219
O14529	Q8TE12	transcriptional regulation	up-regulates quantity by expression	0.285	Lmx1a drives Cux2 expression in the cortical hem through activation of a conserved intronic enhancer. Lmx1a knockdown abolishes activation of the Cux2 enhancer in the cortical hem	SIGNOR-263961
Q6UUV9	Q13131	phosphorylation	down-regulates	0.285	Here we show that both ampk and calcineurin modulate longevity exclusively through post-translational modification of crtc-1, the sole c. elegans crtc. We demonstrate that crtc-1 is a direct ampk target.	SIGNOR-172136
P31260	O43189	transcriptional regulation	down-regulates quantity by repression	0.285	These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression.	SIGNOR-260071
P31271	O15550	transcriptional regulation	up-regulates quantity by expression	0.285	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260022
P60953	Q96PX9	guanine nucleotide exchange factor	up-regulates activity	0.285	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-260565
P78352	Q02156	phosphorylation	up-regulates quantity	0.285	PKCepsilon directly phosphorylated PSD-95 and JNK1 in vitro Inhibiting PKCepsilon, JNK, or calcium/calmodulin dependent kinase II activity prevented the effects of PKCepsilon activators on PSD-95 phosphorylation.\|These results indicate that PKCepsilon promotes synaptogenesis by activating PSD-95 phosphorylation directly through JNK1 and calcium/calmodulin dependent kinase II and also by inducing expression of PSD-95 and synaptophysin.	SIGNOR-280087
P37275	P0C2W1	binding	down-regulates quantity by destabilization	0.285	One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively.	SIGNOR-272179
O43474	Q9Y4K3	ubiquitination	up-regulates quantity by stabilization	0.285	We further found that inhibition of polo-like kinase 1 could downregulate the expression of KLF4 and that PLK1 directly phosphorylated KLF4 at Ser234. Notably, phosphorylation of KLF4 by PLK1 caused the recruitment and binding of the E3 ligase TRAF6, which resulted in KLF4 K32 K63-linked ubiquitination and stabilization.	SIGNOR-277464
P12931	Q9UKA9	post transcriptional regulation	down-regulates quantity by repression	0.285	Splicing of the c-src N1 exon in neuronal cells depends in part on an intronic cluster of RNA regulatory elements called the downstream control sequence (DCS). \|nPTB binds more stably to the DCS RNA than PTB does but is a weaker repressor of splicing in vitro. nPTB also greatly enhances the binding of two other proteins, hnRNP H and KSRP, to the DCS RNA.	SIGNOR-261267
P43403	Q6ISU1	binding	up-regulates activity	0.285	Stimulation of the T-cell antigen receptor (TCR) leads to tyrosine phosphorylation of a number of cellular proteins, including phospholipase C (PLC) gamma 1 and the TCR zeta chain. We describe here a 70-kDa tyrosine phosphoprotein (ZAP-70) that associates with zeta within 15 sec following TCR stimulation. The phosphorylation of ZAP-70 and its association with zeta is independent of the other TCR chains	SIGNOR-134325
P17861-2	Q09472	acetylation	up-regulates quantity by stabilization	0.285	P300 increases the acetylation and protein stability of XBP1s, and enhances its transcriptional activity, whereas SIRT1 deacetylates XBP1s and inhibits its transcriptional activity.. The mRNA encoding the active spliced form of XBP1 (XBP1s) is generated from the unspliced form by IRE1 (inositol-requiring enzyme 1) during the UPR.	SIGNOR-260429
O60331	P12931	phosphorylation	up-regulates	0.285	Phosphorylation by src of the tyrosine adjacent to s650 (y649 in human pipki gamma) was shown to enhance pipki gamma targeting to focal adhesions. We find that y649 phosphorylation does not stimulate directly pipki gamma binding to talin, but may do so indirectly by inhibiting s650 phosphorylation.	SIGNOR-134459
Q9Y6Q9	P48730	phosphorylation	up-regulates	0.284	In this study, we show that both eralpha and aib1 are substrates for ck1delta in vitro, and identify a novel aib1 phosphorylation site (s601) targeted by ck1delta, significant for the co-activator function of aib1.	SIGNOR-184946
P08670	P17252	phosphorylation	down-regulates quantity by destabilization	0.284	We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65.	SIGNOR-248880
O75385	O75592	ubiquitination	down-regulates quantity	0.284	Cell-based results demonstrate that the human PHR protein PAM restricts ULK1 protein levels (Fig.\u00a05h, i), and is sufficient to ubiquitinate ULK1 in a proteasome-dependent manner (Fig.\u00a05j).\|Human PAM ubiquitinates ULK1 and regulates ULK1 levels.	SIGNOR-278765
Q13562	Q12857	transcriptional regulation	up-regulates quantity	0.284	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268890
P30305	P45983	phosphorylation	down-regulates quantity by destabilization	0.284	Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104).	SIGNOR-276352
Q12809	Q8N4C8	binding	up-regulates	0.284	Herg, a human homologue of the ether-a-go-go gene of the fruitfly drosophila melanogaster, encodes aproteinthat produces the rapidly activating cardiac delayed rectifier (i[kr]). / our results show that mink physically associates with herg and that the interaction leads to increased ikr current density.	SIGNOR-49869
Q16665	P98170	ubiquitination	up-regulates activity	0.284	HIF1alpha is ubiquitinated by XIAP.\|Lys 63 -linked ubiquitination of HIF1alpha by XIAP is dependent on the activity of E2 ubiquitin conjugating enzyme Ubc13.\|We find that XIAP and Ubc13 dependent Lys 63 -linked polyubiquitination promotes HIF1alpha nuclear retention leading to an increase in the expression of HIF1 responsive genes.\|The data indicate that XIAP promotes the formation of the non-degradative Lys63-linked ubiquitin chains onto hypoxia inducible factor1\u03b1, but does not affect the formation of Lys48-linked chains.	SIGNOR-278740
P63096	Q9NQS5	binding	up-regulates activity	0.284	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256704
Q70E73	P00519	phosphorylation	up-regulates activity	0.284	Here we show that phosphorylation of Lpd by c-Abl increases its interaction with Ena/VASP proteins. This analysis revealed that, in vitro, four Lpd peptides harboring tyrosines (Y426, Y456, Y513, Y1226) are highly phosphorylated, and eight additional peptides are phosphorylated to a lesser extent (Figure 1C).	SIGNOR-262606
P07359	P78536	cleavage	down-regulates activity	0.284	GPIbα is shed by metalloproteases such as ADAM17, a process that releases a soluble GPIbα fragment termed glycocalicin. ADAM17 cleaves within the GPIbα-based peptide (LRGV465LK) through a mechanism that is only partially understood [42]. GPIbα shedding has been shown to be constitutive but it can be increased by activation of protein kinases C (PKC) or inhibition of calmodulin [42, 43]. Shedding leads to decreased receptor density	SIGNOR-261861
Q9UPS8	Q01543	transcriptional regulation	down-regulates quantity by repression	0.284	In healthy individual, RUNX1/FLI1 complex negatively regulates ANKRD26 gene expression in MKs.	SIGNOR-266070
P46937	Q05397	phosphorylation	up-regulates activity	0.284	Then, FAK phosphorylates and activates YAP, leading to the activation and nuclear translocation of YAP/TAZ transcription factor, which is known to be involved in such cellular mechanoresponses [ xref , xref ].	SIGNOR-280099
