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
P53350	P60484	1	phosphorylation	down-regulates activity	0.534	Subsequently, Plk1 phosphorylation of PTEN was shown to be responsible for its inactivation.	SIGNOR-280070
Q9UPT9	Q96EB6	1	deubiquitination	up-regulates quantity by stabilization	0.534	USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells.	SIGNOR-261561
P00533	Q9UKV8	1	phosphorylation	up-regulates activity	0.534	Furthermore, AGO2 function is directly modulated by EGFR signaling in ERalpha negative breast cancer under states of hypoxic stress.\|Here, EGFR can directly bind and phosphorylate residue Y393 of AGO2[ xref ].	SIGNOR-278931
P11161	P17676	1	transcriptional regulation	up-regulates quantity by expression	0.534	Ectopic expression of krox20 can transactivate the c/ebpbeta promoter and increase c/ebpbeta gene expression in 3t3-l1 preadipocytes	SIGNOR-139292
P31749	P06748	1	phosphorylation	down-regulates activity	0.534	We find that AKT phosphorylation of NPM-Ser48 prevents oligomerization that results in nucleoplasmic localization of ARF, constitutive MDM2 inhibition and stabilization of p53.	SIGNOR-276667
Q14680	P30305	1	phosphorylation	down-regulates activity	0.533	In the present study we show that the human pEg3 kinase is able to specifically phosphorylate CDC25B in vitro. One phosphorylation site was identified and corresponded to serine 323[Ä] Taken together these results suggest that pEg3 is a potential regulator of the G2/M progression and may act antagonistically to the CDC25B phosphatase	SIGNOR-255655
P28482	P55211	1	phosphorylation	down-regulates activity	0.533	ERK/MAPK phosphorylates caspase-9 at Thr(125), and this phosphorylation is crucial for caspase-9 inhibition	SIGNOR-148616
Q8N608	Q9NZV8	1	relocalization	up-regulates activity	0.533	Coexpression of DPP10 changes the subcellular localization of Kv4.2 expressed in COS-7 cells by promoting surface trafficking.DPP10 accelerates Kv4.2 inactivation at high and low voltages	SIGNOR-269006
O75469	P19793	1	binding	up-regulates	0.533	The constitutive androstane receptor (car, nr1i4), like fxr and pxr, binds dna as a heterodimer with rxr?	SIGNOR-111624
Q13177	Q15746	1	phosphorylation	down-regulates activity	0.533	PAK2 can directly phosphorylate MLCK, inhibiting its activity and limiting the development of isometric tension. PAK2 catalyzes MLCK phosphorylation on serine residues 439 and 991.	SIGNOR-250223
P15509	O60674	2	binding	up-regulates activity	0.533	JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation.	SIGNOR-249502
Q9H0M0	P36897	1	ubiquitination	down-regulates	0.533	Similar to smurfs, wwp1 associated with smad7 and induced its nuclear export, and enhanced binding of smad7 to tgf-beta type i receptor to cause ubiquitination and degradation of the receptor. Consistent with these results, wwp1 inhibited phosphorylation of smad2 induced by tgf-beta. Wwp1 thus negatively regulates tgf-beta signaling in cooperation with smad7	SIGNOR-126581
P12931	P41743	1	phosphorylation	up-regulates	0.533	Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase c's via a src kinase pathway. tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain.	SIGNOR-111920
O60674	P15509	2	phosphorylation	up-regulates activity	0.533	JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation.	SIGNOR-249503
Q05655	P08913	1	phosphorylation	up-regulates activity	0.533	Taken together, these results indicate that S232 acts as a selective, PKC-sensitive, modulator of effector coupling of the alpha(2A)AR to inositol phosphate stimulation. This represents one mechanism by which cells route stimuli directed to multifunctional receptors to selected effectors so as to attain finely targeted signaling.	SIGNOR-249126
P31749	P28482	1	phosphorylation	up-regulates activity	0.533	AKT1 stimulated PLD activity via activation of ERK.\|AKT1 actually phosphorylated ERK2 as a substrate (K(m) 1 \u03bcm).	SIGNOR-279136
P45983	Q14653	1	phosphorylation	up-regulates	0.533	In this study, we show that another kinase, c-jun-nh(2)-terminal kinase (jnk), phosphorylates irf3 on its n-terminal serine 173 residuejnk1 can synergize the action of irf3(5d), but not the s173a-irf3(5d) mutant	SIGNOR-183489
P11171	Q14980	1	relocalization	up-regulates activity	0.533	These results indicate that 4.1 proteins recruit NuMA and dynein to the anaphase cell cortex through their conserved CTD (Figure 2I).	SIGNOR-266012
