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
Q01668	P43146	null	up-regulates activity	0.297	DCC activation by a netrin-1 gradient creates a high-level [Ca2+]i gradient by triggering LCC activity and by stimulating the cAMP–PKA pathway, which further activates LCC in the plasma membrane (PM) and Ca2+ channels in the ER.	SIGNOR-268292
P61278	P51608	post transcriptional regulation	up-regulates quantity by expression	0.297	MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1.	SIGNOR-264676
Q9GZQ8	Q96A56	binding	up-regulates	0.297	Tp53inp1-lc3 interaction occurs via a functional lc3-interacting region (lir)	SIGNOR-196673
Q14457	O60674	phosphorylation	up-regulates activity	0.297	Mechanistically, IL-6 triggers the interaction between JAK2 and BECN1, where JAK2 phosphorylates BECN1 at Y333. We demonstrate that BECN1 Y333 phosphorylation is crucial for BECN1 activation and IL-6-induced autophagy by regulating PI3KC3 complex formation.	SIGNOR-277567
P01116	Q0VAM2	binding	up-regulates	0.297	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-183835
Q14738	Q13315	phosphorylation	up-regulates activity	0.297	In the present study, we demonstrate that ataxia-telangiectasia mutated (ATM) directly phosphorylates and specifically regulates B56γ3, B56γ2 and B56δ, after DNA damage. We further show that phosphorylation of B56γ3 at Ser510 leads to an increase in B56γ3-PP2A complexes, and direction of PP2A phosphatase activity toward the substrate p53, activating its tumor-suppressive functions. we show that Ser510 phosphorylation significantly enhances the ability of B56γ3 to inhibit cell proliferation and anchorage-independent growth.	SIGNOR-276319
Q00535	P48729	phosphorylation	up-regulates activity	0.297	We also show that casein kinase I, but not casein kinase II, can phosphorylate and activate cdk5 in vitro. Ser(159) in cdk5 is homologous to the regulatory Thr(160) in cdk2.	SIGNOR-275966
O75925	Q99608	binding	down-regulates quantity by destabilization	0.297	Necdin bound to PIAS1 central domains that are highly conserved among PIAS family proteins and suppressed PIAS1-dependent sumoylation of the substrates STAT1 and PML (promyelocytic leukemia protein). Remarkably, necdin promoted degradation of PIAS1 via the ubiquitin-proteasome pathway. In transfected HEK293A cells, amino- and carboxyl-terminally truncated mutants of PIAS1 bound to necdin but failed to undergo necdin-dependent ubiquitination.	SIGNOR-253387
P27169	Q12772	transcriptional regulation	up-regulates quantity by expression	0.297	we conclude that quercetin exhibits its antiatherogenic property by eliciting the translocation of the mature SREBP2 from endoplasmic reticulum to the nucleus, where it binds to SRE-like sequence in the PON1 promoter and up-regulates PON1 gene transcription and PON1 activity.	SIGNOR-255224
Q13588	P15498	binding	up-regulates	0.297	Here we report that both in cell extracts and within intact mammalian cells vav binds to grb2 (sem-5/ash/drk), an adaptor molecule which plays a key role in ras activation.	SIGNOR-33840
O76061	Q16665	transcriptional regulation	up-regulates quantity by expression	0.297	With the ChIP assay, we demonstrated the direct binding of HIF-1alpha to STC2 promoter. These findings support the notion that HIF-1 is a potent stimulator of STC2 expression. Collectively, this is the first report to show that STC2 was aberrantly hypermethylated in human cancer cells. The findings demonstrated that STC2 epigenetic inactivation may interfere with HIF-1 mediated activation of STC2 expression.	SIGNOR-260389
P12814	Q9UPX8	relocalization	up-regulates activity	0.297	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264584
O95831	Q16611	relocalization	up-regulates	0.297	First, bax/bak-mediated momp leads to the release of a significant part of the cyt c, smac/diablo and htra2/omi proteins. in a third step, cyt c, smac/diablo and htra2/omi, which were released into the cytosol, trigger caspase activation. This is necessary to alter the physical association of aif and endog with the im to enable their relocation to the cytosol.	SIGNOR-192092
P42575	P78527	phosphorylation	up-regulates	0.297	Here we show that dna damage induced by gamma-radiation triggers the phosphorylation of nuclear caspase-2 at the s122 site within its prodomain, leading to its cleavage and activation. This phosphorylation is carried out by the nuclear serine/threonine protein kinase dna-pkcs	SIGNOR-183895
P30793	O95433	binding	up-regulates activity	0.297	The interaction of GCH1 with Aha1 may recruit GCH1 into the eNOS/Hsp90 complex so as to support local changes in nitric oxide production by endothelial cells.	SIGNOR-252213
O00141	P17612	phosphorylation	up-regulates activity	0.297	In this publication, we demonstrate that cAMP can activate Sgk and that this effect is mediated by PKA, which directly phosphorylates Thr369 in Sgk.	SIGNOR-275972
Q96S44	P31749	phosphorylation	up-regulates	0.297	Here we show that such an activation of prpk is mediated by another kinase, akt/pkb, which phosphorylates prpk at ser250.	SIGNOR-252503
P63000	Q3KR16	guanine nucleotide exchange factor	up-regulates activity	0.297	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-260568
Q05655	P08575	dephosphorylation	down-regulates activity	0.297	Taken together, these data indicate that CD45 inhibits PMA dependent PKCdelta activation by impeding PMA dependent PKCdelta tyrosine phosphorylation.\|reduction in CD45 expression caused the duration of peak PMA-induced MEK and extracellular signal-regulated kinase (ERK) 1/2 activity to increase from 5 min to 30 min while leading to a 4-fold increase in PMA-dependent PKCdelta activation.	SIGNOR-277028
O15182	Q15154	relocalization	up-regulates	0.297	Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome	SIGNOR-95016
P05107	Q99704	binding	down-regulates activity	0.297	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257680
P49841	P07384	cleavage	up-regulates activity	0.297	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-251586
P04183	P24941	phosphorylation	down-regulates	0.296	Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase.	SIGNOR-95578
Q03060	P06493	phosphorylation	down-regulates quantity by destabilization	0.296	The MAPKs extracellular signal-regulated kinases 1 and 2 physically interact with ICER and mediated the phosphorylation of ICER on a critical serine residue (Ser-41). A mutant form of ICER in which Ser-41 was substituted by alanine had a half-life 4-5 h longer than its wild-type counterpart. This alteration in stability was due to the inability of the Ser-41-mutant ICER to be efficiently ubiquitinated and degraded via the ubiquitin-proteasome pathway.	SIGNOR-275979
P35670	Q15139	phosphorylation	up-regulates activity	0.296	ATP7B trafficking was markedly reduced by the Ser-478/481/1121/1453 to Ala mutation. We conclude that PKD plays a key role in copper-dependent serine phosphorylation, permitting high levels of ATP7B protein expression and trafficking.	SIGNOR-272295