P19793	Q8IXJ9	binding	up-regulates activity	0.284	In this study, we demonstrate that mammalian ASXL1 interacts with the AF-2 AD core of RAR (and RXR) through a novel, promiscuous NR box (LVMQLL) and enhances transcriptional activity of the receptors in certain cells.	SIGNOR-255911
P32119	P00519	phosphorylation	down-regulates activity	0.284	Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation.	SIGNOR-276280
P25490	P12931	phosphorylation	down-regulates activity	0.284	YY1 phosphorylation is mediated by Src family kinases.	SIGNOR-276940
P28845	P17676	transcriptional regulation	up-regulates quantity by expression	0.284	In conclusion, C/EBPalpha and C/EBPbeta control basal transcription, and TNF-alpha upregulates 11beta-HSD1, most likely by p38 MAPK-mediated increased binding of C/EBPbeta to the human HSD11B1 promoter.	SIGNOR-268972
Q02078	P11802	binding	down-regulates	0.284	In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms.	SIGNOR-176515
P63096	P21728	binding	up-regulates activity	0.284	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257068
P43686	Q92630	phosphorylation	down-regulates quantity by destabilization	0.284	Through a kinome-wide screen, we have identified dual-specificity tyrosine-regulated kinase 2 (DYRK2) as the primary kinase that phosphorylates Rpt3-Thr25, leading to enhanced substrate translocation and degradation.	SIGNOR-275845
P19544	P49841	phosphorylation	down-regulates quantity by destabilization	0.284	Glycogen synthase kinase 3β promoted phosphorylation of cugWT1 at S64, resulting in ubiquitination and degradation of the cugWT1 associated with the F-box-/- WD repeat-containing protein 8.	SIGNOR-277540
Q9HC16	P46934	ubiquitination	up-regulates activity	0.284	APOBEC3G ubiquitination by Nedd4-1 favors its packaging into HIV-1 particles\|This could be explained in at least two ways : first, endogenous Nedd4 is naturally expressed at a level largely sufficient to target APOBEC3G into the VLP or virions.	SIGNOR-278635
Q14500	P17612	phosphorylation	down-regulates activity	0.283	Phosphorylation of the Kir2.2 C terminus by protein kinase A inhibited the association with SAP97.‚	SIGNOR-249998
Q8WXD9	P54762	phosphorylation	up-regulates activity	0.283	EphB1 phosphorylates Caskin1 on tyrosine 296 and 336. Tyrosine phosphorylated Caskin1 then likely promotes reorganization of the actin cytoskeleton leading to spine formation.	SIGNOR-262861
Q7Z434	P17612	phosphorylation	down-regulates activity	0.283	Mutagenesis indicated that PKACalpha phosphorylated wild-type VISA and the VISA mutants VISA (S100A), VISA (T234A) and VISA (S238A) but not VISA (T54A) (XREF_FIG, panel C).\|We found that PKACalpha caused degradation of wild-type VISA but not VISA (T54A) or VISA (K7/500R), in which either the PKACs mediated phosphorylation or MARCH5 mediated K48 linked polyubiquitination residues are mutated (XREF_FIG, panel G).	SIGNOR-279649
Q06413	P11802	binding	down-regulates	0.283	In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms.	SIGNOR-176518
P02818	P09668	cleavage	down-regulates quantity by destabilization	0.283	This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42.	SIGNOR-256325
Q03113	P29371	binding	up-regulates activity	0.283	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257389
P12830	P20794	phosphorylation	down-regulates	0.283	Finally, we speculate that there are two mechanisms whereby MAK inactivates CDH1 : the first is kinase dependent inactivation, modeled after CDK, where phosphorylation dissociates CDH1 from APC/C; the second is through physical binding of CDH1 with MAK.\|These results suggest a cell cycle-dependent phosphorylation of CDH1 by MAK.	SIGNOR-278486
Q14344	P29371	binding	up-regulates activity	0.283	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257438
P22459	Q8TBB1	ubiquitination	down-regulates quantity by destabilization	0.283	We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.The C-terminal LNX1 PDZ1-binding motifs of the ATP-binding cassette, subfamily A member 1 (ABC-1), PBK, glutamate receptor, ionotropic, N-methyl d-aspartate 1 (GRIN1), and Claudin-17 significantly promoted the ubiquitination of the corresponding artificial degrons by LNX1ΔPDZ234.	SIGNOR-272899
P06213	P09958	cleavage	up-regulates activity	0.283	Here we demonstrate that the two IR isoforms are similarly cleaved by furin, but when this furin-dependent maturation is inefficient, IR proforms move to the cell surface where the proprotein convertase PACE4 selectively supports IRB maturation.	SIGNOR-260365
Q13043	Q9H2K8	phosphorylation	up-regulates	0.283	In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2	SIGNOR-192762
P27986	Q5VWQ8	binding	down-regulates activity	0.283	DAB2IP binds the p85 subunit of PI3K through its PR domain and prevents PI3K-p85 relocation from the cytoplasm to the membrane, a necessary step for PI3K activation and signaling to AKT. Notably, DAB2IP reinforces this inhibitory effect by directly binding AKT.2	SIGNOR-254757
O14578	Q96GD4	phosphorylation	down-regulates activity	0.283	Finally, Aurora B phosphorylates CIT-K to control its localization and interaction with central spindle partners.\|Together these findings indicate that CIT-K is an Aurora B substrate and that Aurora B phosphorylation at S699 dampens the association of CIT-K with KIF23 and the chromosomal passenger complex in order to reduce CIT-K accumulation at the spindle midzone in early cytokinesis.	SIGNOR-279140
P04818	Q9HCK8	transcriptional regulation	up-regulates quantity by expression	0.283	In order to identify CHD8 target genes, we performed a transcriptomic analysis of CHD8-depleted cells, finding out that CHD8 controls the expression of cyclin E2 (CCNE2) and thymidylate synthetase (TYMS), two genes expressed in the G1/S transition of the cell cycle. CHD8 was also able to co-activate the CCNE2 promoter in transient transfection experiments. Chromatin immunoprecipitation experiments demonstrated that CHD8 binds directly to the 5' region of both CCNE2 and TYMS genes.	SIGNOR-268805
Q9NQX3	P49841	phosphorylation	down-regulates	0.283	Identification of gsk3_ as the kinase targeting ser-270 /phosphorylation at ser-270 promotes gephyrin processing by calpain	SIGNOR-200957
Q9NY46	Q96PU5	ubiquitination	down-regulates quantity by destabilization	0.283	The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2).	SIGNOR-253464
Q9UQF2	Q7Z6J0	binding	up-regulates	0.283	We find that posh and jips directly associate with one another to form a multiprotein complex, pjac (posh-jip apoptotic complex), that includes all of the known kinase components of the pathway. Our observations indicate that this complex is required for jnk activation and cell death in response to apoptotic stimuli.	SIGNOR-145393
P14136	P17612	phosphorylation	down-regulates activity	0.283	GFAP can serve as a substrate for phosphorylation by CAMP-dependent protein kinase. CAMP-dependent protein kinase or protein kinase C phosphorylated Ser-8, Ser-13, and Ser-34.each phosphorylation was shown to induce disassembly of the glial filaments.	SIGNOR-249713
Q9BZE0	P17612	phosphorylation	down-regulates activity	0.283	Protein kinase a (pka) and glycogen synthase kinase 3beta sequentially phosphorylate gli2 at multiple sites, identified by mutagenesis, thus resulting in a reduction of its transcriptional activity	SIGNOR-145131