P53350	P01106	1	phosphorylation	up-regulates activity	0.533	Here, we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces MYC phosphorylation and protein accumulation. We show that PDK1-PLK1-MYC signaling is critical for cancer cell growth and survival, and small-molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting of MYC dependency	SIGNOR-243522
Q8NG68	Q71U36	1	tyrosination	down-regulates	0.533	Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization	SIGNOR-176912
P49913	P25090	1	binding	up-regulates	0.533	Ll-37 may contribute to innate and adaptive immunity by recruiting neutrophils, monocytes, and t cells to sites of microbial invasion by interacting with fprl1.	SIGNOR-82701
O15379	Q13547	1	binding	up-regulates	0.533	Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes.	SIGNOR-199964
P37231	P25874	1	transcriptional regulation	up-regulates quantity by expression	0.533	NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma\|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog,	SIGNOR-263985
Q96GF1	Q12981	1	polyubiquitination	up-regulates activity	0.533	RNF185 functions as a ubiquitin E3 ligase, enabling BNIP1-p62 interaction. Here we show that human RNF185 is a mitochondrial ubiquitin E3 ligase that regulates selective mitochondrial autophagy in cultured cells. Human BNIP1 colocalizes with RNF185 at mitochondria and is polyubiquitinated by RNF185 through K63-based ubiquitin linkage in vivo. The polyubiquitinated BNIP1 is capable of recruiting autophagy receptor p62, which simultaneously binds both ubiquitin and LC3 to link ubiquitination and autophagy. RNF185 interacts with BNIP1 and ATG5	SIGNOR-271931
P00519	P15391	1	phosphorylation	up-regulates activity	0.533	The results revealed that only tyrosine (Y)490 of CD19 was phosphorylated by c-Abl.	SIGNOR-245283
Q15466	Q07869	1	binding	up-regulates	0.533	Surprisingly, shp potentiated transcription by pparalpha/rxralpha heterodimers from the hd-ppre. This is the first demonstration of positive transcriptional activity attributable to shp. Together, these results suggest that shp can modulate pparalpha/rxralpha-mediated transcription in a response element-specific manner.	SIGNOR-108252
Q15759	Q02078	1	phosphorylation	up-regulates activity	0.533	In this study, we demonstrate that among the different Mitogen-activated protein kinases, the MADS-box transcription factors MEF2A and MEF2C are preferentially phosphorylated and activated by the p38 subfamily members p38alpha and p38beta2.	SIGNOR-280024
P31749	P48431	1	phosphorylation	up-regulates quantity by stabilization	0.532	In contrast, phosphorylation of Sox2 by AKT1 at T118 blocks K119me by Set7 and stabilizes Sox2.	SIGNOR-279003
P31749	Q8N6T7	1	phosphorylation	down-regulates activity	0.532	AKT1 interacts with and phosphorylates SIRT6 on Ser 338.\|Because AKT1 suppresses SIRT6 protein abundance by decreasing its stability, we investigated whether MDM2 is involved in this process.	SIGNOR-278465
P43405	P37840	1	phosphorylation	down-regulates	0.532	Here, we show that alpha-synuclein (alpha-syn) is an outstanding substrate for the protein tyrosine kinase p72syk (syk), which phosphorylates three tyrosyl residues in its c-terminal domain (y-125, y-133, and y-136), here, we show that _-syn is an outstanding substrate for syk and that once it is tyrosine phosphorylated, it loses the ability to form oligomers.	SIGNOR-113065
P63000	Q96Q42	1	binding	up-regulates activity	0.532	Thus, in our system, activeRac1 may recruit ALS2 only at the very early stage ofmacropinocytosis including membrane rufﬂes, suggest-ing that ALS2 is retained by some other mechanismsuntil Rab conversion.	SIGNOR-277777
P27361	O95644	1	phosphorylation	down-regulates	0.532	We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats.	SIGNOR-74564
Q8IWJ2	P20645	1	relocalization	up-regulates activity	0.532	Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector	SIGNOR-253086
O15164	P04637	1	ubiquitination	down-regulates	0.532	New ring-domain e3-ubiquitin ligase trim24 that targets p53 for degradation	SIGNOR-188726
P19525	P25963	1	phosphorylation	down-regulates quantity by destabilization	0.532	As described for other stimuli, following pIC treatment, PKR phosphorylates the NF-kappa B inhibitor I kappa B alpha at serine 32 before degradation.	SIGNOR-249335