P62826	O75592	guanine nucleotide exchange factor	up-regulates activity	0.296	MYCBP2 Is a Nuclear GEF for Ran in DRG Neurons—Next, we studied whether or not MYCBP2 modulates the interaction between Ran/RanGAP1. MYCBP2 contains an N-terminal RCC1-like domain (Fig. 8C) (13), and RCC1 is a known GEF for Ran, indicating a potential functional interaction between MYCBP2 and Ran.	SIGNOR-261204
Q16649	P04150	transcriptional regulation	up-regulates quantity by expression	0.296	GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription	SIGNOR-268051
P53004	P31749	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
Q9Y6K9	P78527	phosphorylation	down-regulates activity	0.296	Here, we show that DNA-dependent protein kinase (DNA-PK), an enzyme involved in DNA double-strand break (DSB) repair, triggers the phosphorylation of NEMO by genotoxic stress, thereby enabling shuttling of NEMO through the nucleus with subsequent NF-κB activation. We identified serine 43 of NEMO as a DNA-PK phosphorylation site and point mutation of this serine to alanine led to a complete block of NF-κB activation by ionizing radiation (IR).	SIGNOR-277508
P09471	P28335	binding	up-regulates activity	0.296	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-257013
P98082	Q05655	phosphorylation	down-regulates	0.296	Mutational analysis revealed that a dab2 ser(24) phosphorylation mutant (s24a) abrogated the inhibitory function of dab2.	SIGNOR-127198
P18846	P68400	phosphorylation	up-regulates	0.296	Camk ii phosphorylates only ser63 (corresponding to ser133 of creb), which is essential for the activation, and not ser72 (corresponding to ser142 of creb), which is a negative regulation site	SIGNOR-42565
O96004	P17612	phosphorylation	down-regulates activity	0.296	In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. We determined that modification of HAND1 at residues 107 and 109 affects dimerization affinities with E-proteins, thus changing the bHLH dimer equilibrium within the cell. These modifications also affect HAND1 function.	SIGNOR-249991
P01137	P08047	transcriptional regulation	up-regulates quantity by expression	0.296	MAPKs have cis-acting regulatory elements in the mouse-TGF promoter region, which respond to various transcription factors, including specificity protein-1 and activating protein 1. Thus, it is possible that apoptotic cell-induced TGF-β mRNA expression is mediated through activation of these transcription factors via MAPK signaling. Xiao et al. reported that all of the MAPK members, including p38/ERK/JNK, are required for apoptotic Jurkat cells up-regulation of TGF-β production	SIGNOR-251740
Q9BW11	Q9UQE7	binding	down-regulates activity	0.296	We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive eects of Mad proteins on c-myc functions.	SIGNOR-241281
P04637	Q92569	binding	up-regulates activity	0.296	N this study, we aimed to explore the interaction of p55PIK with p53 and the role of p55PIK in regulating p53-dependent apoptosis in cancer cells. We found that p55PIK directly binds to the DBD domain of p53 via N24 domain. Moreover, the upregulation of p55PIK expression increases transcriptional levels of p53-dependent apoptosis-related genes including GADD45α, S100A9, MDM2 and AIP1. Furthermore, synthetic N24 translocated to nucleus can significantly inhibit cancer cell growth.	SIGNOR-261492
P45983	Q13464	phosphorylation	up-regulates activity	0.296	Instead, we found that rock activates jnk, which then phosphorylates c-jun and atf2 when bound to the c-jun promoter.	SIGNOR-123717
P49815	O15111	phosphorylation	down-regulates	0.296	Insulin activation of mtor requires akt in a manner that involves ikkalpha, preferentially to ikkbeta, and tsc2 phosphorylation	SIGNOR-178664
Q03112	P24941	phosphorylation	up-regulates activity	0.296	The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A.	SIGNOR-273426
P42261	Q15818	binding	up-regulates activity	0.296	We found that NP1 colocalizes and physically associates with the fast excitatory GluR1 AMPA receptors and that hypoxia induces a time-dependent increase in the NP1-GluR1 interactions. Thus hypoxia recruits NP1 protein to GluR1 subunits concurrent with the hypoxic excitotoxic cascade.\|Rather we propose that through interactions with GluR1 clusters, NP1 modulates the function of AMPA receptors in a manner whereby increased NP1-GluR1 interactions sensitize neurons to hypoxia-induced excitotoxic death.	SIGNOR-261430
P23760	P11802	phosphorylation	up-regulates activity	0.296	In summary, our study showed that Cdk4 phosphorylates and activates PAX3-FOXO1, thereby promoting its oncogenic function.\|These findings suggest that Cdk4 phosphorylates the Ser 430 residue of PAX3-FOXO1 in vitro .	SIGNOR-278512
Q06187	P31749	phosphorylation	down-regulates quantity by destabilization	0.296	The activated serine/threonine kinase Akt/protein kinase B (PKB) phosphorylated Btk on two sites prior to 14-3-3ζ binding. The interaction sites were mapped to phosphoserine pS51 in the pleckstrin homology domain and phosphothreonine pT495 in the kinase domain.	SIGNOR-276466
Q96PM5	Q9UQM7	phosphorylation	down-regulates	0.296	Phosphorylation of pirh2 by calmodulin-dependent kinase ii impairs its ability to ubiquitinate p53	SIGNOR-156064
P09471	P29275	binding	up-regulates activity	0.296	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-257240
Q05195	Q9UQE7	binding	down-regulates activity	0.296	We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive eects of Mad proteins on c-myc functions.	SIGNOR-241278
P60484	O75365	dephosphorylation	down-regulates quantity by destabilization	0.296	As expected, PRL3 clearly reduced PTEN phosphorylation at the tyrosine residue and PTEN protein in PRL3 overexpressing LO2 and HepG2 cell lines, with no significant changes in PRL3 (C104S) mutant cells.\|PRL3 down-regulates PTEN expression, a negative regulator of the Akt pathway.11 Phosphorylation of PTEN at Tyr336 is required for maintenance of PTEN protein stability and prevention of PTEN degradation.17 We therefore speculated that PRL3 might dephosphorylate PTEN at tyrosine sites and consequently reduce the PTEN protein level.	SIGNOR-277010
P50750	Q9UM73	phosphorylation	up-regulates activity	0.296	We report that anaplastic lymphoma kinase (ALK) directly phosphorylates CDK9 at tyrosine-19 to promote homologous recombination (HR) repair and PARP inhibitor resistance. Phospho-CDK9-Tyr19 increases its kinase activity and nuclear localization to stabilize positive transcriptional elongation factor b and activate polymerase II-dependent transcription of HR-repair genes.	SIGNOR-277607
Q14582	Q9UQE7	binding	down-regulates activity	0.296	We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive eects of Mad proteins on c-myc functions.	SIGNOR-241284