O15350	Q9H0M0	polyubiquitination	down-regulates quantity by destabilization	0.283	WWP1 in complex with WWP2 specifically regulates ΔNp73. In our study, we identified WWP2, an E3 ligase, as a novel p73-associated protein that ubiquitinates and degrades p73. In contrast, WWP2 heterodimerizes with another E3 ligase, WWP1, which specifically ubiquitinates and degrades ΔNp73.	SIGNOR-272232
Q01196	O60216	transcriptional regulation	down-regulates quantity by repression	0.283	We observed that depletion of RAD21 (but not CTCF) enhanced RUNX1 transcription in human HL-60 myelocytic leukemia cells	SIGNOR-259973
P05231	Q12968	transcriptional regulation	up-regulates quantity by expression	0.283	The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. \|Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries.	SIGNOR-251732
Q15853	P49841	phosphorylation	up-regulates activity	0.283	Although no study has yet correlated the activity of GSK3beta with the activity of USF2 in a certain tumor setting, the findings of the present study would favor the tumor promoting aspects of GSK3beta and USF2 since GSK3beta activated USF2 enhanced cell migration which may be important in terms of tumor cell metastasis.\|Together, these data show that there are two residues within USF2, namely S155 and T230, which can be phosphorylated by GSK3beta.	SIGNOR-278158
P35612	P17612	phosphorylation	down-regulates activity	0.283	Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of - and -adducin, respectively, were identified as the major phosphorylation sites common for PKA and PKC. Phosphorylation by PKA, but not PKC, reduced the affinity of adducin for spectrin-F-actin complexes as well as the activity of adducin in promoting binding of spectrin to F-actin.	SIGNOR-250332
Q9UGL1	Q99814	transcriptional regulation	up-regulates quantity by expression	0.283	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271578
O14686	O00141	phosphorylation	down-regulates activity	0.283	Elevated SGK1, in turn, phosphorylates KMT2D, suppressing its function, leading to a loss of methylation of lysine 4 on histone H3 (H3K4) and a repressive chromatin state at ER loci to attenuate ER activity.	SIGNOR-277447
Q14934	P28482	phosphorylation	up-regulates	0.283	We demonstrate that p90 ribosomal s6 kinase (rsk) is recruited to the nfat-dna transcription complex upon activation.Bound Rsk phosphorylates ser(676) and potentiates nfatc4 dna binding. Ser(676) is also targeted by the erk map kinase.	SIGNOR-133272
O15350	O00308	polyubiquitination	down-regulates quantity by destabilization	0.283	WWP2 ubiquitinates p73 and controls its protein stability. In our study, we identified WWP2, an E3 ligase, as a novel p73-associated protein that ubiquitinates and degrades p73. In contrast, WWP2 heterodimerizes with another E3 ligase, WWP1, which specifically ubiquitinates and degrades ΔNp73.	SIGNOR-272233
P63092	Q92847	binding	up-regulates activity	0.283	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-256782
P29474	Q13131	phosphorylation	up-regulates	0.283	The central finding of this report is that rosiglitazone rapidly stimulates no production and enos ser-1177 phosphorylation in an ampk-dependent manner	SIGNOR-160838
Q12888	P49841	phosphorylation	up-regulates activity	0.283	Based on these observations, we hypothesized that the IR induced GSK3beta nuclear translocation may activate 53BP1 via phosphorylation at the S/T-Q motif.\|Importantly, our in vivo and in vitro data clearly indicated that GSK3\u03b2 induced the phosphorylation of 53BP1 at the Ser166 site.	SIGNOR-278226
P46937	O15294	glycosylation	up-regulates activity	0.283	Mass spectrometry analysis showed that YAP was the effector protein modified by OGT. In details, YAP Ser109 O-GlcNAcylation promoted the malignant phenotypes in PTC cells by inducing YAP Ser127 dephosphorylation and activation.	SIGNOR-276942
Q13683	P15173	transcriptional regulation	up-regulates quantity by expression	0.283	Only myogenin and MyoD were able to efficiently trans-activate the alpha7 promoter-CAT construct (Fig. 7). Myogenin trans-activated the promoter by _2-fold whereas MyoD was able to trans-activate by nearly 4-fold, indicating that both of these factors may play a role in alpha7 gene expression during muscle development.	SIGNOR-241521
Q07955	P21127	phosphorylation	up-regulates activity	0.283	In comparison, CLK1 expression leads to speckle dissolution and diffuse GFP-SRSF1 localization in the nucleus.\|We showed that CLK1 phosphorylates SRSF1 at approximately 18 sites inducing a gel shift from 35 to about 38 kDa on SDS-PAGE (XREF_FIG, upper panel).	SIGNOR-279499
P16615	P49841	phosphorylation	down-regulates activity	0.283	GSK3β-dependent phosphorylation of SERCA2 at serine 663 in human and mouse hearts. Phosphorylation of SERCA2 at serine 663 regulates SERCA2 activity.	SIGNOR-277886
Q96RR4	P53355	phosphorylation	down-regulates	0.283	Dapk phosphorylates camkk. S511 was identified as the phosphorylation site . a potential mechanism of action was identified on the basis of the location of s511 near the cam recognition domain of camkk and demonstrated by attenuation of cam-stimulated camkk autophosphorylation after dapk phosphorylation.	SIGNOR-126241
P16949	O96013	phosphorylation	down-regulates activity	0.283	Indeed, we show here that inactivating phosphorylation of the endogenous stathmin on serine-16 is also induced by the active PAK4 in mitotic egg extract and is likely to participate in the observed stabilization of the MT asters ( xref , right).	SIGNOR-280058
Q9UNN5	Q14164	phosphorylation	down-regulates quantity by destabilization	0.283	Upon virus infection, the kinase IKKɛ directly phosphorylates FAF1 at Ser556 and triggers FAF1 de-aggregation. Moreover, Ser556 phosphorylation promotes FAF1 lysosomal degradation, consequently relieving FAF1-dependent suppression of MAVS.	SIGNOR-277618
Q13547	Q01664	binding	up-regulates activity	0.282	We also observed moderately increased recruitment of CTCF, HDAC1, and SP1 by the full-length AP-4 onto the WT DNA beads.	SIGNOR-226590
Q14524	Q92915	binding	down-regulates activity	0.282	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253417
P20393	P49841	phosphorylation	up-regulates	0.282	We show here that gsk3beta phosphorylates and stabilizes the orphan nuclear receptor rev-erbalpha, a negative component of the circadian clock.	SIGNOR-144570
Q8WXE1	Q96PY6	binding	up-regulates activity	0.282	It was reported that NEK1 associates with ATR/ATRIP and primes it for activation in response to a variety of genotoxic agents	SIGNOR-275842
P01106	Q15208	phosphorylation	down-regulates activity	0.282	Previously, we demonstrated that STK38 kinase mediates MYC phosphorylation.\|STK38-WT overexpression dramatically reduced MYC half-life (4-fold), compared to control un induced cells (XREF_FIG), while STK38-KD overexpression led to increased MYC half-life (1.7 fold), illustrating an involvement in MYC protein turnover regulation (XREF_FIG).	SIGNOR-280142
Q15172	Q01484	relocalization	up-regulates quantity	0.282	Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins.	SIGNOR-266729
Q01196	Q86X55	methylation	down-regulates activity	0.282	We have found that PRMT4 is highly expressed in HSPCs, where it functions as an inhibitor of myeloid differentiation (Figure 7G). In these cells, PRMT4 methylates RUNX1 at R223, promoting the assembly of a DPF2-containing transcriptional co-repressive complex, and repressing transcription at the miR-223 locus.	SIGNOR-261967