O00533	P16157	1	relocalization	up-regulates quantity	0.532	Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.	SIGNOR-266724
P29350	P14784	1	dephosphorylation	down-regulates	0.532	We have found that il-2 induces association of shp-1 with the il-2 receptor complex, and that once shp-1 is recruited to the activated receptor it is able to decrease tyrosine phosphorylation of il-2rbeta and the associated tyrosine kinases jak1 and jak3.	SIGNOR-55989
P62820	O75385	1	relocalization	up-regulates activity	0.532	C9orf72 acts as an effector of Rab1a that recruits active Rab1a to theULK1 complex to promote translocation of the ULK1 complex to thephagophore during autophagy initiation	SIGNOR-261299
Q13882	P23246	1	phosphorylation	down-regulates activity	0.531	BRK phosphorylates PSF promoting its cytoplasmic localization and cell cycle arrest.\|These data suggest that BRK activity impedes the ability of PSF to bind RNA.To map the PSF tyrosine residues phosphorylated by BRK and assess if the PSF N-terminal is required for phosphorylation, we co-transfected HEK293 cells with various GFP-PSF deletion mutants in the presence or absence myc-BRK-YF.	SIGNOR-279754
P17252	P10721	1	phosphorylation	down-regulates	0.531	Phosphorylation of kit/scfr by pkc-_ in vitro: identification of ser-741 and ser-746 as the major phosphorylation sites for pkc / pkc, which acts in an scf-stimulated feedback loop, that negatively controls kit/scfr kinase activity	SIGNOR-28605
Q13153	O15143	1	phosphorylation	up-regulates	0.531	The formation of new branched actin filament networks at the cell cortex of migrating cells is choreographed by the actin-related protein (arp) 2/3 complex. Despite the fundamental role of the arp2/3 complex in actin nucleation and branching, upstream signals that control the functions of p41-arc, a putative regulatory component of the mammalian arp2/3 complex. Pak1 phosphorylation of p41-arc regulates its localization with the arp2/3 complex in the cortical nucleation regions of cells. Pak1 phosphorylates p41-arc on threonine 21	SIGNOR-121642
P04233	P61073	1	binding	up-regulates	0.531	Cd74 forms functional complexes with cxcr4 that mediate mif-specific signaling.	SIGNOR-187461
P43403	P51452	1	phosphorylation	up-regulates activity	0.531	ZAP-70 and Syk also tyrosine-phosphorylated VHR in COS-1 cells (Fig. 2d), whereas other kinases (Csk, Lck, Fyn, Jak2, Bcr-Abl and Itk) had little effect. Finally, recombinant ZAP-70 readily phosphorylated VHR in vitro (Fig. 2f).	SIGNOR-276000
Q9BUB5	O43597	1	phosphorylation	down-regulates	0.531	The spry2/nedd4 association involves the ww domains of nedd4 and requires phosphorylation of the mnk2 kinase sites, ser(112) and ser(121), on spry2. mnk2 silencing decreased spry2-nedd4 interactions and also augmented the ability of spry2 to inhibit fibroblast growth factor signaling. endogenous and overexpressed nedd4 polyubiquitinate spry2 via lys(48) on ubiquitin and decrease its stability.	SIGNOR-188889
O14757	P38936	1	phosphorylation	down-regulates quantity by destabilization	0.531	Responsible for this degradation is the checkpoint kinase Chk1, which phosphorylates p21(Waf1) on T145 and S146 residues and induces its proteasome-dependent proteolysis.	SIGNOR-279325
Q15154	P41208	1	relocalization	up-regulates	0.531	Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome	SIGNOR-94990
P17252	P16144	1	phosphorylation	down-regulates	0.531	Egf stimulates a pkc-?-Dependent pathway that results in the phosphorylation of the ?4 Integrin subunit on serine residues and its redistribution to actin-rich structures together, these results highlight the importance of serine phosphorylation in regulating type ii hemidesmosome disassembly, implicate a cluster of serine residues within the connecting segment of ?4, and argue for a key role for pkc-? In regulating these structures	SIGNOR-124494
O15034	Q9UQ26	1	binding	down-regulates activity	0.531	SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.	SIGNOR-264366
Q8N0Z6	Q8N9B5	1	binding	up-regulates activity	0.531	DNA damage activates ATM kinase which then phosphorylates Strap at Ser 203 (red circles). Phosphorylated Strap is stabilized and undergoes nuclear accumulation where it assembles into a co-activator complex, which includes p300 and cofactors such as JMY	SIGNOR-262647