P07333	Q9H334	transcriptional regulation	down-regulates quantity by repression	0.296	Overexpression of MFH/Foxp1 markedly attenuated phorbol ester-induced expression of c-fms, which encodes the M-CSF receptor and is obligatory for macrophage differentiation.	SIGNOR-269048
Q13224	P60484	dephosphorylation	down-regulates activity	0.296	GluN2B Y1472 site is dephosphorylated by PTEN .	SIGNOR-277165
Q9UKT8	Q86Y07	phosphorylation	down-regulates activity	0.296	Collectively, CK1 and VRK2, but not GRK2 kinase, appears to mediate FBXW2 phosphorylation at the beta-TrCP binding motif.\|We followed this lead, and inactivated VRK2 and GRK2 by siRNA silencing, or CK1 and VRK2 by small molecule inhibitor IC-261, and found that GRK2 knockdown had no effect, whereas CK1 and VRK2 inhibition or VRK2 silencing largely blocked the degradation of exogenously expressed FBXW2 (XREF_FIG and XREF_SUPPLEMENTARY).	SIGNOR-280161
Q8WWK9	Q96GD4	phosphorylation	up-regulates	0.296	Here, we report that tmap is a novel substrate of the aurora b kinase. Ser627 of tmap was specifically phosphorylated by aurora b both in vitro and in vivo. Nearly all mutations at the phosphorylation motif had dramatic effects on the subcellular localization of tmap.	SIGNOR-165410
Q9NZA1	P06241	phosphorylation	up-regulates activity	0.296	In this paper, we demonstrate that p64 becomes tyrosine phosphorylated when co-expressed with p59(fyn) in HeLa cells.	SIGNOR-274006
Q99574	Q9UKV5	polyubiquitination	down-regulates quantity by destabilization	0.296	In this study, we demonstrate that two ER-associated E3 ligases, Hrd1 and gp78, are involved in the ubiquitination and degradation of mutant neuroserpin.	SIGNOR-272756
P48736	P01375	binding	up-regulates	0.296	Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k)	SIGNOR-70625
Q6WCQ1	Q13464	phosphorylation	down-regulates	0.296	Enhanced rho kinase activity induces endothelial barrier dysfunction by a contractile mechanism via inactivation of myosin phosphatase (mp)..	SIGNOR-157593
Q13043	O60346	dephosphorylation	up-regulates activity	0.295	PHLPPs dephosphorylate Mst1 on the T387 inhibitory site, which activate Mst1 and its downstream effectors p38 and JNK to induce apoptosis.	SIGNOR-248329
O95477	P00533	phosphorylation	down-regulates quantity by destabilization	0.295	We further provide in vitro evidence that epidermal growth factor receptor (EGFR)-mediated phosphorylation regulated ABCA1 ubiquitination \|The EGFR selective inhibitor PD168393 blocked the EGFR-ABCA1 interaction and abolished ABCA1Ser2054 phosphorylation\|	SIGNOR-264419
P28482	O43353	phosphorylation	up-regulates activity	0.295	RIP2 directly phosphorylates and activates ERK2 in vivo and in vitro.	SIGNOR-279106
Q13546	Q96AX9	ubiquitination	down-regulates quantity by destabilization	0.295	These data suggest that after binding, MIB2 inhibits RIPK1 through a mechanism that is dependent on the E3 ligase activity of MIB2.\|Whereas MIB2 readily ubiquitylated wild-type RIPK1, mutating K377 to R significantly reduced MIB2 mediated ubiquitylation of RIPK1 (XREF_SUPPLEMENTARY A).	SIGNOR-278633
O95997	P67775	dephosphorylation	up-regulates quantity by stabilization	0.295	CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase	SIGNOR-276376
Q9UQL6	Q9BZL6	phosphorylation	up-regulates activity	0.295	Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67].	SIGNOR-275929
O43318	P29350	dephosphorylation	down-regulates activity	0.295	Mechanistically, the association of EHEC Tir with SHP-1 facilitated the recruitment of SHP-1 to TAK1 and inhibited TAK1 phosphorylation, which then negatively regulated K63-linked polyubiquitination of TAK1 and downstream signal transduction.\|SHP-1 inhibits TAK1 activity to down-regulate signal transduction and subsequent cytokine production.Innate immune responses are achieved by the activation of several pathogen-recognition receptors (PRPs), including TLRs, retinoic acid inducible gene I (RIG-I)-like receptors (RLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs).	SIGNOR-277128
Q9GZQ8	Q9Y4K3	polyubiquitination	down-regulates quantity by destabilization	0.295	TRAF6 catalyzes K63-linked polyubiquitination of LC3B and promotes the formation of the LC3B-ATG7 and LC3B-CTNNB1 complexes.	SIGNOR-277439
P10912	P17706	dephosphorylation	down-regulates activity	0.295	PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates	SIGNOR-248394
Q15637	P18146	binding	up-regulates activity	0.295	GNRH1 induces expression of early growth response 1 (EGR1), which interacts with steroidogenic factor 1 (SF1) and paired-like homeodomain transcription factor 1 (PITX1) to regulate Lhb promoter activity.	SIGNOR-254914
P43354	Q9UPW6	transcriptional regulation	down-regulates quantity	0.295	Satb2 represses the transcription of Nr4a2. The misexpression of Nr4a2 together with Ctip2 induces expression of SubC-specific genes in wild-type Rsp, and simultaneous knockdown of these two genes in Rsp Satb2-mutant cells prevents their fate transition to SubC identity. Thus, Satb2 serves as a determinant gene in the Rsp regionalization by repressing Nr4a2 and Ctip2 during cortical development	SIGNOR-268930
P17612	O43823	binding	up-regulates activity	0.295	To determine whether AKAP95 and p105 were present in a complex in mammalian cells, FLAG-tagged AKAP95 wascoexpressed with Myc-tagged p105 in human embryonic kidney (HEK) 293 cells. Immunoprecipitation of either protein pulled down a complex containing AKAP95, p105, and PKA-Ca (Fig. 6D).\|The identification of a PKA phosphorylation site in the C-terminal region of p105 suggests that p105 is a candidate substrate for AKAP95-targeted PKA.	SIGNOR-260302
P50219	P49841	phosphorylation	down-regulates	0.295	Here we show that gsk-3_ inactivates the proapoptotic activity of hlxb9 by phosphorylating hlxb9 at ser-78/ser-80 (phlxb9).	SIGNOR-203657
P01100	O75534	post transcriptional regulation	down-regulates quantity	0.295	By testing different classes of mammalian poly(A) nucleases, we identified CCR4 as a poly(A) nuclease involved in the mCRD-mediated rapid deadenylation in viv	SIGNOR-261145
P10912	Q9HD43	dephosphorylation	down-regulates activity	0.295	Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR	SIGNOR-248802
Q8NEB9	Q9Y2M5	binding	down-regulates quantity by destabilization	0.295	Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination. KLHL20 promotes ubiquitination of phagophore-residing VPS34 and Beclin-1	SIGNOR-272414
P35711	Q8IYA7	transcriptional regulation	up-regulates quantity by expression	0.295	MKX is a meniscus-enriched transcription factor. In human meniscus cells, MKX regulates the expression of meniscus marker genes, OA-related genes, and other transcription factors, including Scleraxis (SCX), SRY Box 5 (SOX5), and Runt domain-related transcription factor 2 (RUNX2).	SIGNOR-267214
P10912	P23467	dephosphorylation	down-regulates	0.295	Inally, mrna tissue distribution of these ptps by rt-pcr analysis and coexpression of the wild-type ptps to test their ability to dephosphorylate ligand-activated ghr suggest ptp-h1 and ptp1b as potential candidates involved in ghr signaling.	SIGNOR-104580
