GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels float64 0 2	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
P27361	O60674	1	phosphorylation	down-regulates	0.523	We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner	SIGNOR-146747
Q99986	P04637	1	phosphorylation	up-regulates	0.523	Vrk1 phosphorylates murine p53 in threonine 18. This threonine is within the p53 hydrophobic loop (residues 13-23) required for the interaction of p53 with the cleft of its inhibitor mdm-2.	SIGNOR-81222
P63000	P45984	1	binding	up-regulates	0.523	We show that rac1 activates jnk2 that in turn phosphorylates beta-catenin on critical residues and controls its nuclear translocation.	SIGNOR-178265
P24941	P15172	1	phosphorylation	down-regulates	0.522	Cyclin e/cdk2 can phosphorylate myod at serine 200, which causes ubiquitination and degradation of this transcription factor during g1, preventing its accumulation and a commitment to differentiation.	SIGNOR-176509
P31749	Q9BXL7	1	phosphorylation	up-regulates activity	0.522	Akt phosphorylates S637 and S645 in the linker region of Carma1	SIGNOR-276621
Q14192	P10275	1	binding	up-regulates	0.522	Fhl2 contains a strong, autonomous transactivation function and binds specifically to the ar in vitro and in vivo.	SIGNOR-74703
Q13315	Q5VTR2	1	phosphorylation	up-regulates	0.522	E3 ubiquitin ligase, a heterodimeric complex of the ringfinger rfn20/rfn40 is phosphorylated by atm.	SIGNOR-174949
P30556	Q14344	1	binding	up-regulates	0.522	These results indicate that ang ii increases endothelial arginase activity/expression through galfa12/13 g proteins coupled to at(1) receptors and subsequent activation of rhoa/rock/p38 mapk pathways leading to endothelial dysfunction.	SIGNOR-171760
P07900	P43034	1	binding	up-regulates quantity by stabilization	0.522	The type I lissencephaly gene product LIS1, a key regulator of cytoplasmic dynein, is critical for cell proliferation, survival, and neuronal migration. However, little is known about the regulation of LIS1. Here, we identify a previously uncharacterized mammalian homolog of Aspergillus NudC, NudCL2 (NudC-like protein 2), as a regulator of LIS1. NudCL2 is localized to the centrosome in interphase, and spindle poles and kinetochores during mitosis, a pattern similar to the localization of LIS1 and cytoplasmic dynein. Depletion of NudCL2 destabilized LIS1 and led to phenotypes resembling those of either dynein or LIS1 deficiency. NudCL2 complexed with and enhanced the interaction between LIS1 and Hsp90. Either disruption of the LIS1-Hsp90 interaction with the C terminus of NudCL2 or inhibition of Hsp90 chaperone function by geldanamycin decreased LIS1 stability.	SIGNOR-252168
Q06124	O95297	1	dephosphorylation	down-regulates	0.522	In vitro, tyrosine-phosphorylated pzr was efficiently dephosphorylated by the full-length form of shp-2 but not by its sh2 domain-truncated form. The coexisting binding and dephosphorylation of pzr by shp-2 may function to terminate signal transduction initiated by pzr and shp-2 and to set a threshold for the signal transduction to be initiated.	SIGNOR-75220
O15530	P05771	1	phosphorylation	up-regulates	0.522	One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated.	SIGNOR-126069
Q13315	P16220	1	phosphorylation	down-regulates	0.522	Individual ala substitutions at thr-100, ser-111, or ser-121 inhibited atm-catalyzed phosphate incorporationatm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp)	SIGNOR-124051
Q9Y484	Q2TAZ0	1	binding	up-regulates activity	0.522	WIPI4 interacts with ATG2, AMPK and ULK1. Upon starvation and AMPK activation, WIPI4-ATG2 dissociates from AMPK and ULK1 and localizes at nascent autophagosomes, potentially supporting further autophagosome maturation.	SIGNOR-268483
P04899	O43306	1	binding	down-regulates activity	0.522	Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3	SIGNOR-278078
Q13535	Q00987	1	phosphorylation	down-regulates activity	0.522	We found that a major kinase responsible for s407 phosphorylation is atrs407 phosphorylation of mdm2 by atr reduces mdm2-dependent export of p53 from nuclei to cytoplasm.	SIGNOR-119546
Q9UBK2	P20393	1	transcriptional regulation	up-regulates quantity by expression	0.522	Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism. Here we show that PGC-1alpha (Ppargc1a), a transcriptional coactivator that regulates energy metabolism, is rhythmically expressed in the liver and skeletal muscle of mice. PGC-1alpha stimulates the expression of clock genes, notably Bmal1 (Arntl) and Rev-erbalpha (Nr1d1), through coactivation of the ROR family of orphan nuclear receptors. Chromatin immunoprecipitation (ChIP) assays in HepG2 cells indicate that PGC-1α is present near RORE on the proximal Bmal1 promoter.These results indicate that PGC-1α activates Bmal1 transcription by altering the local chromatin environment from a repressive to an active state.	SIGNOR-268030
Q13207	Q8N726	1	transcriptional regulation	down-regulates quantity by repression	0.522	TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS	SIGNOR-249594
Q16611	Q9NR28	1	relocalization	up-regulates	0.522	Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi	SIGNOR-118905
P29350	P32927	1	dephosphorylation	down-regulates	0.522	However, inhibition of shp2 binding to betac, did not prevent tyrosine phosphorylation of shp2. Interestingly, this same phosphopeptide served as a substrate for the tyrosine phosphatase activity of both shp1 and shp2.	SIGNOR-114597
Q9Y572	P06737	1	binding	up-regulates	0.522	Rip3 directly interacts with glycogen phosphorylase (pygl), glutamate ammonia ligase (glul), and glutamate dehydrogenase 1 (glud1). Rip kinase activity is required to enhance the activities of all three enzymes both in vivo and in vitro.	SIGNOR-186939
Q96BY6	P63000	1	guanine nucleotide exchange factor	up-regulates activity	0.522	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-260549
P36897	Q01082	1	phosphorylation	up-regulates	0.522	This suggests that, upon stimulation with tgf-beta1, phosphorylation of elf could induce a conformational change that reduces its affinity for ankyrin and tropomyosin and facilitates an association with smad3 and smad4 instead.	SIGNOR-97626
P17612	P61224	1	phosphorylation	up-regulates	0.522	These results provide a mechanistic explanation for the differential effects of rap1 phosphorylation by pka on effector protein interaction. camp is one among several pathways leading to rap1 activation	SIGNOR-187410
P54727	P35244	1	binding	up-regulates activity	0.522	GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process\|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).\|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo	SIGNOR-275700
P52945	P11168	1	transcriptional regulation	up-regulates quantity by expression	0.522	In conclusion, Pdx1 confers the expression of pancreatic β-cell-specific genes, such as genes encoding insulin, islet amyloid polypeptide, Glut2, and Nkx6.1.	SIGNOR-255540
P98082	Q5VWQ8	1	binding	up-regulates activity	0.521	In prostate cancer cells, DAB2IP was shown to be recruited by the adaptor protein DAB2/DOC2 to promote Ras inactivation and inhibition of MAPK signaling upon receptor stimulation.	SIGNOR-254744
Q9HBY8	O43524	1	phosphorylation	down-regulates activity	0.521	Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)\|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis.	SIGNOR-249130
P48729	Q99835	1	phosphorylation	up-regulates	0.521	We demonstrate that mammalian Smo (mSmo) is activated through multi-site phosphorylation of its carboxyl-terminal tail by CK1α and GRK2. Phosphorylation of mSmo induces its active conformation and simultaneously promotes its ciliary accumulation.	SIGNOR-174542