P35222

O96013

0

phosphorylation

up-regulates

0.286

Pak4 interacts with and phosphorylates _-catenin on ser675, which promotes the tcf/lef transcriptional activity and stabilizes _-catenin through inhibition of its degradation.

SIGNOR-191557

P51809

P12931

0

phosphorylation

up-regulates activity

0.286

We found that TI-VAMP is phosphorylated in vitro by c-Src kinase on tyrosine 45 of the Longin domain.Mimicking tyrosine 45 phosphorylation activates both t-SNARE binding and exocytosis of TI-VAMP.

SIGNOR-273819

Q9BSA4

Q96PU5

0

polyubiquitination

down-regulates quantity by destabilization

0.286

Our data indicate that Nedd4-2 binds to two family members, TTYH2 and TTYH3, which contain consensus PY ((L/P)PXY) binding sites for HECT type E3 ubiquitin ligases, but not to TTYH1, which lacks this motif. Consistently, Nedd4-2 ubiquitinates both TTYH2 and TTYH3. Importantly, we have shown that endogenous TTYH2 and Nedd4-2 are binding partners and demonstrated that the TTYH2 PY motif is essential for these interactions. We have also shown that Nedd4-2-mediated ubiquitination of TTYH2 is a critical regulator of cell surface and total cellular levels of this protein.

SIGNOR-272632

P68366

Q8NG68

0

tyrosination

down-regulates

0.286

Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization

SIGNOR-176927

P35222

P35790

0

phosphorylation

down-regulates activity

0.286

The data suggest that CKI phosphorylates and destabilizes the beta-catenin degradation complex, likely through the dissociation of PP2A, providing a mechanism by which CKI stabilizes beta-catenin and propagates the Wnt signal.

SIGNOR-279161

P13640

Q16236

0

transcriptional regulation

up-regulates quantity by expression

0.286

NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification. The expression of MT1G during ferroptosis is regulated by the NFE2L2 signaling pathway. In the context of cancer, particularly HCC, the upregulation of MT1G has been linked to resistance against sorafenib, a kinase inhibitor commonly used in cancer therapy

SIGNOR-279866

P55957

P68400

0

phosphorylation

up-regulates activity

0.286

Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.

SIGNOR-250831

O43602

P45983

0

phosphorylation

up-regulates activity

0.286

DCX phosphorylation by JNK1 is required for glioma suppression.

SIGNOR-279217

Q96CF2

Q6PHR2

0

phosphorylation

down-regulates activity

0.286

CHMP4C was phosphorylated by recombinant ULK3 in these experiments, whereas CHMP4A and CHMP4B were not (Figure 7\u2014figure supplement 1A).

SIGNOR-279771

Q96QZ7

Q15418

0

phosphorylation

up-regulates activity

0.286

We report herein that p90RSK associates with MAGI1 in ECs and executes 2 independently regulated PTMs of MAGI1: S741 phosphorylation and K931 deSUMOylation. MAGI1-S741 phosphorylation is vital for Rap1 activation.