P04626	Q96N67	1	phosphorylation	up-regulates	0.531	We show that the nrg1 receptor erbb2 directly binds and activates dock7 by phosphorylating tyr-1118. thus, dock7 functions as an intracellular substrate for erbb2 to promote schwann cell migration. This provides an unanticipated mechanism through which ligand-dependent tyrosine phosphorylation can trigger the activation of rho gtpase-gefs of the dock180 family.	SIGNOR-178348
Q96P48	P60953	1	gtpase-activating protein	down-regulates activity	0.531	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-260452
P81133	P27540	1	binding	up-regulates activity	0.531	We demonstrate that both SIM1 and SIM2 can heterodimerize via their helix-loop-helix·PAS regions with ARNT, but not with AHR, and that they do not form homodimers. Furthermore, SIM1 may have a dual role, both negatively affecting AHR·ARNT binding to the XRE and also acting in concert with ARNT as a novel DNA-binding heterodimer.	SIGNOR-240759
Q9Y3C5	O95630	1	binding	down-regulates quantity by destabilization	0.531	RNF11 recruits AMSH to Smurf2 E3 ligase. Smurf2 promotes ubiquitination of AMSH in the presence of wt RNF11. Previously, we have shown that RNF11 interacts with the HECT-type E3 ligases AIP4 and Smurf2. Here, we show that RNF11 binds to AMSH in mammalian cells and that this interaction is independent of the RNF11 RING-finger domain and the PY motif. Our results also demonstrate that AMSH is ubiquitinated by Smurf2 E3 ligase in the presence of RNF11 and that a consequent reduction in its steady-state level requires both RNF11 and Smurf2. RNF11 therefore recruits AMSH to Smurf2 for ubiquitination, leading to its degradation by the 26S proteasome.	SIGNOR-272953
P49137	Q13151	1	phosphorylation	up-regulates activity	0.531	MAPKAP-K2 phosphorylated hnRNP A0 at Ser84 in vitro and this residue became phosphorylated in LPS-stimulated cells. The simplest explanation for these findings is that the phosphorylation of hnRNP A0 at Ser84 by MAPKAP-K2 enhances binding to the AREs of these mRNAs or allows hnRNP A0 to displace another protein(s) from the AREs.	SIGNOR-262951
P49761	Q07955	1	phosphorylation	up-regulates activity	0.531	In vitro, Clk/Sty efficiently phosphorylated the SR family member ASF/SF2 on serine residues located within its serine/arginine-rich region (the RS domain). Overexpression of the active Clk/Sty kinase caused a redistribution of SR proteins within the nucleus. These results suggest that Clk/Sty kinase directly regulates the activity and compartmentalization of SR splicing factors.	SIGNOR-273859
P68400	O15379	1	phosphorylation	up-regulates activity	0.531	A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity.	SIGNOR-250889
Q01105	P67775	1	binding	down-regulates	0.531	Here we report that both the amino terminal fragment (i(2ntf);aa 1-175) and the carboxy terminal fragment (i(2ctf);aa 176-277) of i(2)(pp2a) inhibit pp2a by binding to its catalytic subunit pp2ac	SIGNOR-175719
P46937	P35222	1	binding	up-regulates	0.531	Additionally, the hippo and wnts also cooperate in the nucleus, where yap interacts with beta-catenin and induces the expression of canonical wnt target genes, such as sox2 and snai2 in mouse heart tissue.	SIGNOR-201939
O15264	P10636	1	phosphorylation	down-regulates activity	0.531	Phosphorylation of tau by SAPK3 and SAPK4 resulted in a marked reduction in the ability of tau to promote microtubule assembly.	SIGNOR-278313
P02511	P07315	1	binding	up-regulates activity	0.531	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-253622
P51608	P16220	1	post transcriptional regulation	up-regulates quantity by expression	0.531	Interestingly, Creb1 was one of the activated MeCP2 targets that we validated by quantitative real-time RT-PCR (Fig. 1C), and using ChIP analysis we found that in vivo MeCP2 binds to the promoter region of Creb1, with significantly enhanced binding in MECP2-Tg samples compared to WT (p < 0.05) \| In addition, Sst and CREB1 protein levels were increased in MECP2-Tg hypothalami compared to WT, indicating that MeCP2 indeed enhances expression of Sst and Creb1	SIGNOR-264682
P06744	Q9UKV5	2	binding	up-regulates	0.53	Pgi is a housekeeping gene encoding phosphoglucose isomerase (pgi) a glycolytic enzyme that also functions as a cytokine (autocrine motility factor (amf)/neuroleukin/maturation factor) upon secretion from the cell and binding to its 78 kda seven-transmembrane domain receptor (gp78/amf-r)	SIGNOR-97270