P12931	A1X283	1	phosphorylation	up-regulates activity	0.521	C-Src-mediated phosphorylation of NoxA1 and Tks4 induces the reactive oxygen species (ROS)-dependent formation of functional invadopodia in human colon cancer cells\|Here, we show that the interaction of noxa1 and tks proteins is dependent on src activity. Interestingly, the abolishment of src-mediated phosphorylation of tyr110 on noxa1 and of tyr508 on tks4 blocks their binding and decreases nox1-dependent ros generation.	SIGNOR-264705
P00533	Q14457	1	phosphorylation	down-regulates activity	0.521	The mechanism by which EGFR suppresses Beclin 1 function involves EGFR interaction with two domains (BH3 and ECD) of Beclin 1; EGFR mediated multisite tyrosine phosphorylation of Beclin 1 on residues Y229, Y233 and Y352; and EGFR mediated alterations in the Beclin 1 interactome (increased binding to the negative regulators, Bcl-2 and Rubicon, and decreased binding to the VPS34 lipid kinase).\|Thus, EGFR signaling suppresses autophagy via its interaction with Beclin 1 during normal mitogenic signaling as well as during aberrant cell proliferation in cancer cells.	SIGNOR-278357
P17612	P62834	1	phosphorylation	down-regulates activity	0.521	Phosphorylation of Rap1A by PKA abolished its binding activity to CRR. a mutant Rap1A(S180E), whose sole PKA phosphorylation residue, Ser-180, was substituted by an acidic residue, Glu, to mimic its phosphorylated form, failed to suppress Ras-dependent Raf-1 activation in COS-7 cells.	SIGNOR-250042
Q9HCE1	Q92900	1	binding	up-regulates activity	0.521	MOV10 has been shown to promote mRNA degradation by associating with UPF1, this activity requires the helicase activity of MOV10.	SIGNOR-261139
Q8WWN8	P60953	1	gtpase-activating protein	down-regulates activity	0.521	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-260457
P0DP24	P48454	1	binding	up-regulates	0.521	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-266324
O95819	Q12933	1	phosphorylation	down-regulates quantity	0.521	A key finding of our study is that HGK induces lysosomal degradation of TRAF2 by directly phosphorylating TRAF2 Ser35.\|Conversely, TRAF2 levels were decreased by ectopically expressed HGK in an overexpression system (XREF_FIG).	SIGNOR-279536
O43567	O95295	1	polyubiquitination	up-regulates activity	0.521	RNF13 directly interacted with snapin, a SNAP-25-interacting protein. Interestingly, snapin was ubiquitinated by RNF13 via the lysine-29 conjugated polyubiquitin chain, which in turn promoted the association of snapin with SNAP-25. Consistently, we found an attenuated interaction between snapin and SNAP-25 in the RNF13-null mice. Therefore, these results suggest that RNF13 is involved in the regulation of the SNARE complex, which thereby controls synaptic function.	SIGNOR-272044
P32245	Q5JWF2	1	null	up-regulates activity	0.521	We hypothesize that XLŒ±s may be involved in this regulatory loop by coupling to melanocortin receptors 3 and 4 in the hypothalamus.	SIGNOR-253067
Q16539	O43524	1	phosphorylation	up-regulates	0.521	Ogether, our results suggest that p38 phosphorylation of foxo3a on ser-7 is essential for its nuclear relocalization in response to doxorubicin	SIGNOR-177927
Q9NS91	Q9BXW9	1	ubiquitination	up-regulates activity	0.521	In summary, these findings suggest a model, where Rad18 promotes monoubiquitination of FANCD2, and associates with a functional complex involving Rad51, BRCA2, and FANCD2 in the repair of CPT induced stalled or collapsed forks.\|In this study we focused on the role of Rad18 mediated activation of FANCD2 and its functional relationship with BRCA2 and Rad51 proteins in repair of CPT induced lesions.	SIGNOR-278712
P27361	Q9NRA0	1	phosphorylation	up-regulates	0.521	Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1	SIGNOR-153387
P17252	P21731-2	1	phosphorylation	down-regulates activity	0.521	These data suggest a model whereby agonist-induced PKC phosphorylation of Ser(145) partially impairs TPbeta signalling while GRK2/3 phosphorylation at both Ser(239) and Ser(357) within its IC(3) and C-tail domains, respectively, sterically inhibits G-protein coupling, profoundly desensitizing signalling, and promotes beta-arrestin association and, in turn, facilitates TPbeta internalization.	SIGNOR-274092
P32245	P63092	1	binding	up-regulates activity	0.521	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268707
O00124	P55072	1	relocalization	down-regulates quantity	0.521	The human protein named Rep8 or Ubxd6 as a new cofactor of p97. Rep8 tethers p97 to the ER membrane for efficient ER-associated degradation.	SIGNOR-261002
P34969	P63092	1	binding	up-regulates activity	0.521	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-256783
P21860	P42338	1	binding	up-regulates	0.521	Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4.	SIGNOR-146864
P49137	P07101	1	phosphorylation	up-regulates activity	0.52	MAPKAP-K2 phosphorylates both Ser19 and Ser40 of TH. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation.	SIGNOR-250149
Q9UKV5	P11441	1	polyubiquitination	down-regulates activity	0.52	USP13 and gp78 control ubiquitination of Ubl4A.These data suggest that USP13 and gp78 play antagonizing roles in regulation of Ubl4A ubiquitination: While gp78 assembles ubiquitin chains on Ubl4A, USP13 antagonizes this activity to limit Ubl4A ubiquitination.Ubiquitination of Ubl4A preferentially occurs on Lys48. We identify the Bag6 cofactor Ubl4A as a shared substrate of gp78 and USP13. USP13 depletion is associated with hyper-ubiquitination of Ubl4A and altered interaction between the Bag6 complex and its co-chaperone SGTA. Because the interaction of Ubl4A with SGTA is mediated by positively-charged residues in Ubl4A including Lys48 (Chartron et al., 2012; Xu et al., 2012), which happens to be the major ubiquitination site, the simplest model to explain reduced Bag6-SGTA interaction in USP13 knockdown cells is that ubiquitin conjugates on Ubl4A sterically hinder SGTA binding.	SIGNOR-272856
O14757	O15151	1	phosphorylation	down-regulates activity	0.52	MDMX is a direct substrate for Chk1 and Chk2 in vitro. Phosphorylation of MDMX leads to increased binding to MDM2 and more efficient ubiquitination, providing an explanation for the enhanced degradation of MDMX after DNA damage. \| Western blot showed that Chk1 modified S342 and S367, but with strong preference for S342.	SIGNOR-250770
P02511	P07320	1	binding	up-regulates activity	0.52	Human gamma-crystallins are long-lived, unusually stable proteins of the eye lens exhibiting duplicated, double Greek key domains. The lens also contains high concentrations of the small heat shock chaperone alpha-crystallin, which suppresses aggregation of model substrates in vitro. Mature-onset cataract is believed to represent an aggregated state of partially unfolded and covalently damaged crystallins. The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. These in vitro results provide support for protein unfolding/protein aggregation models for cataract, with alpha-crystallin suppressing aggregation of damaged or unfolded proteins through early adulthood but becoming saturated with advancing age.	SIGNOR-253621
P19086	O95622	1	binding	down-regulates activity	0.52	Activated a z inhibits the activity of type I and type V adenylyl cyclases.	SIGNOR-278045
Q9UJ55	P14373	1	binding	up-regulates activity	0.52	MAGE proteins are a family of proteins that contain a conserved domain known as the MAGE homology domain. Recently, we showed that MAGE proteins function biochemically to bind to and enhance the activity of E3 RING ubiquitin ligases. The E3 RING ubiquitin ligase TRIM27 was identified as a major binding partner of MAGE-L2.	SIGNOR-253513
O14920	P04637	1	phosphorylation	up-regulates activity	0.52	Here , we show that IKKbeta modulates the activity of p53 in response to glutamine depletion to promote cancer cell adaptation .\|Taken together, these results indicate that IKK\u03b2 phosphorylates p53 on Ser392 as an early response to glutamine deprivation and possibly later facilitates its phosphorylation at Ser15 and transcriptional activity.	SIGNOR-278516