SIGNOR-273837

P40763

Q07912

0

phosphorylation

up-regulates activity

0.286

Since STAT1 and STAT3 are structurally related [3], we also assessed if ACK1 could induce the phosphorylation of STAT3 at residue Y705 (p-STAT3).|Our work demonstrates that catalytically active ACK1 can promote the activation of STAT1 and STAT3.|Here we demonstrate that catalytically active ACK1 induces the tyrosine phosphorylation of STAT1 and STAT3.

SIGNOR-279312

Q92769

P00519

0

phosphorylation

up-regulates quantity by stabilization

0.285

C-Abl stabilizes HDAC2 levels by tyrosine phosphorylation repressing neuronal gene expression in Alzheimer's disease.

SIGNOR-260928

Q9BZS1

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.285

Our previous study showed, by mass spectrometry analysis, that GSK-3β phosphorylates Foxp3 at Ser270 and Ser275

SIGNOR-277245

Q8TEA8

P68400

0

phosphorylation

up-regulates activity

0.285

Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D).

SIGNOR-273970

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

P09429

Q16566

0

phosphorylation

up-regulates activity

0.285

Collectively, our results demonstrate that CaMKIV promotes the nucleocytoplasmic shuttling of HMGB1 and suggest that the process may be mediated through CaMKIV-dependent serine phosphorylation of HMGB1.

SIGNOR-278510

P49841

P17655

0

cleavage

up-regulates activity

0.285

Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase

SIGNOR-251613

O15379

P49841

0

phosphorylation

up-regulates activity

0.285

Given that pharmacological inhibition of GSK3beta inhibits HDAC3 neurotoxicity, we explored the possibility that HDAC3 was directly phosphorylated by GSK3beta.|HDAC3 is directly phosphorylated by GSK3\u03b2, suggesting that the neuronal death-promoting action of GSK3\u03b2 could be mediated through HDAC3 phosphorylation.

SIGNOR-278400

Q9UJD0

Q9UFD9

0

binding

down-regulates activity

0.285

SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.

SIGNOR-264370

P06213

P23469

0

dephosphorylation

down-regulates activity

0.285

In this study, we showed that receptor-type PTPepsilon (PTP epsilonM) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163| These results suggest that PTPepsilonM is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver.

SIGNOR-248444

P04004

P05129

0

phosphorylation

up-regulates quantity by stabilization

0.285

Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin.

SIGNOR-248964

Q99986

Q05655

0

phosphorylation

down-regulates activity

0.285

PKC\u03b4 phosphorylates VRK1 on Ser-355 in vitro.|PKCdelta negatively regulates VRK1 kinase activity in vitro.

SIGNOR-278219

O14529

Q8TE12

0

transcriptional regulation

up-regulates quantity by expression

0.285

Lmx1a drives Cux2 expression in the cortical hem through activation of a conserved intronic enhancer. Lmx1a knockdown abolishes activation of the Cux2 enhancer in the cortical hem

SIGNOR-263961

Q6UUV9

Q13131

0

phosphorylation

down-regulates

0.285

Here we show that both ampk and calcineurin modulate longevity exclusively through post-translational modification of crtc-1, the sole c. elegans crtc. We demonstrate that crtc-1 is a direct ampk target.

SIGNOR-172136

P31260

O43189

0

transcriptional regulation

down-regulates quantity by repression

0.285

These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression.

SIGNOR-260071

P31271

O15550

0

transcriptional regulation

up-regulates quantity by expression

0.285

Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.

SIGNOR-260022

P60953

Q96PX9

0

guanine nucleotide exchange factor

up-regulates activity

0.285

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-260565

P78352

Q02156

0

phosphorylation

up-regulates quantity

0.285

PKCepsilon directly phosphorylated PSD-95 and JNK1 in vitro Inhibiting PKCepsilon, JNK, or calcium/calmodulin dependent kinase II activity prevented the effects of PKCepsilon activators on PSD-95 phosphorylation.|These results indicate that PKCepsilon promotes synaptogenesis by activating PSD-95 phosphorylation directly through JNK1 and calcium/calmodulin dependent kinase II and also by inducing expression of PSD-95 and synaptophysin.

SIGNOR-280087

P37275

P0C2W1

0

binding

down-regulates quantity by destabilization

0.285

One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively.

SIGNOR-272179

O43474

Q9Y4K3

0

ubiquitination

up-regulates quantity by stabilization

0.285

We further found that inhibition of polo-like kinase 1 could downregulate the expression of KLF4 and that PLK1 directly phosphorylated KLF4 at Ser234. Notably, phosphorylation of KLF4 by PLK1 caused the recruitment and binding of the E3 ligase TRAF6, which resulted in KLF4 K32 K63-linked ubiquitination and stabilization.

SIGNOR-277464

P12931

Q9UKA9

0

post transcriptional regulation

down-regulates quantity by repression

0.285

Splicing of the c-src N1 exon in neuronal cells depends in part on an intronic cluster of RNA regulatory elements called the downstream control sequence (DCS). |nPTB binds more stably to the DCS RNA than PTB does but is a weaker repressor of splicing in vitro. nPTB also greatly enhances the binding of two other proteins, hnRNP H and KSRP, to the DCS RNA.

SIGNOR-261267

P43403

Q6ISU1

0

binding

up-regulates activity

0.285

Stimulation of the T-cell antigen receptor (TCR) leads to tyrosine phosphorylation of a number of cellular proteins, including phospholipase C (PLC) gamma 1 and the TCR zeta chain. We describe here a 70-kDa tyrosine phosphoprotein (ZAP-70) that associates with zeta within 15 sec following TCR stimulation. The phosphorylation of ZAP-70 and its association with zeta is independent of the other TCR chains

SIGNOR-134325

P17861-2

Q09472

0

acetylation

up-regulates quantity by stabilization

0.285

P300 increases the acetylation and protein stability of XBP1s, and enhances its transcriptional activity, whereas SIRT1 deacetylates XBP1s and inhibits its transcriptional activity.. The mRNA encoding the active spliced form of XBP1 (XBP1s) is generated from the unspliced form by IRE1 (inositol-requiring enzyme 1) during the UPR.