Q92481	Q15139	phosphorylation	down-regulates activity	0.295	Mechanistically, we observed that PKD phosphorylates AP2\u03b2 at Ser-258 and Ser-277 and suppresses its nuclear accumulation.\|Using ChIP analyses, here we found that PKD knockdown in HUVECs increases binding of AP2beta to the VEGFR-2 promoter.	SIGNOR-279267
P11021	O95260	post transcriptional regulation	down-regulates quantity by destabilization	0.295	We showed that the molecular chaperone BiP (also known as GRP78) was short-lived under basal conditions and ER stress. The turnover of BiP was in part driven by its amino-terminal arginylation (Nt-arginylation) by the arginyltransferase ATE1, which generated an autophagic N-degron of the N-end rule pathway.	SIGNOR-261345
Q92934	P23443	phosphorylation	down-regulates activity	0.295	P70S6K, the downstream target of mTORC1, can phosphorylate and inactivate pro apoptotic BAD by producing a reaction that disrupts BAD 's binding to other pro apoptotic molecules thereby allowing cell survival.\|p70S6K, the downstream target of mTORC1, can phosphorylate and inactivate pro-apoptotic BAD by producing a reaction that disrupts BAD\u2019s binding to other pro-apoptotic molecules thereby allowing cell survival. xref , xref On the other hand, in a recent study, Li et al showed that increased expression of anti-apoptotic BCL2 was induced in myeloid progenitor cells upon activation of p76S6K, thereby promoting cell survival. xref Further studies are needed to better understand the effect of rapamycin and its derivatives on apoptosis in various cancer cells.	SIGNOR-280016
Q15208	P17612	phosphorylation	down-regulates activity	0.295	GSK-3β phosphorylated STK38 on residues S6 and T7 in vitro, depending largely on a PKA-mediated priming phosphorylation of STK38 on residues S10 and S11, respectively. Our results indicate that that GSK-3β inhibits STK38's full activation, and suggest that STK38 activation is required to prevent cell death in response to oxidative stress.	SIGNOR-276390
O43464	Q16611	relocalization	up-regulates	0.295	Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi	SIGNOR-118908
Q9BY11	O96013	phosphorylation	up-regulates activity	0.295	We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo.	SIGNOR-263023
Q9UL17	Q96NM4	transcriptional regulation	up-regulates quantity by expression	0.294	We subsequently found that TOX2 was independent of ETS-1 but could directly upregulate the transcription of TBX21 (encoding T-BET).	SIGNOR-266097
P27694	Q9NUX5	binding	down-regulates activity	0.294	The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA	SIGNOR-263325
P18084	Q99704	binding	down-regulates activity	0.294	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257691
Q9UHP3	Q86Y07	phosphorylation	down-regulates activity	0.294	Here, we report that USP25 is a novel TRiC interacting protein that is also phosphorylated by VRK2. USP25 catalyzed deubiquitination of the TRiC protein and stabilized the chaperonin, thereby reducing accumulation of misfolded polyglutamine protein aggregates. Notably, USP25 deubiquitinating activity was suppressed when VRK2 phosphorylated the Thr(680), Thr(727), and Ser(745) residues.	SIGNOR-273579
P49768	Q99590	cleavage	up-regulates activity	0.294	Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis.	SIGNOR-261758
P56750	Q8TBB1	ubiquitination	down-regulates quantity by destabilization	0.294	We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.	SIGNOR-272900
P27986	P63092	binding	up-regulates	0.294	Notably, the fzd7 receptor complex was associated with g_?(s) and pi(3)k and these components were required for wnt7a to activate the akt/mtor growth pathway in myotubes. These data led us to hypothesize that g_?s Mediates the activation of pi3kinase following wnt7a binding to fzd7.	SIGNOR-191561
O75030	P49840	phosphorylation	up-regulates	0.294	Glycogen synthase kinase 3 (gsk3) was found to phosphorylate ser298 in vitro, thereby enhancing the binding of mitf to the tyrosinase promoter	SIGNOR-72878
P49841	P27361	phosphorylation	down-regulates activity	0.294	We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels	SIGNOR-262523
Q9H3M7	P28482	phosphorylation	down-regulates quantity by destabilization	0.294	ERK-dependent Txnip ubiquitination and proteasome degradation depended upon phosphorylation of a PXTP motif threonine (Thr349) located within the C-terminal α-arrestin domain and proximal to a previously characterized E3 ubiquitin ligase-binding site.	SIGNOR-277468
P23760	P54727	binding	down-regulates activity	0.294	Monoubiquitinated Pax3 was shuttled to the intrinsic proteasomal protein S5a by interacting specifically with the ubiquitin-binding protein Rad23B.	SIGNOR-237667
P15172	Q14469	transcriptional regulation	down-regulates activity	0.294	Notch signaling up-regulated HES1 mRNA expression within 1 h and subsequently reduced expression of MyoD mRNA	SIGNOR-243181
P22223	Q9UQB3	binding	up-regulates quantity by stabilization	0.294	To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member.	SIGNOR-252130
P12268	P01106	transcriptional regulation	up-regulates quantity by expression	0.294	Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation.	SIGNOR-267375
P15056	P62136	dephosphorylation	up-regulates activity	0.294	To address whether PP1\u03b1 activates B-Raf through these inhibitory sites, we made use of B-Raf protein mutants in which an individual inhibitory site, as well as all four sites (4A), were mutated to alanine.\|We confirmed that GST-B-Raf was phosphorylated by ERK2 in vitro xref , mainly on S151 and T753 (Fig.\u00a0 xref ), and found that PP1\u03b1 dephosphorylated B-Raf on both ERK phosphorylation sites (Fig.\u00a0 xref ).	SIGNOR-277160
P53350	P11309	phosphorylation	down-regulates activity	0.294	This data strongly indicates that Pim1 phosphorylates PLK1 at threonine 210, a site previously reported to be phosphorylated by aurora A kinase during mitosis.	SIGNOR-279749
Q15465	Q92935	binding	down-regulates	0.294	A study in mice suggests that ext1 proteins might negatively regulate shh signaling by synthesizing hspgs, which sequester the ligand	SIGNOR-132606
P04150	Q53ET0	binding	up-regulates activity	0.294	We show here that CRTC2 also functions as a coactivator for the glucocorticoid receptor (GR).	SIGNOR-256101
Q15052	Q8TDY4	binding	up-regulates activity	0.294	ArfGAP With Coiled-Coil, Ankyrin Repeat And PH Domains 4 (ACAP4) is an ADP-ribosylation factor 6 (ARF6) GTPase-activating protein essential for EGF-elicited cell migration. \|The crystal structure of the catalytic core of ACAP4 in a complex with ARF6 reveals the structural determinants underlying ACAP4 selectivity and specificity as an ARF6 GTPase-activating protein	SIGNOR-272235
P07196	P61981	binding	down-regulates activity	0.294	These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments.	SIGNOR-252400