P49137	P15923	1	phosphorylation	up-regulates	0.52	Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2	SIGNOR-166643
Q12986	O14746	1	transcriptional regulation	up-regulates quantity by expression	0.52	NFX1-123 positively regulated hTERT expression, as its knockdown decreased hTERT mRNA levels and telomerase activity and its overexpression increased telomerase activity. NFX1-123 was found to interact with cytoplasmic poly(A) binding proteins (PABPCs), and together they synergistically augmented expression from the hTERT promoter when activated by HPV16 E6.	SIGNOR-261050
P36406	Q9UHD2	1	binding	up-regulates activity	0.519	TRIM23 interacts with TBK1 and p62. TRIM23 GTPase activates TBK1 to phosphorylate p62. Biochemical characterization showed that TRIM23 binds with its C-terminal ARF domain to the N-terminal KD of TBK1, and that GTP hydrolysis activity of the ARF stimulates TBK1-mediated phosphorylation of p62 at S403 in its ubiquitin-associated (UBA) domain, which was shown to promote cargo recruitment and autophagic flux	SIGNOR-266654
Q9UBK2	O00327	1	transcriptional regulation	up-regulates quantity by expression	0.519	Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism. Here we show that PGC-1alpha (Ppargc1a), a transcriptional coactivator that regulates energy metabolism, is rhythmically expressed in the liver and skeletal muscle of mice. PGC-1alpha stimulates the expression of clock genes, notably Bmal1 (Arntl) and Rev-erbalpha (Nr1d1), through coactivation of the ROR family of orphan nuclear receptors.	SIGNOR-268031
P08754	O95622	1	binding	down-regulates activity	0.519	Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3	SIGNOR-278076
Q12913	P35222	1	dephosphorylation	up-regulates activity	0.519	Our data demonstrate that CD148 promotes E-cadherin cell adhesion by regulating Rac1 activity, concomitant with modulation of p120, \u03b2-catenin, and Src tyrosine phosphorylation, and that this effect requires E-cadherin and p120 association.\|Taken together, it is likely that CD148 dephosphorylation of \u03b2-catenin enhances the cadherin cell adhesion independent of Rho family GTPases.	SIGNOR-276992
Q9UDY2	P46937	1	binding	down-regulates	0.519	The Crumbs complex component AMOT co-localizes with MST1_ 2, LATS1_ 2 and YAP in a complex at the tight junction to control cell growth. Zona occludens-2 (ZO-2) in the tight junction, and a-catenin, b-catenin, or PTPN14 in the adherence junction, also bind to YAP_TAZ.	SIGNOR-230754
P04637	P55957	1	transcriptional regulation	up-regulates quantity by expression	0.519	Bid is a p53 primary-response gene.	SIGNOR-140248
P35638	P49715	1	transcriptional regulation	down-regulates quantity	0.519	We find that expression of CHOP, a nuclear protein that dimerizes avidly with C/EBP isoforms alpha and beta and directs the resulting heterodimer away from classic C/EBP-binding sites, markedly inhibits this differentiation process.	SIGNOR-255913
P50461	P15173	1	binding	up-regulates activity	0.519	we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements.	SIGNOR-241113
P28482	P05023	1	phosphorylation	down-regulates activity	0.519	Parathyroid hormone (PTH) inhibits Na+,K+-ATPase activity through protein kinase C- (PKC) and extracellular signal-regulated kinase- (ERK) dependent pathways and increases serine phosphorylation of the α1-subunit. These results suggest that PTH regulates Na(+),K(+)-ATPase by PKC and ERK-dependent alpha(1)-subunit phosphorylation and that the phosphorylation requires the expression of a serine at the 11 position of the Na(+),K(+)-ATPase alpha(1)-subunit.	SIGNOR-262940
P28482	P09874	1	phosphorylation	up-regulates	0.519	Parp1 phosphorylation by erk1/2 is required for maximal parp-1 activation after dna damage. S372a and t373a mutations impaired parp-1 activation.	SIGNOR-146224
P17612	Q13972	1	phosphorylation	up-regulates	0.519	Phosphorylation of serine 916 of ras-grf1 contributes to the activation of exchange factor activity by muscarinic receptors.	SIGNOR-73202
Q05513	Q8N2W9	1	phosphorylation	down-regulates quantity by destabilization	0.519	In this study, we discovered a new protein isoform encoded by KIAA0317, termed fibrosis-inducing E3 ligase 1 (FIEL1), which potently stimulates the TGFbeta signaling pathway through the site-specific ubiquitination of PIAS4.FIEL1 targets PIAS4 using a double locking mechanism that is facilitated by the kinases PKCzeta and GSK3beta. Specifically, PKCzeta phosphorylation of PIAS4 and GSK3beta phosphorylation of FIEL1 are both essential for the degradation of PIAS4.\|These experiments suggested that PKCzeta is an authentic regulator of PIAS4 protein stability; Q21 and phosphorylated S18 of PIAS4 are both required for FIEL1 interaction.	SIGNOR-275513
P53990	Q9UBP0	1	relocalization	up-regulates activity	0.519	Our results suggest that inclusion of IST1 into the ESCRT complex allows recruitment of spastin to promote fission of recycling tubules from the endosome. Thus, we reveal a novel cellular role for MT severing and identify a mechanism by which endosomal recycling can be coordinated with the degradative machinery.	SIGNOR-269047
P53350	Q2M2Z5	1	phosphorylation	up-regulates	0.519	Here, we identify a novel centrosomal substrate of plk1, kizuna (kiz), depletion of which causes fragmentation and dissociation of the pericentriolar material from centrioles at prometaphase, resulting in multipolar spindles. Plk1 maintains the integrity of the spindle poles by phosphorylating kiz.	SIGNOR-149630
O95198	Q96J92	1	binding	down-regulates quantity by destabilization	0.519	We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body.	SIGNOR-272118
Q08050	P35222	1	binding	up-regulates activity	0.519	Nuclear FoxM1 then directly interacted with nuclear β‐catenin, which released β‐catenin from ICAT and enhanced recruitment of β‐catenin to the promoter of Wnt target gene, hence increasing the expression of Wnt target gene.	SIGNOR-277211
P49137	Q00613	1	phosphorylation	down-regulates activity	0.519	A potential mechanism for MK2-induced HSF1 inactivation is suggested by the findings that phosphorylation of serine 121 enhances HSF1 binding to HSP90, a major repressor of HSF1.\|Phosphorylation of HSF1 by MAPK activated protein kinase 2 on serine 121, inhibits transcriptional activity and promotes HSP90 binding.	SIGNOR-279541
P49841	O15294	1	phosphorylation	up-regulates activity	0.518	But OGT activity is modulated by GSK3beta (XREF_FIG) and GSK3beta activity is known to oscillate through Ser9 phoshorylation.\|Here, we found that OGT is phosphorylated at serines 3 or 4 by GSK3beta and that O GlcNAcylation of OGT also occurs on the same or neighboring serine residues, suggesting interacting phosphorylation and O GlcNAcylation events on OGT itself.	SIGNOR-279528
P06493	P06748	1	phosphorylation	down-regulates activity	0.518	However, under the experimental conditions used here, the t199 residue was the most likely candidate to be phosphorylated by cyclin b/cdc2 these results strongly support the concept that the rna binding activity of b23.1 is inactivated by cyclin b/cdc2-mediated phosphorylation.	SIGNOR-89605
O15111	Q92793	1	binding	up-regulates	0.518	Ikk-alpha interacts with creb-binding protein and in conjunction with rel a is recruited to nf-kappab-responsive promoters and mediates the cytokine-induced phosphorylation and subsequent acetylation of specific residues in histone h3.	SIGNOR-101539
P14416	P09471	1	binding	up-regulates activity	0.518	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-256980