SIGNOR-260429

O60331

P12931

0

phosphorylation

up-regulates

0.285

Phosphorylation by src of the tyrosine adjacent to s650 (y649 in human pipki gamma) was shown to enhance pipki gamma targeting to focal adhesions. We find that y649 phosphorylation does not stimulate directly pipki gamma binding to talin, but may do so indirectly by inhibiting s650 phosphorylation.

SIGNOR-134459

Q9Y6Q9

P48730

0

phosphorylation

up-regulates

0.284

In this study, we show that both eralpha and aib1 are substrates for ck1delta in vitro, and identify a novel aib1 phosphorylation site (s601) targeted by ck1delta, significant for the co-activator function of aib1.

SIGNOR-184946

P08670

P17252

0

phosphorylation

down-regulates quantity by destabilization

0.284

We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65.

SIGNOR-248880

O75385

O75592

0

ubiquitination

down-regulates quantity

0.284

Cell-based results demonstrate that the human PHR protein PAM restricts ULK1 protein levels (Fig.\u00a05h, i), and is sufficient to ubiquitinate ULK1 in a proteasome-dependent manner (Fig.\u00a05j).|Human PAM ubiquitinates ULK1 and regulates ULK1 levels.

SIGNOR-278765

Q13562

Q12857

0

transcriptional regulation

up-regulates quantity

0.284

For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)

SIGNOR-268890

P30305

P45983

0

phosphorylation

down-regulates quantity by destabilization

0.284

Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104).

SIGNOR-276352

Q12809

Q8N4C8

0

binding

up-regulates

0.284

Herg, a human homologue of the ether-a-go-go gene of the fruitfly drosophila melanogaster, encodes aproteinthat produces the rapidly activating cardiac delayed rectifier (i[kr]). / our results show that mink physically associates with herg and that the interaction leads to increased ikr current density.

SIGNOR-49869

Q16665

P98170

0

ubiquitination

up-regulates activity

0.284

HIF1alpha is ubiquitinated by XIAP.|Lys 63 -linked ubiquitination of HIF1alpha by XIAP is dependent on the activity of E2 ubiquitin conjugating enzyme Ubc13.|We find that XIAP and Ubc13 dependent Lys 63 -linked polyubiquitination promotes HIF1alpha nuclear retention leading to an increase in the expression of HIF1 responsive genes.|The data indicate that XIAP promotes the formation of the non-degradative Lys63-linked ubiquitin chains onto hypoxia inducible factor1\u03b1, but does not affect the formation of Lys48-linked chains.

SIGNOR-278740

P63096

Q9NQS5

0

binding

up-regulates activity

0.284

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-256704

Q70E73

P00519

0

phosphorylation

up-regulates activity

0.284

Here we show that phosphorylation of Lpd by c-Abl increases its interaction with Ena/VASP proteins. This analysis revealed that, in vitro, four Lpd peptides harboring tyrosines (Y426, Y456, Y513, Y1226) are highly phosphorylated, and eight additional peptides are phosphorylated to a lesser extent (Figure 1C).

SIGNOR-262606

P07359

P78536

0

cleavage

down-regulates activity

0.284

GPIbα is shed by metalloproteases such as ADAM17, a process that releases a soluble GPIbα fragment termed glycocalicin. ADAM17 cleaves within the GPIbα-based peptide (LRGV465LK) through a mechanism that is only partially understood [42]. GPIbα shedding has been shown to be constitutive but it can be increased by activation of protein kinases C (PKC) or inhibition of calmodulin [42, 43]. Shedding leads to decreased receptor density

SIGNOR-261861

Q9UPS8

Q01543

0

transcriptional regulation

down-regulates quantity by repression

0.284

In healthy individual, RUNX1/FLI1 complex negatively regulates ANKRD26 gene expression in MKs.

SIGNOR-266070

P46937

Q05397

0

phosphorylation

up-regulates activity

0.284

Then, FAK phosphorylates and activates YAP, leading to the activation and nuclear translocation of YAP/TAZ transcription factor, which is known to be involved in such cellular mechanoresponses [ xref , xref ].

SIGNOR-280099

P19793

Q8IXJ9

0

binding

up-regulates activity

0.284

In this study, we demonstrate that mammalian ASXL1 interacts with the AF-2 AD core of RAR (and RXR) through a novel, promiscuous NR box (LVMQLL) and enhances transcriptional activity of the receptors in certain cells.

SIGNOR-255911

P32119

P00519

0

phosphorylation

down-regulates activity

0.284

Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation.

SIGNOR-276280

P25490

P12931

0

phosphorylation

down-regulates activity

0.284

YY1 phosphorylation is mediated by Src family kinases.

SIGNOR-276940

P28845

P17676

0

transcriptional regulation

up-regulates quantity by expression

0.284

In conclusion, C/EBPalpha and C/EBPbeta control basal transcription, and TNF-alpha upregulates 11beta-HSD1, most likely by p38 MAPK-mediated increased binding of C/EBPbeta to the human HSD11B1 promoter.

SIGNOR-268972

Q02078

P11802

0

binding

down-regulates

0.284

In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms.

SIGNOR-176515

P63096

P21728

0

binding

up-regulates activity

0.284

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-257068

P43686

Q92630

0

phosphorylation

down-regulates quantity by destabilization

0.284

Through a kinome-wide screen, we have identified dual-specificity tyrosine-regulated kinase 2 (DYRK2) as the primary kinase that phosphorylates Rpt3-Thr25, leading to enhanced substrate translocation and degradation.

SIGNOR-275845

P19544

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.284

Glycogen synthase kinase 3β promoted phosphorylation of cugWT1 at S64, resulting in ubiquitination and degradation of the cugWT1 associated with the F-box-/- WD repeat-containing protein 8.

SIGNOR-277540

Q9HC16

P46934

0

ubiquitination

up-regulates activity

0.284

APOBEC3G ubiquitination by Nedd4-1 favors its packaging into HIV-1 particles|This could be explained in at least two ways : first, endogenous Nedd4 is naturally expressed at a level largely sufficient to target APOBEC3G into the VLP or virions.

SIGNOR-278635

Q14500

P17612

0

phosphorylation

down-regulates activity

0.283

Phosphorylation of the Kir2.2 C terminus by protein kinase A inhibited the association with SAP97.‚

SIGNOR-249998

Q8WXD9

P54762

0

phosphorylation

up-regulates activity

0.283

EphB1 phosphorylates Caskin1 on tyrosine 296 and 336. Tyrosine phosphorylated Caskin1 then likely promotes reorganization of the actin cytoskeleton leading to spine formation.