Q01668

P43146

0

null

up-regulates activity

0.297

DCC activation by a netrin-1 gradient creates a high-level [Ca2+]i gradient by triggering LCC activity and by stimulating the cAMP–PKA pathway, which further activates LCC in the plasma membrane (PM) and Ca2+ channels in the ER.

SIGNOR-268292

P61278

P51608

0

post transcriptional regulation

up-regulates quantity by expression

0.297

MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1.

SIGNOR-264676

Q9GZQ8

Q96A56

0

binding

up-regulates

0.297

Tp53inp1-lc3 interaction occurs via a functional lc3-interacting region (lir)

SIGNOR-196673

Q14457

O60674

0

phosphorylation

up-regulates activity

0.297

Mechanistically, IL-6 triggers the interaction between JAK2 and BECN1, where JAK2 phosphorylates BECN1 at Y333. We demonstrate that BECN1 Y333 phosphorylation is crucial for BECN1 activation and IL-6-induced autophagy by regulating PI3KC3 complex formation.

SIGNOR-277567

P01116

Q0VAM2

0

binding

up-regulates

0.297

Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.

SIGNOR-183835

Q14738

Q13315

0

phosphorylation

up-regulates activity

0.297

In the present study, we demonstrate that ataxia-telangiectasia mutated (ATM) directly phosphorylates and specifically regulates B56γ3, B56γ2 and B56δ, after DNA damage. We further show that phosphorylation of B56γ3 at Ser510 leads to an increase in B56γ3-PP2A complexes, and direction of PP2A phosphatase activity toward the substrate p53, activating its tumor-suppressive functions. we show that Ser510 phosphorylation significantly enhances the ability of B56γ3 to inhibit cell proliferation and anchorage-independent growth.

SIGNOR-276319

Q00535

P48729

0

phosphorylation

up-regulates activity

0.297

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

SIGNOR-275966

O75925

Q99608

0

binding

down-regulates quantity by destabilization

0.297

Necdin bound to PIAS1 central domains that are highly conserved among PIAS family proteins and suppressed PIAS1-dependent sumoylation of the substrates STAT1 and PML (promyelocytic leukemia protein). Remarkably, necdin promoted degradation of PIAS1 via the ubiquitin-proteasome pathway. In transfected HEK293A cells, amino- and carboxyl-terminally truncated mutants of PIAS1 bound to necdin but failed to undergo necdin-dependent ubiquitination.

SIGNOR-253387

P27169

Q12772

0

transcriptional regulation

up-regulates quantity by expression

0.297

we conclude that quercetin exhibits its antiatherogenic property by eliciting the translocation of the mature SREBP2 from endoplasmic reticulum to the nucleus, where it binds to SRE-like sequence in the PON1 promoter and up-regulates PON1 gene transcription and PON1 activity.

SIGNOR-255224

Q13588

P15498

0

binding

up-regulates

0.297

Here we report that both in cell extracts and within intact mammalian cells vav binds to grb2 (sem-5/ash/drk), an adaptor molecule which plays a key role in ras activation.

SIGNOR-33840

O76061

Q16665

0

transcriptional regulation

up-regulates quantity by expression

0.297

With the ChIP assay, we demonstrated the direct binding of HIF-1alpha to STC2 promoter. These findings support the notion that HIF-1 is a potent stimulator of STC2 expression. Collectively, this is the first report to show that STC2 was aberrantly hypermethylated in human cancer cells. The findings demonstrated that STC2 epigenetic inactivation may interfere with HIF-1 mediated activation of STC2 expression.

SIGNOR-260389

P12814

Q9UPX8

0

relocalization

up-regulates activity

0.297

SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).

SIGNOR-264584

O95831

Q16611

0

relocalization

up-regulates

0.297

First, bax/bak-mediated momp leads to the release of a significant part of the cyt c, smac/diablo and htra2/omi proteins. in a third step, cyt c, smac/diablo and htra2/omi, which were released into the cytosol, trigger caspase activation. This is necessary to alter the physical association of aif and endog with the im to enable their relocation to the cytosol.

SIGNOR-192092

P42575

P78527

0

phosphorylation

up-regulates

0.297

Here we show that dna damage induced by gamma-radiation triggers the phosphorylation of nuclear caspase-2 at the s122 site within its prodomain, leading to its cleavage and activation. This phosphorylation is carried out by the nuclear serine/threonine protein kinase dna-pkcs

SIGNOR-183895

P30793

O95433

0

binding

up-regulates activity

0.297

The interaction of GCH1 with Aha1 may recruit GCH1 into the eNOS/Hsp90 complex so as to support local changes in nitric oxide production by endothelial cells.

SIGNOR-252213

O00141

P17612

0

phosphorylation

up-regulates activity

0.297

In this publication, we demonstrate that cAMP can activate Sgk and that this effect is mediated by PKA, which directly phosphorylates Thr369 in Sgk.

SIGNOR-275972

Q96S44

P31749

0

phosphorylation

up-regulates

0.297

Here we show that such an activation of prpk is mediated by another kinase, akt/pkb, which phosphorylates prpk at ser250.

SIGNOR-252503

P63000

Q3KR16

0

guanine nucleotide exchange factor

up-regulates activity

0.297

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-260568

Q05655

P08575

0

dephosphorylation

down-regulates activity

0.297

Taken together, these data indicate that CD45 inhibits PMA dependent PKCdelta activation by impeding PMA dependent PKCdelta tyrosine phosphorylation.|reduction in CD45 expression caused the duration of peak PMA-induced MEK and extracellular signal-regulated kinase (ERK) 1/2 activity to increase from 5 min to 30 min while leading to a 4-fold increase in PMA-dependent PKCdelta activation.

SIGNOR-277028

O15182

Q15154

0

relocalization

up-regulates

0.297

Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome

SIGNOR-95016

P05107

Q99704

0

binding

down-regulates activity

0.297

Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation

SIGNOR-257680

P49841

P07384

0

cleavage

up-regulates activity

0.297

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-251586

P04183

P24941

0

phosphorylation

down-regulates

0.296

Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase.

SIGNOR-95578

Q03060

P06493

0

phosphorylation

down-regulates quantity by destabilization

0.296

The MAPKs extracellular signal-regulated kinases 1 and 2 physically interact with ICER and mediated the phosphorylation of ICER on a critical serine residue (Ser-41). A mutant form of ICER in which Ser-41 was substituted by alanine had a half-life 4-5 h longer than its wild-type counterpart. This alteration in stability was due to the inability of the Ser-41-mutant ICER to be efficiently ubiquitinated and degraded via the ubiquitin-proteasome pathway.

SIGNOR-275979

P35670

Q15139

0

phosphorylation

up-regulates activity

0.296

ATP7B trafficking was markedly reduced by the Ser-478/481/1121/1453 to Ala mutation. We conclude that PKD plays a key role in copper-dependent serine phosphorylation, permitting high levels of ATP7B protein expression and trafficking.

SIGNOR-272295

P62826

O75592

0

guanine nucleotide exchange factor

up-regulates activity

0.296

MYCBP2 Is a Nuclear GEF for Ran in DRG Neurons—Next, we studied whether or not MYCBP2 modulates the interaction between Ran/RanGAP1. MYCBP2 contains an N-terminal RCC1-like domain (Fig. 8C) (13), and RCC1 is a known GEF for Ran, indicating a potential functional interaction between MYCBP2 and Ran.