P17612	P01100	1	phosphorylation	up-regulates activity	0.518	Human c-Fos protein is phosphorylated in vitro by PKA. phosphorylation of Fos occurs at serine residue 362. Modification of the Fos protein by phosphorylation with PKA then allows it to act as a regulator of its own synthesis by downregulating fos gene expression at a transcriptional level	SIGNOR-250356
P80370	P46531	1	binding	down-regulates activity	0.518	Moreover, the interaction of DLK1 with NOTCH1 caused an inhibition of basal NOTCH signaling in preadipocytes and mesenchymal multipotent cells. In this work, we demonstrate, for the first time, that DLK2 interacts with itself, with DLK1, and with the same NOTCH1 receptor region as DLK1 does. We demonstrate also that the interaction of DLK2 with NOTCH1 similarly results in an inhibition of NOTCH signaling in preadipocytes and Mouse Embryo fibloblasts.	SIGNOR-172830
P42224	Q04206	1	binding	down-regulates	0.518	Acetylated stat1 is able to interact with nf-kappab p65. As a consequence, p65 dna binding, nuclear localization, and expression of anti-apoptotic nf-kappab target genes decrease.	SIGNOR-144561
P28482	Q8N122	1	phosphorylation	up-regulates activity	0.518	We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1.	SIGNOR-188916
P06213	O14654	1	phosphorylation	up-regulates activity	0.518	The binding of insulin to the subunit of IR not only concentrates insulin at its site of action, but also induces conformational changes in the receptor, which in turn stimulates the tyrosine kinase activity intrinsic to the _ subunit of the IR and triggers the signaling cascades (Fig. 3). Insulin receptors trans phosphorylate several immediate substrates (on Tyr residues) including IRS1-4, Shc, and Gab 1, Cbl, APS, and P60dok.	SIGNOR-217897
P17612	P61586	1	phosphorylation	down-regulates activity	0.518	PKA phosphorylates RhoA on Ser188. the addition of a negative charge to Ser188 is sufficient to diminish both RhoA activation and activity within the context of a cell.	SIGNOR-250047
P08603	P00751	1	binding	down-regulates activity	0.518	As a regulator of the alternative pathway, FH binds to C3b and inhibits the binding of factor B to C3b, acts as a cofactor for the factor I-mediated cleavage of C3b to iC3b (cofactor activity), and accelerates the decay of C3bBb, the alternative pathway C3 convertase (decay-accelerating activity)	SIGNOR-252142
P24941	P98177	1	phosphorylation	down-regulates	0.518	Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity	SIGNOR-183655
Q9Y243	P55211	1	phosphorylation	down-regulates	0.518	Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity	SIGNOR-61565
Q8IWR1	Q9BQ95	1	binding	down-regulates activity	0.518	In this study, we showed that one of the TRIM family ubiquitin ligases, TRIM59, interacts with ECSIT as an adaptor protein required for the TLR-mediated transduction pathway. The B-box and RING domains of TRIM59 are important for interaction with ECSIT.\|ECSIT enhances IPS-1-mediated IFN-Beta promoter activation.\|Luciferase reporter assays using reporter plasmids including NF-kappaB responsive element, interferon beta (IFN-beta) promoter and interferon-sensitive response element (ISRE) showed that overexpression of TRIM59 repressed their transcriptional activities, whereas knockdown of TRIM59 enhanced their transcriptional activities.	SIGNOR-260369
Q4KMG0	P00519	1	binding	up-regulates activity	0.518	Abl binds a proline-rich motif in cdo via its sh3 domain, and these regions of abl and cdo are required for their promyogenic effects. Cdo is important for full abl kinase activity	SIGNOR-185762
O96013	Q92974	1	phosphorylation	down-regulates activity	0.518	PAK4 specifically phosphorylates GefH1, and this is thought to inhibit its ability to activate Rho, consequently inhibiting stress fiber formation.	SIGNOR-279245
Q01543	P15976	1	binding	up-regulates activity	0.518	On the other hand, our data demonstrate that FLI-1 also interacts with GATA-1. However, FLI-1 does not repress but enhances GATA-1 activity.	SIGNOR-256045
P61812	Q03167	1	binding	up-regulates	0.518	Betaglycan binds tgf-b isoforms with high affinity and increases the functional interaction between tgf-b and its type ii and type i signalling receptors.	SIGNOR-76473
Q5VWQ8	P01116	1	gtpase-activating protein	down-regulates activity	0.518	The GAP domain of DAB2IP is homologous to other Ras-GAPs, such as GAP120 and neurofibromin (NF1), and can stimulate the GTPase activity of RAS proteins both in vitro and in cancer cell lines. DAB2IP is able to stimulate in vitro and in vivo the GTPase activity of RAS proteins (H-Ras, K-Ras, and N-Ras) facilitating GTP hydrolysis to GDP.	SIGNOR-254746
Q9BQS8	Q9GZQ8	1	binding	up-regulates activity	0.517	The preferential binding to LC3A and -B was confirmed in vivo by co-immunoprecipitation experiments of Myc-tagged FYCO1 and GFP fusions of human ATG8 family pro-teins expressed in HEK293 cells (Fig. 2B). GFP-LC3A and GFP-LC3B were efficiently co-precipitated with Myc-FYCO1,whereas GFP-LC3C, GFP-GABARAP, GFP-GABARAPL1 and-L2 were not. The effects we see on late steps of basal autophagy on mutation of the FYCO1 LIR motif correlate with a role of FYCO1 in regulating kinesin-mediated transport of LC3-positive autophagic structures.	SIGNOR-260597
Q9NS75	P50148	1	binding	up-regulates activity	0.517	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-257024
Q06187	P78347	1	phosphorylation	up-regulates activity	0.517	These residues, tyr248, tyr357, and tyr462, were also found to be the major sites for btk-dependent phosphorylation of bap/tfii-i in vivo. Residues tyr357 and tyr462 are contained within the loop regions of adjacent helix-loop-helix-like repeats within bap/tfii-i. Mutation of either tyr248, tyr357, or tyr462 to phenylalanine reduced transcription from a c-fos promoter relative to wild-type bap/tfii-i in transfected cos-7 cells, consistent with the interpretation that phosphorylation at these sites contributes to transcriptional activation.	SIGNOR-108346
Q92765	P04628	1	binding	down-regulates	0.517	We and others demonstrated that fzb-1 blocks wnt-1 and xwnt-8 signaling in xenopus embryos,	SIGNOR-51762
P23468	P40763	1	dephosphorylation	down-regulates activity	0.517	Transfection of wild-type PTPRD resulted in the specific dephosphorylation of STAT3 at tyrosine 705, a residue that must be phosphorylated for STAT3 to be active	SIGNOR-248442
Q05513	O14920	1	phosphorylation	up-regulates activity	0.517	Activation of IkappaB kinase beta by protein kinase C isoforms. \| Interestingly, recombinant active zetaPKC and alphaPKC are able to stimulate in vitro the activity of IKKbeta but not that of IKKalpha. In addition, evidence is presented here that recombinant zetaPKC directly phosphorylates IKKbeta in vitro, involving Ser177 and Ser181. Collectively, these results demonstrate a critical role for the PKC isoforms in the NF-kappaB pathway at the level of IKKbeta activation and IkappaB degradation.	SIGNOR-249015
P27361	Q9HBH9	1	phosphorylation	up-regulates	0.517	Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity.	SIGNOR-48355
P08254	Q99075	1	cleavage	up-regulates	0.517	It was concluded that mmp-3 cleaves hb-egf at a specific site in the jm domain and that this enzyme might regulate the conversion of hb-egf from being a juxtacrine to a paracrine/autocrine growth factor.	SIGNOR-83339
Q13191	P27986	1	polyubiquitination	down-regulates quantity by destabilization	0.517	Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells.Here it is shown that Cbl-b interacts with and induces ubiquitin conjugation to the p85 regulatory subunit of phosphatidylinositol 3-kinase, an upstream regulator of Vav.	SIGNOR-272583
P50613	Q00535	1	phosphorylation	up-regulates activity	0.517	In addition, the Cdk7 substrate, CTD of RNAPII, causes a dose-dependent decline in Cdk5 activation by Cdk7.\|Likewise, Cdk7 or cyclin H immunoprecipitate from mouse brain specifically phosphorylates wt Cdk5 at Ser159 and enhances Cdk5 and p25 activity.	SIGNOR-278923