SIGNOR-262861

Q7Z434

P17612

0

phosphorylation

down-regulates activity

0.283

Mutagenesis indicated that PKACalpha phosphorylated wild-type VISA and the VISA mutants VISA (S100A), VISA (T234A) and VISA (S238A) but not VISA (T54A) (XREF_FIG, panel C).|We found that PKACalpha caused degradation of wild-type VISA but not VISA (T54A) or VISA (K7/500R), in which either the PKACs mediated phosphorylation or MARCH5 mediated K48 linked polyubiquitination residues are mutated (XREF_FIG, panel G).

SIGNOR-279649

Q06413

P11802

0

binding

down-regulates

0.283

In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms.

SIGNOR-176518

P02818

P09668

0

cleavage

down-regulates quantity by destabilization

0.283

This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42.

SIGNOR-256325

Q03113

P29371

0

binding

up-regulates activity

0.283

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-257389

P12830

P20794

0

phosphorylation

down-regulates

0.283

Finally, we speculate that there are two mechanisms whereby MAK inactivates CDH1 : the first is kinase dependent inactivation, modeled after CDK, where phosphorylation dissociates CDH1 from APC/C; the second is through physical binding of CDH1 with MAK.|These results suggest a cell cycle-dependent phosphorylation of CDH1 by MAK.

SIGNOR-278486

Q14344

P29371

0

binding

up-regulates activity

0.283

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-257438

P22459

Q8TBB1

0

ubiquitination

down-regulates quantity by destabilization

0.283

We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.The C-terminal LNX1 PDZ1-binding motifs of the ATP-binding cassette, subfamily A member 1 (ABC-1), PBK, glutamate receptor, ionotropic, N-methyl d-aspartate 1 (GRIN1), and Claudin-17 significantly promoted the ubiquitination of the corresponding artificial degrons by LNX1ΔPDZ234.

SIGNOR-272899

P06213

P09958

0

cleavage

up-regulates activity

0.283

Here we demonstrate that the two IR isoforms are similarly cleaved by furin, but when this furin-dependent maturation is inefficient, IR proforms move to the cell surface where the proprotein convertase PACE4 selectively supports IRB maturation.

SIGNOR-260365

Q13043

Q9H2K8

0

phosphorylation

up-regulates

0.283

In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2

SIGNOR-192762

P27986

Q5VWQ8

0

binding

down-regulates activity

0.283

DAB2IP binds the p85 subunit of PI3K through its PR domain and prevents PI3K-p85 relocation from the cytoplasm to the membrane, a necessary step for PI3K activation and signaling to AKT. Notably, DAB2IP reinforces this inhibitory effect by directly binding AKT.2

SIGNOR-254757

O14578

Q96GD4

0

phosphorylation

down-regulates activity

0.283

Finally, Aurora B phosphorylates CIT-K to control its localization and interaction with central spindle partners.|Together these findings indicate that CIT-K is an Aurora B substrate and that Aurora B phosphorylation at S699 dampens the association of CIT-K with KIF23 and the chromosomal passenger complex in order to reduce CIT-K accumulation at the spindle midzone in early cytokinesis.

SIGNOR-279140

P04818

Q9HCK8

0

transcriptional regulation

up-regulates quantity by expression

0.283

In order to identify CHD8 target genes, we performed a transcriptomic analysis of CHD8-depleted cells, finding out that CHD8 controls the expression of cyclin E2 (CCNE2) and thymidylate synthetase (TYMS), two genes expressed in the G1/S transition of the cell cycle. CHD8 was also able to co-activate the CCNE2 promoter in transient transfection experiments. Chromatin immunoprecipitation experiments demonstrated that CHD8 binds directly to the 5' region of both CCNE2 and TYMS genes.

SIGNOR-268805

Q9NQX3

P49841

0

phosphorylation

down-regulates

0.283

Identification of gsk3_ as the kinase targeting ser-270 /phosphorylation at ser-270 promotes gephyrin processing by calpain

SIGNOR-200957

Q9NY46

Q96PU5

0

ubiquitination

down-regulates quantity by destabilization

0.283

The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2).

SIGNOR-253464

Q9UQF2

Q7Z6J0

0

binding

up-regulates

0.283

We find that posh and jips directly associate with one another to form a multiprotein complex, pjac (posh-jip apoptotic complex), that includes all of the known kinase components of the pathway. Our observations indicate that this complex is required for jnk activation and cell death in response to apoptotic stimuli.

SIGNOR-145393

P14136

P17612

0

phosphorylation

down-regulates activity

0.283

GFAP can serve as a substrate for phosphorylation by CAMP-dependent protein kinase. CAMP-dependent protein kinase or protein kinase C phosphorylated Ser-8, Ser-13, and Ser-34.each phosphorylation was shown to induce disassembly of the glial filaments.

SIGNOR-249713

Q9BZE0

P17612

0

phosphorylation

down-regulates activity

0.283

Protein kinase a (pka) and glycogen synthase kinase 3beta sequentially phosphorylate gli2 at multiple sites, identified by mutagenesis, thus resulting in a reduction of its transcriptional activity

SIGNOR-145131

O15350

Q9H0M0

0

polyubiquitination

down-regulates quantity by destabilization

0.283

WWP1 in complex with WWP2 specifically regulates ΔNp73. In our study, we identified WWP2, an E3 ligase, as a novel p73-associated protein that ubiquitinates and degrades p73. In contrast, WWP2 heterodimerizes with another E3 ligase, WWP1, which specifically ubiquitinates and degrades ΔNp73.

SIGNOR-272232

Q01196

O60216

0

transcriptional regulation

down-regulates quantity by repression

0.283

We observed that depletion of RAD21 (but not CTCF) enhanced RUNX1 transcription in human HL-60 myelocytic leukemia cells

SIGNOR-259973

P05231

Q12968

0

transcriptional regulation

up-regulates quantity by expression

0.283

The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. |Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries.

SIGNOR-251732

Q15853

P49841

0

phosphorylation

up-regulates activity

0.283

Although no study has yet correlated the activity of GSK3beta with the activity of USF2 in a certain tumor setting, the findings of the present study would favor the tumor promoting aspects of GSK3beta and USF2 since GSK3beta activated USF2 enhanced cell migration which may be important in terms of tumor cell metastasis.|Together, these data show that there are two residues within USF2, namely S155 and T230, which can be phosphorylated by GSK3beta.