SIGNOR-261204

Q16649

P04150

0

transcriptional regulation

up-regulates quantity by expression

0.296

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

SIGNOR-268051

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

Q9Y6K9

P78527

0

phosphorylation

down-regulates activity

0.296

Here, we show that DNA-dependent protein kinase (DNA-PK), an enzyme involved in DNA double-strand break (DSB) repair, triggers the phosphorylation of NEMO by genotoxic stress, thereby enabling shuttling of NEMO through the nucleus with subsequent NF-κB activation. We identified serine 43 of NEMO as a DNA-PK phosphorylation site and point mutation of this serine to alanine led to a complete block of NF-κB activation by ionizing radiation (IR).

SIGNOR-277508

P09471

P28335

0

binding

up-regulates activity

0.296

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-257013

P98082

Q05655

0

phosphorylation

down-regulates

0.296

Mutational analysis revealed that a dab2 ser(24) phosphorylation mutant (s24a) abrogated the inhibitory function of dab2.

SIGNOR-127198

P18846

P68400

0

phosphorylation

up-regulates

0.296

Camk ii phosphorylates only ser63 (corresponding to ser133 of creb), which is essential for the activation, and not ser72 (corresponding to ser142 of creb), which is a negative regulation site

SIGNOR-42565

O96004

P17612

0

phosphorylation

down-regulates activity

0.296

In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. We determined that modification of HAND1 at residues 107 and 109 affects dimerization affinities with E-proteins, thus changing the bHLH dimer equilibrium within the cell. These modifications also affect HAND1 function.

SIGNOR-249991

P01137

P08047

0

transcriptional regulation

up-regulates quantity by expression

0.296

MAPKs have cis-acting regulatory elements in the mouse-TGF promoter region, which respond to various transcription factors, including specificity protein-1 and activating protein 1. Thus, it is possible that apoptotic cell-induced TGF-β mRNA expression is mediated through activation of these transcription factors via MAPK signaling. Xiao et al. reported that all of the MAPK members, including p38/ERK/JNK, are required for apoptotic Jurkat cells up-regulation of TGF-β production

SIGNOR-251740

Q9BW11

Q9UQE7

0

binding

down-regulates activity

0.296

We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive eects of Mad proteins on c-myc functions.

SIGNOR-241281

P04637

Q92569

0

binding

up-regulates activity

0.296

N this study, we aimed to explore the interaction of p55PIK with p53 and the role of p55PIK in regulating p53-dependent apoptosis in cancer cells. We found that p55PIK directly binds to the DBD domain of p53 via N24 domain. Moreover, the upregulation of p55PIK expression increases transcriptional levels of p53-dependent apoptosis-related genes including GADD45α, S100A9, MDM2 and AIP1. Furthermore, synthetic N24 translocated to nucleus can significantly inhibit cancer cell growth.

SIGNOR-261492

P45983

Q13464

0

phosphorylation

up-regulates activity

0.296

Instead, we found that rock activates jnk, which then phosphorylates c-jun and atf2 when bound to the c-jun promoter.

SIGNOR-123717

P49815

O15111

0

phosphorylation

down-regulates

0.296

Insulin activation of mtor requires akt in a manner that involves ikkalpha, preferentially to ikkbeta, and tsc2 phosphorylation

SIGNOR-178664

Q03112

P24941

0

phosphorylation

up-regulates activity

0.296

The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A.

SIGNOR-273426

P42261

Q15818

0

binding

up-regulates activity

0.296

We found that NP1 colocalizes and physically associates with the fast excitatory GluR1 AMPA receptors and that hypoxia induces a time-dependent increase in the NP1-GluR1 interactions. Thus hypoxia recruits NP1 protein to GluR1 subunits concurrent with the hypoxic excitotoxic cascade.|Rather we propose that through interactions with GluR1 clusters, NP1 modulates the function of AMPA receptors in a manner whereby increased NP1-GluR1 interactions sensitize neurons to hypoxia-induced excitotoxic death.

SIGNOR-261430

P23760

P11802

0

phosphorylation

up-regulates activity

0.296

In summary, our study showed that Cdk4 phosphorylates and activates PAX3-FOXO1, thereby promoting its oncogenic function.|These findings suggest that Cdk4 phosphorylates the Ser 430 residue of PAX3-FOXO1 in vitro .

SIGNOR-278512

Q06187

P31749

0

phosphorylation

down-regulates quantity by destabilization

0.296

The activated serine/threonine kinase Akt/protein kinase B (PKB) phosphorylated Btk on two sites prior to 14-3-3ζ binding. The interaction sites were mapped to phosphoserine pS51 in the pleckstrin homology domain and phosphothreonine pT495 in the kinase domain.

SIGNOR-276466

Q96PM5

Q9UQM7

0

phosphorylation

down-regulates

0.296

Phosphorylation of pirh2 by calmodulin-dependent kinase ii impairs its ability to ubiquitinate p53

SIGNOR-156064

P09471

P29275

0

binding

up-regulates activity

0.296

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-257240

Q05195

Q9UQE7

0

binding

down-regulates activity

0.296

We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive eects of Mad proteins on c-myc functions.

SIGNOR-241278

P60484

O75365

0

dephosphorylation

down-regulates quantity by destabilization

0.296

As expected, PRL3 clearly reduced PTEN phosphorylation at the tyrosine residue and PTEN protein in PRL3 overexpressing LO2 and HepG2 cell lines, with no significant changes in PRL3 (C104S) mutant cells.|PRL3 down-regulates PTEN expression, a negative regulator of the Akt pathway.11 Phosphorylation of PTEN at Tyr336 is required for maintenance of PTEN protein stability and prevention of PTEN degradation.17 We therefore speculated that PRL3 might dephosphorylate PTEN at tyrosine sites and consequently reduce the PTEN protein level.

SIGNOR-277010

P50750

Q9UM73

0

phosphorylation

up-regulates activity

0.296

We report that anaplastic lymphoma kinase (ALK) directly phosphorylates CDK9 at tyrosine-19 to promote homologous recombination (HR) repair and PARP inhibitor resistance. Phospho-CDK9-Tyr19 increases its kinase activity and nuclear localization to stabilize positive transcriptional elongation factor b and activate polymerase II-dependent transcription of HR-repair genes.

SIGNOR-277607

Q14582

Q9UQE7

0

binding

down-regulates activity

0.296

We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive eects of Mad proteins on c-myc functions.

SIGNOR-241284

P07333

Q9H334

0

transcriptional regulation

down-regulates quantity by repression

0.296

Overexpression of MFH/Foxp1 markedly attenuated phorbol ester-induced expression of c-fms, which encodes the M-CSF receptor and is obligatory for macrophage differentiation.

SIGNOR-269048

Q13224

P60484

0

dephosphorylation

down-regulates activity

0.296

GluN2B Y1472 site is dephosphorylated by PTEN .