P27361

O60674

1

phosphorylation

down-regulates

0.523

We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner

SIGNOR-146747

Q99986

P04637

1

phosphorylation

up-regulates

0.523

Vrk1 phosphorylates murine p53 in threonine 18. This threonine is within the p53 hydrophobic loop (residues 13-23) required for the interaction of p53 with the cleft of its inhibitor mdm-2.

SIGNOR-81222

P63000

P45984

1

binding

up-regulates

0.523

We show that rac1 activates jnk2 that in turn phosphorylates beta-catenin on critical residues and controls its nuclear translocation.

SIGNOR-178265

P24941

P15172

1

phosphorylation

down-regulates

0.522

Cyclin e/cdk2 can phosphorylate myod at serine 200, which causes ubiquitination and degradation of this transcription factor during g1, preventing its accumulation and a commitment to differentiation.

SIGNOR-176509

P31749

Q9BXL7

1

phosphorylation

up-regulates activity

0.522

Akt phosphorylates S637 and S645 in the linker region of Carma1

SIGNOR-276621

Q14192

P10275

1

binding

up-regulates

0.522

Fhl2 contains a strong, autonomous transactivation function and binds specifically to the ar in vitro and in vivo.

SIGNOR-74703

Q13315

Q5VTR2

1

phosphorylation

up-regulates

0.522

E3 ubiquitin ligase, a heterodimeric complex of the ringfinger rfn20/rfn40 is phosphorylated by atm.

SIGNOR-174949

P30556

Q14344

1

binding

up-regulates

0.522

These results indicate that ang ii increases endothelial arginase activity/expression through galfa12/13 g proteins coupled to at(1) receptors and subsequent activation of rhoa/rock/p38 mapk pathways leading to endothelial dysfunction.

SIGNOR-171760

P07900

P43034

1

binding

up-regulates quantity by stabilization

0.522

The type I lissencephaly gene product LIS1, a key regulator of cytoplasmic dynein, is critical for cell proliferation, survival, and neuronal migration. However, little is known about the regulation of LIS1. Here, we identify a previously uncharacterized mammalian homolog of Aspergillus NudC, NudCL2 (NudC-like protein 2), as a regulator of LIS1. NudCL2 is localized to the centrosome in interphase, and spindle poles and kinetochores during mitosis, a pattern similar to the localization of LIS1 and cytoplasmic dynein. Depletion of NudCL2 destabilized LIS1 and led to phenotypes resembling those of either dynein or LIS1 deficiency. NudCL2 complexed with and enhanced the interaction between LIS1 and Hsp90. Either disruption of the LIS1-Hsp90 interaction with the C terminus of NudCL2 or inhibition of Hsp90 chaperone function by geldanamycin decreased LIS1 stability.

SIGNOR-252168

Q06124

O95297

1

dephosphorylation

down-regulates

0.522

In vitro, tyrosine-phosphorylated pzr was efficiently dephosphorylated by the full-length form of shp-2 but not by its sh2 domain-truncated form. The coexisting binding and dephosphorylation of pzr by shp-2 may function to terminate signal transduction initiated by pzr and shp-2 and to set a threshold for the signal transduction to be initiated.

SIGNOR-75220

O15530

P05771

1

phosphorylation

up-regulates

0.522

One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated.

SIGNOR-126069

Q13315

P16220

1

phosphorylation

down-regulates

0.522

Individual ala substitutions at thr-100, ser-111, or ser-121 inhibited atm-catalyzed phosphate incorporationatm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp)

SIGNOR-124051

Q9Y484

Q2TAZ0

1

binding

up-regulates activity

0.522

WIPI4 interacts with ATG2, AMPK and ULK1. Upon starvation and AMPK activation, WIPI4-ATG2 dissociates from AMPK and ULK1 and localizes at nascent autophagosomes, potentially supporting further autophagosome maturation.

SIGNOR-268483

P04899

O43306

1

binding

down-regulates activity

0.522

Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3

SIGNOR-278078

Q13535

Q00987

1

phosphorylation

down-regulates activity

0.522

We found that a major kinase responsible for s407 phosphorylation is atrs407 phosphorylation of mdm2 by atr reduces mdm2-dependent export of p53 from nuclei to cytoplasm.

SIGNOR-119546

Q9UBK2

P20393

1

transcriptional regulation

up-regulates quantity by expression

0.522

Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism. Here we show that PGC-1alpha (Ppargc1a), a transcriptional coactivator that regulates energy metabolism, is rhythmically expressed in the liver and skeletal muscle of mice. PGC-1alpha stimulates the expression of clock genes, notably Bmal1 (Arntl) and Rev-erbalpha (Nr1d1), through coactivation of the ROR family of orphan nuclear receptors. Chromatin immunoprecipitation (ChIP) assays in HepG2 cells indicate that PGC-1α is present near RORE on the proximal Bmal1 promoter.These results indicate that PGC-1α activates Bmal1 transcription by altering the local chromatin environment from a repressive to an active state.

SIGNOR-268030

Q13207

Q8N726

1

transcriptional regulation

down-regulates quantity by repression

0.522

TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS

SIGNOR-249594

Q16611

Q9NR28

1

relocalization

up-regulates

0.522

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

SIGNOR-118905

P29350

P32927

1

dephosphorylation

down-regulates

0.522

However, inhibition of shp2 binding to betac, did not prevent tyrosine phosphorylation of shp2. Interestingly, this same phosphopeptide served as a substrate for the tyrosine phosphatase activity of both shp1 and shp2.

SIGNOR-114597

Q9Y572

P06737

1

binding

up-regulates

0.522

Rip3 directly interacts with glycogen phosphorylase (pygl), glutamate ammonia ligase (glul), and glutamate dehydrogenase 1 (glud1). Rip kinase activity is required to enhance the activities of all three enzymes both in vivo and in vitro.

SIGNOR-186939

Q96BY6

P63000

1

guanine nucleotide exchange factor

up-regulates activity

0.522

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-260549

P36897

Q01082

1

phosphorylation

up-regulates

0.522

This suggests that, upon stimulation with tgf-beta1, phosphorylation of elf could induce a conformational change that reduces its affinity for ankyrin and tropomyosin and facilitates an association with smad3 and smad4 instead.

SIGNOR-97626

P17612

P61224

1

phosphorylation

up-regulates

0.522

These results provide a mechanistic explanation for the differential effects of rap1 phosphorylation by pka on effector protein interaction. camp is one among several pathways leading to rap1 activation

SIGNOR-187410

P54727

P35244

1

binding

up-regulates activity

0.522

GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo

SIGNOR-275700

P52945

P11168

1

transcriptional regulation

up-regulates quantity by expression

0.522

In conclusion, Pdx1 confers the expression of pancreatic β-cell-specific genes, such as genes encoding insulin, islet amyloid polypeptide, Glut2, and Nkx6.1.

SIGNOR-255540

P98082

Q5VWQ8

1

binding

up-regulates activity

0.521

In prostate cancer cells, DAB2IP was shown to be recruited by the adaptor protein DAB2/DOC2 to promote Ras inactivation and inhibition of MAPK signaling upon receptor stimulation.

SIGNOR-254744

Q9HBY8

O43524

1

phosphorylation

down-regulates activity

0.521

Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis.