SIGNOR-278158

P35612

P17612

0

phosphorylation

down-regulates activity

0.283

Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of - and -adducin, respectively, were identified as the major phosphorylation sites common for PKA and PKC. Phosphorylation by PKA, but not PKC, reduced the affinity of adducin for spectrin-F-actin complexes as well as the activity of adducin in promoting binding of spectrin to F-actin.

SIGNOR-250332

Q9UGL1

Q99814

0

transcriptional regulation

up-regulates quantity by expression

0.283

To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.

SIGNOR-271578

O14686

O00141

0

phosphorylation

down-regulates activity

0.283

Elevated SGK1, in turn, phosphorylates KMT2D, suppressing its function, leading to a loss of methylation of lysine 4 on histone H3 (H3K4) and a repressive chromatin state at ER loci to attenuate ER activity.

SIGNOR-277447

Q14934

P28482

0

phosphorylation

up-regulates

0.283

We demonstrate that p90 ribosomal s6 kinase (rsk) is recruited to the nfat-dna transcription complex upon activation.Bound Rsk phosphorylates ser(676) and potentiates nfatc4 dna binding. Ser(676) is also targeted by the erk map kinase.

SIGNOR-133272

O15350

O00308

0

polyubiquitination

down-regulates quantity by destabilization

0.283

WWP2 ubiquitinates p73 and controls its protein stability. In our study, we identified WWP2, an E3 ligase, as a novel p73-associated protein that ubiquitinates and degrades p73. In contrast, WWP2 heterodimerizes with another E3 ligase, WWP1, which specifically ubiquitinates and degrades ΔNp73.

SIGNOR-272233

P63092

Q92847

0

binding

up-regulates activity

0.283

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0.

SIGNOR-256782

P29474

Q13131

0

phosphorylation

up-regulates

0.283

The central finding of this report is that rosiglitazone rapidly stimulates no production and enos ser-1177 phosphorylation in an ampk-dependent manner

SIGNOR-160838

Q12888

P49841

0

phosphorylation

up-regulates activity

0.283

Based on these observations, we hypothesized that the IR induced GSK3beta nuclear translocation may activate 53BP1 via phosphorylation at the S/T-Q motif.|Importantly, our in vivo and in vitro data clearly indicated that GSK3\u03b2 induced the phosphorylation of 53BP1 at the Ser166 site.

SIGNOR-278226

P46937

O15294

0

glycosylation

up-regulates activity

0.283

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

SIGNOR-276942

Q13683

P15173

0

transcriptional regulation

up-regulates quantity by expression

0.283

Only myogenin and MyoD were able to efficiently trans-activate the alpha7 promoter-CAT construct (Fig. 7). Myogenin trans-activated the promoter by _2-fold whereas MyoD was able to trans-activate by nearly 4-fold, indicating that both of these factors may play a role in alpha7 gene expression during muscle development.

SIGNOR-241521

Q07955

P21127

0

phosphorylation

up-regulates activity

0.283

In comparison, CLK1 expression leads to speckle dissolution and diffuse GFP-SRSF1 localization in the nucleus.|We showed that CLK1 phosphorylates SRSF1 at approximately 18 sites inducing a gel shift from 35 to about 38 kDa on SDS-PAGE (XREF_FIG, upper panel).

SIGNOR-279499

P16615

P49841

0

phosphorylation

down-regulates activity

0.283

GSK3β-dependent phosphorylation of SERCA2 at serine 663 in human and mouse hearts. Phosphorylation of SERCA2 at serine 663 regulates SERCA2 activity.

SIGNOR-277886

Q96RR4

P53355

0

phosphorylation

down-regulates

0.283

Dapk phosphorylates camkk. S511 was identified as the phosphorylation site . a potential mechanism of action was identified on the basis of the location of s511 near the cam recognition domain of camkk and demonstrated by attenuation of cam-stimulated camkk autophosphorylation after dapk phosphorylation.

SIGNOR-126241

P16949

O96013

0

phosphorylation

down-regulates activity

0.283

Indeed, we show here that inactivating phosphorylation of the endogenous stathmin on serine-16 is also induced by the active PAK4 in mitotic egg extract and is likely to participate in the observed stabilization of the MT asters ( xref , right).

SIGNOR-280058

Q9UNN5

Q14164

0

phosphorylation

down-regulates quantity by destabilization

0.283

Upon virus infection, the kinase IKKɛ directly phosphorylates FAF1 at Ser556 and triggers FAF1 de-aggregation. Moreover, Ser556 phosphorylation promotes FAF1 lysosomal degradation, consequently relieving FAF1-dependent suppression of MAVS.

SIGNOR-277618

Q13547

Q01664

0

binding

up-regulates activity

0.282

We also observed moderately increased recruitment of CTCF, HDAC1, and SP1 by the full-length AP-4 onto the WT DNA beads.

SIGNOR-226590

Q14524

Q92915

0

binding

down-regulates activity

0.282

Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.

SIGNOR-253417

P20393

P49841

0

phosphorylation

up-regulates

0.282

We show here that gsk3beta phosphorylates and stabilizes the orphan nuclear receptor rev-erbalpha, a negative component of the circadian clock.

SIGNOR-144570

Q8WXE1

Q96PY6

0

binding

up-regulates activity

0.282

It was reported that NEK1 associates with ATR/ATRIP and primes it for activation in response to a variety of genotoxic agents

SIGNOR-275842

P01106

Q15208

0

phosphorylation

down-regulates activity

0.282

Previously, we demonstrated that STK38 kinase mediates MYC phosphorylation.|STK38-WT overexpression dramatically reduced MYC half-life (4-fold), compared to control un induced cells (XREF_FIG), while STK38-KD overexpression led to increased MYC half-life (1.7 fold), illustrating an involvement in MYC protein turnover regulation (XREF_FIG).

SIGNOR-280142

Q15172

Q01484

0

relocalization

up-regulates quantity

0.282

Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins.

SIGNOR-266729

Q01196

Q86X55

0

methylation

down-regulates activity

0.282

We have found that PRMT4 is highly expressed in HSPCs, where it functions as an inhibitor of myeloid differentiation (Figure 7G). In these cells, PRMT4 methylates RUNX1 at R223, promoting the assembly of a DPF2-containing transcriptional co-repressive complex, and repressing transcription at the miR-223 locus.

SIGNOR-261967