SIGNOR-277165

Q9UKT8

Q86Y07

0

phosphorylation

down-regulates activity

0.296

Collectively, CK1 and VRK2, but not GRK2 kinase, appears to mediate FBXW2 phosphorylation at the beta-TrCP binding motif.|We followed this lead, and inactivated VRK2 and GRK2 by siRNA silencing, or CK1 and VRK2 by small molecule inhibitor IC-261, and found that GRK2 knockdown had no effect, whereas CK1 and VRK2 inhibition or VRK2 silencing largely blocked the degradation of exogenously expressed FBXW2 (XREF_FIG and XREF_SUPPLEMENTARY).

SIGNOR-280161

Q8WWK9

Q96GD4

0

phosphorylation

up-regulates

0.296

Here, we report that tmap is a novel substrate of the aurora b kinase. Ser627 of tmap was specifically phosphorylated by aurora b both in vitro and in vivo. Nearly all mutations at the phosphorylation motif had dramatic effects on the subcellular localization of tmap.

SIGNOR-165410

Q9NZA1

P06241

0

phosphorylation

up-regulates activity

0.296

In this paper, we demonstrate that p64 becomes tyrosine phosphorylated when co-expressed with p59(fyn) in HeLa cells.

SIGNOR-274006

Q99574

Q9UKV5

0

polyubiquitination

down-regulates quantity by destabilization

0.296

In this study, we demonstrate that two ER-associated E3 ligases, Hrd1 and gp78, are involved in the ubiquitination and degradation of mutant neuroserpin.

SIGNOR-272756

P48736

P01375

0

binding

up-regulates

0.296

Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k)

SIGNOR-70625

Q6WCQ1

Q13464

0

phosphorylation

down-regulates

0.296

Enhanced rho kinase activity induces endothelial barrier dysfunction by a contractile mechanism via inactivation of myosin phosphatase (mp)..

SIGNOR-157593

Q13043

O60346

0

dephosphorylation

up-regulates activity

0.295

PHLPPs dephosphorylate Mst1 on the T387 inhibitory site, which activate Mst1 and its downstream effectors p38 and JNK to induce apoptosis.

SIGNOR-248329

O95477

P00533

0

phosphorylation

down-regulates quantity by destabilization

0.295

We further provide in vitro evidence that epidermal growth factor receptor (EGFR)-mediated phosphorylation regulated ABCA1 ubiquitination |The EGFR selective inhibitor PD168393 blocked the EGFR-ABCA1 interaction and abolished ABCA1Ser2054 phosphorylation|

SIGNOR-264419

P28482

O43353

0

phosphorylation

up-regulates activity

0.295

RIP2 directly phosphorylates and activates ERK2 in vivo and in vitro.

SIGNOR-279106

Q13546

Q96AX9

0

ubiquitination

down-regulates quantity by destabilization

0.295

These data suggest that after binding, MIB2 inhibits RIPK1 through a mechanism that is dependent on the E3 ligase activity of MIB2.|Whereas MIB2 readily ubiquitylated wild-type RIPK1, mutating K377 to R significantly reduced MIB2 mediated ubiquitylation of RIPK1 (XREF_SUPPLEMENTARY A).

SIGNOR-278633

O95997

P67775

0

dephosphorylation

up-regulates quantity by stabilization

0.295

CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase

SIGNOR-276376

Q9UQL6

Q9BZL6

0

phosphorylation

up-regulates activity

0.295

Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67].

SIGNOR-275929

O43318

P29350

0

dephosphorylation

down-regulates activity

0.295

Mechanistically, the association of EHEC Tir with SHP-1 facilitated the recruitment of SHP-1 to TAK1 and inhibited TAK1 phosphorylation, which then negatively regulated K63-linked polyubiquitination of TAK1 and downstream signal transduction.|SHP-1 inhibits TAK1 activity to down-regulate signal transduction and subsequent cytokine production.Innate immune responses are achieved by the activation of several pathogen-recognition receptors (PRPs), including TLRs, retinoic acid inducible gene I (RIG-I)-like receptors (RLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs).

SIGNOR-277128

Q9GZQ8

Q9Y4K3

0

polyubiquitination

down-regulates quantity by destabilization

0.295

TRAF6 catalyzes K63-linked polyubiquitination of LC3B and promotes the formation of the LC3B-ATG7 and LC3B-CTNNB1 complexes.

SIGNOR-277439

P10912

P17706

0

dephosphorylation

down-regulates activity

0.295

PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates

SIGNOR-248394

Q15637

P18146

0

binding

up-regulates activity

0.295

GNRH1 induces expression of early growth response 1 (EGR1), which interacts with steroidogenic factor 1 (SF1) and paired-like homeodomain transcription factor 1 (PITX1) to regulate Lhb promoter activity.

SIGNOR-254914

P43354

Q9UPW6

0

transcriptional regulation

down-regulates quantity

0.295

Satb2 represses the transcription of Nr4a2. The misexpression of Nr4a2 together with Ctip2 induces expression of SubC-specific genes in wild-type Rsp, and simultaneous knockdown of these two genes in Rsp Satb2-mutant cells prevents their fate transition to SubC identity. Thus, Satb2 serves as a determinant gene in the Rsp regionalization by repressing Nr4a2 and Ctip2 during cortical development

SIGNOR-268930

P17612

O43823

0

binding

up-regulates activity

0.295

To determine whether AKAP95 and p105 were present in a complex in mammalian cells, FLAG-tagged AKAP95 wascoexpressed with Myc-tagged p105 in human embryonic kidney (HEK) 293 cells. Immunoprecipitation of either protein pulled down a complex containing AKAP95, p105, and PKA-Ca (Fig. 6D).|The identification of a PKA phosphorylation site in the C-terminal region of p105 suggests that p105 is a candidate substrate for AKAP95-targeted PKA.

SIGNOR-260302

P50219

P49841

0

phosphorylation

down-regulates

0.295

Here we show that gsk-3_ inactivates the proapoptotic activity of hlxb9 by phosphorylating hlxb9 at ser-78/ser-80 (phlxb9).

SIGNOR-203657

P01100

O75534

0

post transcriptional regulation

down-regulates quantity

0.295

By testing different classes of mammalian poly(A) nucleases, we identified CCR4 as a poly(A) nuclease involved in the mCRD-mediated rapid deadenylation in viv

SIGNOR-261145

P10912

Q9HD43

0

dephosphorylation

down-regulates activity

0.295

Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR

SIGNOR-248802

Q8NEB9

Q9Y2M5

0

binding

down-regulates quantity by destabilization

0.295

Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination. KLHL20 promotes ubiquitination of phagophore-residing VPS34 and Beclin-1

SIGNOR-272414

P35711

Q8IYA7

0

transcriptional regulation

up-regulates quantity by expression

0.295

MKX is a meniscus-enriched transcription factor. In human meniscus cells, MKX regulates the expression of meniscus marker genes, OA-related genes, and other transcription factors, including Scleraxis (SCX), SRY Box 5 (SOX5), and Runt domain-related transcription factor 2 (RUNX2).

SIGNOR-267214

P10912

P23467

0

dephosphorylation

down-regulates

0.295

Inally, mrna tissue distribution of these ptps by rt-pcr analysis and coexpression of the wild-type ptps to test their ability to dephosphorylate ligand-activated ghr suggest ptp-h1 and ptp1b as potential candidates involved in ghr signaling.