SIGNOR-249130

P48729

Q99835

1

phosphorylation

up-regulates

0.521

We demonstrate that mammalian Smo (mSmo) is activated through multi-site phosphorylation of its carboxyl-terminal tail by CK1α and GRK2. Phosphorylation of mSmo induces its active conformation and simultaneously promotes its ciliary accumulation.

SIGNOR-174542

P12931

A1X283

1

phosphorylation

up-regulates activity

0.521

C-Src-mediated phosphorylation of NoxA1 and Tks4 induces the reactive oxygen species (ROS)-dependent formation of functional invadopodia in human colon cancer cells|Here, we show that the interaction of noxa1 and tks proteins is dependent on src activity. Interestingly, the abolishment of src-mediated phosphorylation of tyr110 on noxa1 and of tyr508 on tks4 blocks their binding and decreases nox1-dependent ros generation.

SIGNOR-264705

P00533

Q14457

1

phosphorylation

down-regulates activity

0.521

The mechanism by which EGFR suppresses Beclin 1 function involves EGFR interaction with two domains (BH3 and ECD) of Beclin 1; EGFR mediated multisite tyrosine phosphorylation of Beclin 1 on residues Y229, Y233 and Y352; and EGFR mediated alterations in the Beclin 1 interactome (increased binding to the negative regulators, Bcl-2 and Rubicon, and decreased binding to the VPS34 lipid kinase).|Thus, EGFR signaling suppresses autophagy via its interaction with Beclin 1 during normal mitogenic signaling as well as during aberrant cell proliferation in cancer cells.

SIGNOR-278357

P17612

P62834

1

phosphorylation

down-regulates activity

0.521

Phosphorylation of Rap1A by PKA abolished its binding activity to CRR. a mutant Rap1A(S180E), whose sole PKA phosphorylation residue, Ser-180, was substituted by an acidic residue, Glu, to mimic its phosphorylated form, failed to suppress Ras-dependent Raf-1 activation in COS-7 cells.

SIGNOR-250042

Q9HCE1

Q92900

1

binding

up-regulates activity

0.521

MOV10 has been shown to promote mRNA degradation by associating with UPF1, this activity requires the helicase activity of MOV10.

SIGNOR-261139

Q8WWN8

P60953

1

gtpase-activating protein

down-regulates activity

0.521

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-260457

P0DP24

P48454

1

binding

up-regulates

0.521

Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.

SIGNOR-266324

O95819

Q12933

1

phosphorylation

down-regulates quantity

0.521

A key finding of our study is that HGK induces lysosomal degradation of TRAF2 by directly phosphorylating TRAF2 Ser35.|Conversely, TRAF2 levels were decreased by ectopically expressed HGK in an overexpression system (XREF_FIG).

SIGNOR-279536

O43567

O95295

1

polyubiquitination

up-regulates activity

0.521

RNF13 directly interacted with snapin, a SNAP-25-interacting protein. Interestingly, snapin was ubiquitinated by RNF13 via the lysine-29 conjugated polyubiquitin chain, which in turn promoted the association of snapin with SNAP-25. Consistently, we found an attenuated interaction between snapin and SNAP-25 in the RNF13-null mice. Therefore, these results suggest that RNF13 is involved in the regulation of the SNARE complex, which thereby controls synaptic function.

SIGNOR-272044

P32245

Q5JWF2

1

null

up-regulates activity

0.521

We hypothesize that XLŒ±s may be involved in this regulatory loop by coupling to melanocortin receptors 3 and 4 in the hypothalamus.

SIGNOR-253067

Q16539

O43524

1

phosphorylation

up-regulates

0.521

Ogether, our results suggest that p38 phosphorylation of foxo3a on ser-7 is essential for its nuclear relocalization in response to doxorubicin

SIGNOR-177927

Q9NS91

Q9BXW9

1

ubiquitination

up-regulates activity

0.521

In summary, these findings suggest a model, where Rad18 promotes monoubiquitination of FANCD2, and associates with a functional complex involving Rad51, BRCA2, and FANCD2 in the repair of CPT induced stalled or collapsed forks.|In this study we focused on the role of Rad18 mediated activation of FANCD2 and its functional relationship with BRCA2 and Rad51 proteins in repair of CPT induced lesions.

SIGNOR-278712

P27361

Q9NRA0

1

phosphorylation

up-regulates

0.521

Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1

SIGNOR-153387

P17252

P21731-2

1

phosphorylation

down-regulates activity

0.521

These data suggest a model whereby agonist-induced PKC phosphorylation of Ser(145) partially impairs TPbeta signalling while GRK2/3 phosphorylation at both Ser(239) and Ser(357) within its IC(3) and C-tail domains, respectively, sterically inhibits G-protein coupling, profoundly desensitizing signalling, and promotes beta-arrestin association and, in turn, facilitates TPbeta internalization.

SIGNOR-274092

P32245

P63092

1

binding

up-regulates activity

0.521

The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins

SIGNOR-268707

O00124

P55072

1

relocalization

down-regulates quantity

0.521

The human protein named Rep8 or Ubxd6 as a new cofactor of p97. Rep8 tethers p97 to the ER membrane for efficient ER-associated degradation.

SIGNOR-261002

P34969

P63092

1

binding

up-regulates activity

0.521

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-256783

P21860

P42338

1

binding

up-regulates

0.521

Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4.

SIGNOR-146864

P49137

P07101

1

phosphorylation

up-regulates activity

0.52

MAPKAP-K2 phosphorylates both Ser19 and Ser40 of TH. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation.

SIGNOR-250149

Q9UKV5

P11441

1

polyubiquitination

down-regulates activity

0.52

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

SIGNOR-272856

O14757

O15151

1

phosphorylation

down-regulates activity

0.52

MDMX is a direct substrate for Chk1 and Chk2 in vitro. Phosphorylation of MDMX leads to increased binding to MDM2 and more efficient ubiquitination, providing an explanation for the enhanced degradation of MDMX after DNA damage. | Western blot showed that Chk1 modified S342 and S367, but with strong preference for S342.

SIGNOR-250770

P02511

P07320

1

binding

up-regulates activity

0.52

Human gamma-crystallins are long-lived, unusually stable proteins of the eye lens exhibiting duplicated, double Greek key domains. The lens also contains high concentrations of the small heat shock chaperone alpha-crystallin, which suppresses aggregation of model substrates in vitro. Mature-onset cataract is believed to represent an aggregated state of partially unfolded and covalently damaged crystallins. The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. These in vitro results provide support for protein unfolding/protein aggregation models for cataract, with alpha-crystallin suppressing aggregation of damaged or unfolded proteins through early adulthood but becoming saturated with advancing age.

SIGNOR-253621

P19086

O95622

1

binding

down-regulates activity

0.52

Activated a z inhibits the activity of type I and type V adenylyl cyclases.

SIGNOR-278045

Q9UJ55

P14373

1

binding

up-regulates activity

0.52

MAGE proteins are a family of proteins that contain a conserved domain known as the MAGE homology domain. Recently, we showed that MAGE proteins function biochemically to bind to and enhance the activity of E3 RING ubiquitin ligases. The E3 RING ubiquitin ligase TRIM27 was identified as a major binding partner of MAGE-L2.

SIGNOR-253513

O14920

P04637

1

phosphorylation

up-regulates activity

0.52

Here , we show that IKKbeta modulates the activity of p53 in response to glutamine depletion to promote cancer cell adaptation .|Taken together, these results indicate that IKK\u03b2 phosphorylates p53 on Ser392 as an early response to glutamine deprivation and possibly later facilitates its phosphorylation at Ser15 and transcriptional activity.

SIGNOR-278516

P49137

P15923

1

phosphorylation

up-regulates

0.52

Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2

SIGNOR-166643

Q12986

O14746

1

transcriptional regulation

up-regulates quantity by expression

0.52

NFX1-123 positively regulated hTERT expression, as its knockdown decreased hTERT mRNA levels and telomerase activity and its overexpression increased telomerase activity. NFX1-123 was found to interact with cytoplasmic poly(A) binding proteins (PABPCs), and together they synergistically augmented expression from the hTERT promoter when activated by HPV16 E6.

SIGNOR-261050

P36406

Q9UHD2

1

binding

up-regulates activity

0.519

TRIM23 interacts with TBK1 and p62. TRIM23 GTPase activates TBK1 to phosphorylate p62. Biochemical characterization showed that TRIM23 binds with its C-terminal ARF domain to the N-terminal KD of TBK1, and that GTP hydrolysis activity of the ARF stimulates TBK1-mediated phosphorylation of p62 at S403 in its ubiquitin-associated (UBA) domain, which was shown to promote cargo recruitment and autophagic flux

SIGNOR-266654

Q9UBK2

O00327

1

transcriptional regulation

up-regulates quantity by expression

0.519

Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism. Here we show that PGC-1alpha (Ppargc1a), a transcriptional coactivator that regulates energy metabolism, is rhythmically expressed in the liver and skeletal muscle of mice. PGC-1alpha stimulates the expression of clock genes, notably Bmal1 (Arntl) and Rev-erbalpha (Nr1d1), through coactivation of the ROR family of orphan nuclear receptors.

SIGNOR-268031

P08754

O95622

1

binding

down-regulates activity

0.519

Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3

SIGNOR-278076

Q12913

P35222

1

dephosphorylation

up-regulates activity

0.519

Our data demonstrate that CD148 promotes E-cadherin cell adhesion by regulating Rac1 activity, concomitant with modulation of p120, \u03b2-catenin, and Src tyrosine phosphorylation, and that this effect requires E-cadherin and p120 association.|Taken together, it is likely that CD148 dephosphorylation of \u03b2-catenin enhances the cadherin cell adhesion independent of Rho family GTPases.

SIGNOR-276992

Q9UDY2

P46937

1

binding

down-regulates

0.519

The Crumbs complex component AMOT co-localizes with MST1_ 2, LATS1_ 2 and YAP in a complex at the tight junction to control cell growth. Zona occludens-2 (ZO-2) in the tight junction, and a-catenin, b-catenin, or PTPN14 in the adherence junction, also bind to YAP_TAZ.

SIGNOR-230754

P04637

P55957

1

transcriptional regulation

up-regulates quantity by expression

0.519

Bid is a p53 primary-response gene.

SIGNOR-140248

P35638

P49715

1

transcriptional regulation

down-regulates quantity

0.519

We find that expression of CHOP, a nuclear protein that dimerizes avidly with C/EBP isoforms alpha and beta and directs the resulting heterodimer away from classic C/EBP-binding sites, markedly inhibits this differentiation process.

SIGNOR-255913

P50461

P15173

1

binding

up-regulates activity

0.519

we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements.

SIGNOR-241113

P28482

P05023

1

phosphorylation

down-regulates activity

0.519

Parathyroid hormone (PTH) inhibits Na+,K+-ATPase activity through protein kinase C- (PKC) and extracellular signal-regulated kinase- (ERK) dependent pathways and increases serine phosphorylation of the α1-subunit. These results suggest that PTH regulates Na(+),K(+)-ATPase by PKC and ERK-dependent alpha(1)-subunit phosphorylation and that the phosphorylation requires the expression of a serine at the 11 position of the Na(+),K(+)-ATPase alpha(1)-subunit.

SIGNOR-262940

P28482

P09874

1

phosphorylation

up-regulates

0.519

Parp1 phosphorylation by erk1/2 is required for maximal parp-1 activation after dna damage. S372a and t373a mutations impaired parp-1 activation.

SIGNOR-146224

P17612

Q13972

1

phosphorylation

up-regulates

0.519

Phosphorylation of serine 916 of ras-grf1 contributes to the activation of exchange factor activity by muscarinic receptors.

SIGNOR-73202

Q05513

Q8N2W9

1

phosphorylation

down-regulates quantity by destabilization

0.519

In this study, we discovered a new protein isoform encoded by KIAA0317, termed fibrosis-inducing E3 ligase 1 (FIEL1), which potently stimulates the TGFbeta signaling pathway through the site-specific ubiquitination of PIAS4.FIEL1 targets PIAS4 using a double locking mechanism that is facilitated by the kinases PKCzeta and GSK3beta. Specifically, PKCzeta phosphorylation of PIAS4 and GSK3beta phosphorylation of FIEL1 are both essential for the degradation of PIAS4.|These experiments suggested that PKCzeta is an authentic regulator of PIAS4 protein stability; Q21 and phosphorylated S18 of PIAS4 are both required for FIEL1 interaction.

SIGNOR-275513

P53990

Q9UBP0

1

relocalization

up-regulates activity

0.519

Our results suggest that inclusion of IST1 into the ESCRT complex allows recruitment of spastin to promote fission of recycling tubules from the endosome. Thus, we reveal a novel cellular role for MT severing and identify a mechanism by which endosomal recycling can be coordinated with the degradative machinery.

SIGNOR-269047

P53350

Q2M2Z5

1

phosphorylation

up-regulates

0.519

Here, we identify a novel centrosomal substrate of plk1, kizuna (kiz), depletion of which causes fragmentation and dissociation of the pericentriolar material from centrioles at prometaphase, resulting in multipolar spindles. Plk1 maintains the integrity of the spindle poles by phosphorylating kiz.

SIGNOR-149630

O95198

Q96J92

1

binding

down-regulates quantity by destabilization

0.519

We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body.

SIGNOR-272118

Q08050

P35222

1

binding

up-regulates activity

0.519

Nuclear FoxM1 then directly interacted with nuclear β‐catenin, which released β‐catenin from ICAT and enhanced recruitment of β‐catenin to the promoter of Wnt target gene, hence increasing the expression of Wnt target gene.

SIGNOR-277211

P49137

Q00613

1

phosphorylation

down-regulates activity

0.519

A potential mechanism for MK2-induced HSF1 inactivation is suggested by the findings that phosphorylation of serine 121 enhances HSF1 binding to HSP90, a major repressor of HSF1.|Phosphorylation of HSF1 by MAPK activated protein kinase 2 on serine 121, inhibits transcriptional activity and promotes HSP90 binding.

SIGNOR-279541

P49841

O15294

1

phosphorylation

up-regulates activity

0.518

But OGT activity is modulated by GSK3beta (XREF_FIG) and GSK3beta activity is known to oscillate through Ser9 phoshorylation.|Here, we found that OGT is phosphorylated at serines 3 or 4 by GSK3beta and that O GlcNAcylation of OGT also occurs on the same or neighboring serine residues, suggesting interacting phosphorylation and O GlcNAcylation events on OGT itself.

SIGNOR-279528

P06493

P06748

1

phosphorylation

down-regulates activity

0.518

However, under the experimental conditions used here, the t199 residue was the most likely candidate to be phosphorylated by cyclin b/cdc2 these results strongly support the concept that the rna binding activity of b23.1 is inactivated by cyclin b/cdc2-mediated phosphorylation.

SIGNOR-89605

O15111

Q92793

1

binding

up-regulates

0.518

Ikk-alpha interacts with creb-binding protein and in conjunction with rel a is recruited to nf-kappab-responsive promoters and mediates the cytokine-induced phosphorylation and subsequent acetylation of specific residues in histone h3.

SIGNOR-101539

P14416

P09471

1

binding

up-regulates activity

0.518

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-256980

P17612

P01100

1

phosphorylation

up-regulates activity

0.518

Human c-Fos protein is phosphorylated in vitro by PKA. phosphorylation of Fos occurs at serine residue 362. Modification of the Fos protein by phosphorylation with PKA then allows it to act as a regulator of its own synthesis by downregulating fos gene expression at a transcriptional level

SIGNOR-250356

P80370

P46531

1

binding

down-regulates activity

0.518

Moreover, the interaction of DLK1 with NOTCH1 caused an inhibition of basal NOTCH signaling in preadipocytes and mesenchymal multipotent cells. In this work, we demonstrate, for the first time, that DLK2 interacts with itself, with DLK1, and with the same NOTCH1 receptor region as DLK1 does. We demonstrate also that the interaction of DLK2 with NOTCH1 similarly results in an inhibition of NOTCH signaling in preadipocytes and Mouse Embryo fibloblasts.