SIGNOR-104580

Q92481

Q15139

0

phosphorylation

down-regulates activity

0.295

Mechanistically, we observed that PKD phosphorylates AP2\u03b2 at Ser-258 and Ser-277 and suppresses its nuclear accumulation.|Using ChIP analyses, here we found that PKD knockdown in HUVECs increases binding of AP2beta to the VEGFR-2 promoter.

SIGNOR-279267

P11021

O95260

0

post transcriptional regulation

down-regulates quantity by destabilization

0.295

We showed that the molecular chaperone BiP (also known as GRP78) was short-lived under basal conditions and ER stress. The turnover of BiP was in part driven by its amino-terminal arginylation (Nt-arginylation) by the arginyltransferase ATE1, which generated an autophagic N-degron of the N-end rule pathway.

SIGNOR-261345

Q92934

P23443

0

phosphorylation

down-regulates activity

0.295

P70S6K, the downstream target of mTORC1, can phosphorylate and inactivate pro apoptotic BAD by producing a reaction that disrupts BAD 's binding to other pro apoptotic molecules thereby allowing cell survival.|p70S6K, the downstream target of mTORC1, can phosphorylate and inactivate pro-apoptotic BAD by producing a reaction that disrupts BAD\u2019s binding to other pro-apoptotic molecules thereby allowing cell survival. xref , xref On the other hand, in a recent study, Li et al showed that increased expression of anti-apoptotic BCL2 was induced in myeloid progenitor cells upon activation of p76S6K, thereby promoting cell survival. xref Further studies are needed to better understand the effect of rapamycin and its derivatives on apoptosis in various cancer cells.

SIGNOR-280016

Q15208

P17612

0

phosphorylation

down-regulates activity

0.295

GSK-3β phosphorylated STK38 on residues S6 and T7 in vitro, depending largely on a PKA-mediated priming phosphorylation of STK38 on residues S10 and S11, respectively. Our results indicate that that GSK-3β inhibits STK38's full activation, and suggest that STK38 activation is required to prevent cell death in response to oxidative stress.

SIGNOR-276390

O43464

Q16611

0

relocalization

up-regulates

0.295

Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi

SIGNOR-118908

Q9BY11

O96013

0

phosphorylation

up-regulates activity

0.295

We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo.

SIGNOR-263023

Q9UL17

Q96NM4

0

transcriptional regulation

up-regulates quantity by expression

0.294

We subsequently found that TOX2 was independent of ETS-1 but could directly upregulate the transcription of TBX21 (encoding T-BET).

SIGNOR-266097

P27694

Q9NUX5

0

binding

down-regulates activity

0.294

The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA

SIGNOR-263325

P18084

Q99704

0

binding

down-regulates activity

0.294

Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation

SIGNOR-257691

Q9UHP3

Q86Y07

0

phosphorylation

down-regulates activity

0.294

Here, we report that USP25 is a novel TRiC interacting protein that is also phosphorylated by VRK2. USP25 catalyzed deubiquitination of the TRiC protein and stabilized the chaperonin, thereby reducing accumulation of misfolded polyglutamine protein aggregates. Notably, USP25 deubiquitinating activity was suppressed when VRK2 phosphorylated the Thr(680), Thr(727), and Ser(745) residues.

SIGNOR-273579

P49768

Q99590

0

cleavage

up-regulates activity

0.294

Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis.

SIGNOR-261758

P56750

Q8TBB1

0

ubiquitination

down-regulates quantity by destabilization

0.294

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

SIGNOR-272900

P27986

P63092

0

binding

up-regulates

0.294

Notably, the fzd7 receptor complex was associated with g_?(s) and pi(3)k and these components were required for wnt7a to activate the akt/mtor growth pathway in myotubes. These data led us to hypothesize that g_?s Mediates the activation of pi3kinase following wnt7a binding to fzd7.

SIGNOR-191561

O75030

P49840

0

phosphorylation

up-regulates

0.294

Glycogen synthase kinase 3 (gsk3) was found to phosphorylate ser298 in vitro, thereby enhancing the binding of mitf to the tyrosinase promoter

SIGNOR-72878

P49841

P27361

0

phosphorylation

down-regulates activity

0.294

We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels

SIGNOR-262523

Q9H3M7

P28482

0

phosphorylation

down-regulates quantity by destabilization

0.294

ERK-dependent Txnip ubiquitination and proteasome degradation depended upon phosphorylation of a PXTP motif threonine (Thr349) located within the C-terminal α-arrestin domain and proximal to a previously characterized E3 ubiquitin ligase-binding site.

SIGNOR-277468

P23760

P54727

0

binding

down-regulates activity

0.294

Monoubiquitinated Pax3 was shuttled to the intrinsic proteasomal protein S5a by interacting specifically with the ubiquitin-binding protein Rad23B.

SIGNOR-237667

P15172

Q14469

0

transcriptional regulation

down-regulates activity

0.294

Notch signaling up-regulated HES1 mRNA expression within 1 h and subsequently reduced expression of MyoD mRNA

SIGNOR-243181

P22223

Q9UQB3

0

binding

up-regulates quantity by stabilization

0.294

To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member.

SIGNOR-252130

P12268

P01106

0

transcriptional regulation

up-regulates quantity by expression

0.294

Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation.

SIGNOR-267375

P15056

P62136

0

dephosphorylation

up-regulates activity

0.294

To address whether PP1\u03b1 activates B-Raf through these inhibitory sites, we made use of B-Raf protein mutants in which an individual inhibitory site, as well as all four sites (4A), were mutated to alanine.|We confirmed that GST-B-Raf was phosphorylated by ERK2 in vitro xref , mainly on S151 and T753 (Fig.\u00a0 xref ), and found that PP1\u03b1 dephosphorylated B-Raf on both ERK phosphorylation sites (Fig.\u00a0 xref ).

SIGNOR-277160

P53350

P11309

0

phosphorylation

down-regulates activity

0.294

This data strongly indicates that Pim1 phosphorylates PLK1 at threonine 210, a site previously reported to be phosphorylated by aurora A kinase during mitosis.

SIGNOR-279749

Q15465

Q92935

0

binding

down-regulates

0.294

A study in mice suggests that ext1 proteins might negatively regulate shh signaling by synthesizing hspgs, which sequester the ligand

SIGNOR-132606

P04150

Q53ET0

0

binding

up-regulates activity

0.294

We show here that CRTC2 also functions as a coactivator for the glucocorticoid receptor (GR).

SIGNOR-256101

Q15052

Q8TDY4

0

binding

up-regulates activity

0.294

ArfGAP With Coiled-Coil, Ankyrin Repeat And PH Domains 4 (ACAP4) is an ADP-ribosylation factor 6 (ARF6) GTPase-activating protein essential for EGF-elicited cell migration. |The crystal structure of the catalytic core of ACAP4 in a complex with ARF6 reveals the structural determinants underlying ACAP4 selectivity and specificity as an ARF6 GTPase-activating protein

SIGNOR-272235

P07196

P61981

0

binding

down-regulates activity

0.294

These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments.

SIGNOR-252400