SIGNOR-172830

P42224

Q04206

1

binding

down-regulates

0.518

Acetylated stat1 is able to interact with nf-kappab p65. As a consequence, p65 dna binding, nuclear localization, and expression of anti-apoptotic nf-kappab target genes decrease.

SIGNOR-144561

P28482

Q8N122

1

phosphorylation

up-regulates activity

0.518

We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1.

SIGNOR-188916

P06213

O14654

1

phosphorylation

up-regulates activity

0.518

The binding of insulin to the subunit of IR not only concentrates insulin at its site of action, but also induces conformational changes in the receptor, which in turn stimulates the tyrosine kinase activity intrinsic to the _ subunit of the IR and triggers the signaling cascades (Fig. 3). Insulin receptors trans phosphorylate several immediate substrates (on Tyr residues) including IRS1-4, Shc, and Gab 1, Cbl, APS, and P60dok.

SIGNOR-217897

P17612

P61586

1

phosphorylation

down-regulates activity

0.518

PKA phosphorylates RhoA on Ser188. the addition of a negative charge to Ser188 is sufficient to diminish both RhoA activation and activity within the context of a cell.

SIGNOR-250047

P08603

P00751

1

binding

down-regulates activity

0.518

As a regulator of the alternative pathway, FH binds to C3b and inhibits the binding of factor B to C3b, acts as a cofactor for the factor I-mediated cleavage of C3b to iC3b (cofactor activity), and accelerates the decay of C3bBb, the alternative pathway C3 convertase (decay-accelerating activity)

SIGNOR-252142

P24941

P98177

1

phosphorylation

down-regulates

0.518

Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity

SIGNOR-183655

Q9Y243

P55211

1

phosphorylation

down-regulates

0.518

Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity

SIGNOR-61565

Q8IWR1

Q9BQ95

1

binding

down-regulates activity

0.518

In this study, we showed that one of the TRIM family ubiquitin ligases, TRIM59, interacts with ECSIT as an adaptor protein required for the TLR-mediated transduction pathway. The B-box and RING domains of TRIM59 are important for interaction with ECSIT.|ECSIT enhances IPS-1-mediated IFN-Beta promoter activation.|Luciferase reporter assays using reporter plasmids including NF-kappaB responsive element, interferon beta (IFN-beta) promoter and interferon-sensitive response element (ISRE) showed that overexpression of TRIM59 repressed their transcriptional activities, whereas knockdown of TRIM59 enhanced their transcriptional activities.

SIGNOR-260369

Q4KMG0

P00519

1

binding

up-regulates activity

0.518

Abl binds a proline-rich motif in cdo via its sh3 domain, and these regions of abl and cdo are required for their promyogenic effects. Cdo is important for full abl kinase activity

SIGNOR-185762

O96013

Q92974

1

phosphorylation

down-regulates activity

0.518

PAK4 specifically phosphorylates GefH1, and this is thought to inhibit its ability to activate Rho, consequently inhibiting stress fiber formation.

SIGNOR-279245

Q01543

P15976

1

binding

up-regulates activity

0.518

On the other hand, our data demonstrate that FLI-1 also interacts with GATA-1. However, FLI-1 does not repress but enhances GATA-1 activity.

SIGNOR-256045

P61812

Q03167

1

binding

up-regulates

0.518

Betaglycan binds tgf-b isoforms with high affinity and increases the functional interaction between tgf-b and its type ii and type i signalling receptors.

SIGNOR-76473

Q5VWQ8

P01116

1

gtpase-activating protein

down-regulates activity

0.518

The GAP domain of DAB2IP is homologous to other Ras-GAPs, such as GAP120 and neurofibromin (NF1), and can stimulate the GTPase activity of RAS proteins both in vitro and in cancer cell lines. DAB2IP is able to stimulate in vitro and in vivo the GTPase activity of RAS proteins (H-Ras, K-Ras, and N-Ras) facilitating GTP hydrolysis to GDP.

SIGNOR-254746

Q9BQS8

Q9GZQ8

1

binding

up-regulates activity

0.517

The preferential binding to LC3A and -B was confirmed in vivo by co-immunoprecipitation experiments of Myc-tagged FYCO1 and GFP fusions of human ATG8 family pro-teins expressed in HEK293 cells (Fig. 2B). GFP-LC3A and GFP-LC3B were efficiently co-precipitated with Myc-FYCO1,whereas GFP-LC3C, GFP-GABARAP, GFP-GABARAPL1 and-L2 were not. The effects we see on late steps of basal autophagy on mutation of the FYCO1 LIR motif correlate with a role of FYCO1 in regulating kinesin-mediated transport of LC3-positive autophagic structures.

SIGNOR-260597

Q9NS75

P50148

1

binding

up-regulates activity

0.517

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-257024

Q06187

P78347

1

phosphorylation

up-regulates activity

0.517

These residues, tyr248, tyr357, and tyr462, were also found to be the major sites for btk-dependent phosphorylation of bap/tfii-i in vivo. Residues tyr357 and tyr462 are contained within the loop regions of adjacent helix-loop-helix-like repeats within bap/tfii-i. Mutation of either tyr248, tyr357, or tyr462 to phenylalanine reduced transcription from a c-fos promoter relative to wild-type bap/tfii-i in transfected cos-7 cells, consistent with the interpretation that phosphorylation at these sites contributes to transcriptional activation.

SIGNOR-108346

Q92765

P04628

1

binding

down-regulates

0.517

We and others demonstrated that fzb-1 blocks wnt-1 and xwnt-8 signaling in xenopus embryos,

SIGNOR-51762

P23468

P40763

1

dephosphorylation

down-regulates activity

0.517

Transfection of wild-type PTPRD resulted in the specific dephosphorylation of STAT3 at tyrosine 705, a residue that must be phosphorylated for STAT3 to be active

SIGNOR-248442

Q05513

O14920

1

phosphorylation

up-regulates activity

0.517

Activation of IkappaB kinase beta by protein kinase C isoforms. | Interestingly, recombinant active zetaPKC and alphaPKC are able to stimulate in vitro the activity of IKKbeta but not that of IKKalpha. In addition, evidence is presented here that recombinant zetaPKC directly phosphorylates IKKbeta in vitro, involving Ser177 and Ser181. Collectively, these results demonstrate a critical role for the PKC isoforms in the NF-kappaB pathway at the level of IKKbeta activation and IkappaB degradation.

SIGNOR-249015

P27361

Q9HBH9

1

phosphorylation

up-regulates

0.517

Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity.

SIGNOR-48355

P08254

Q99075

1

cleavage

up-regulates

0.517

It was concluded that mmp-3 cleaves hb-egf at a specific site in the jm domain and that this enzyme might regulate the conversion of hb-egf from being a juxtacrine to a paracrine/autocrine growth factor.

SIGNOR-83339

Q13191

P27986

1

polyubiquitination

down-regulates quantity by destabilization

0.517

Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells.Here it is shown that Cbl-b interacts with and induces ubiquitin conjugation to the p85 regulatory subunit of phosphatidylinositol 3-kinase, an upstream regulator of Vav.

SIGNOR-272583

P50613

Q00535

1

phosphorylation

up-regulates activity

0.517

In addition, the Cdk7 substrate, CTD of RNAPII, causes a dose-dependent decline in Cdk5 activation by Cdk7.|Likewise, Cdk7 or cyclin H immunoprecipitate from mouse brain specifically phosphorylates wt Cdk5 at Ser159 and enhances Cdk5 and p25 activity.

SIGNOR-278923