Q8IXJ6	Q92831	1	binding	down-regulates	0.53	Sir2 forms a complex with the acetyltransferase pcaf and myod and, when overexpressed, retards muscle differentiation.	SIGNOR-104248
P04637	P14921	1	binding	down-regulates activity	0.53	We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and inter-related manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription. We show that ets-1 and p53 associate physically in vitro and in vivo and that their interaction, rather than a direct binding of p53 to the TXSA promoter, is required for transcriptional repression of TXSA by wild-type p53.	SIGNOR-254087
Q8IWV8	O94761	1	binding	up-regulates	0.53	The isolated recql4, assayed as a complex with ubr1 and ubr2, exhibited dna-stimulated atpase activity but was inactive as either dna helicase or dna translocase / the discovery, in the present work, that these ub ligases, ubr1 and ubr2, interact with the putative helicase recql4 (fig. 2), and that recql4 is a long-lived, non-ubiquitylated protein in hela cells	SIGNOR-128214
Q01484	P11532	1	relocalization	up-regulates quantity	0.53	We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4.	SIGNOR-266712
Q92995	Q14457	2	deubiquitination	up-regulates quantity by stabilization	0.53	Similarly, the overexpression of USP13 reduced the levels of ubiquitinated Beclin1 which was inhibited by spautin-1 (Figure 4E)	SIGNOR-260295
Q6SZW1	Q8IUC6	1	binding	down-regulates	0.53	SARM utilizes its TIR domain to negatively regulate TRIF	SIGNOR-252068
O95136	P50148	1	binding	up-regulates activity	0.53	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-257215
Q12959	P43403	1	phosphorylation	up-regulates activity	0.53	Immunoblot analysis showed that phosphorylation of the activating ZAP70 kinase domain residue Tyr 493 was decreased in the DLG1 KD cells. Similarly, the Tyr 319 residue of ZAP70 and Tyr 83 residue of TCR- ζ also showed reduced phosphorylation.	SIGNOR-274142
P06493	P10275	1	phosphorylation	up-regulates	0.53	At first, the data show that cdk5 enables phosphorylation of ar at ser-81 site through direct biochemical interaction and, therefore, results in the stabilization of ar proteins although ar was reported as substrates for cdk9 (5) as well as cdk1	SIGNOR-175692
P43119	P63092	1	binding	up-regulates activity	0.53	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-256806
O95600	P56545	1	binding	up-regulates activity	0.53	Here we report the characterisation of KLF8/ZNF741/BKLF3 (KLF8). We demonstrate that this protein is able to bind CACCC-boxes in DNA and can repress gene expression by associating with CtBP co-repressors.	SIGNOR-236962
Q13237	Q03393	1	phosphorylation	up-regulates	0.53	Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps. Addition of cgmp stimulated phosphotransferase activity 2-fold. Extracts from transfected cos-1 cells overexpressing cgkii stimulated ser(19) phosphorylation more than 100-fold.In assays with purified enzymes, wild-type but not ptps-s19a was a specific substrate for the cgmp-dependent protein kinase (cgk) type i and ii. Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps	SIGNOR-71751
Q9BXW4	Q14596	1	binding	down-regulates	0.53	We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family. . downregulation of either lc3 or gabarap (or both) family members leads to stabilization and p62-dependent aggregation of nbr1.	SIGNOR-184258
Q9UKV5	P06744	2	polyubiquitination	down-regulates quantity by destabilization	0.53	Gp78 is a ubiquitin ligase that plays a vital role in endoplasmic reticulum (ER)-associated degradation (ERAD). Here we report that autocrine motility factor (AMF), also known as phosphoglucose isomerase (PGI), is a novel substrate of gp78. We show that polyubiquitylation of AMF requires cooperative interaction between gp78 and the ubiquitin ligase TRIM25 (tripartite motif-containing protein 25). While TRIM25 mediates the initial round of ubiquitylation, gp78 catalyzes polyubiquitylation of AMF.	SIGNOR-272177
Q14457	Q92995	2	deubiquitination	up-regulates quantity by stabilization	0.53	We found that endogenous Beclin1 can interact with USP13 and the interaction was reduced in the presence of spautin-1 (Figure 5C). Interestingly, the DUB activities were significantly increased when USP13 and USP10 coincubated together or with Beclin1 or all 3 proteins together, suggesting the DUB activity can be significantly enhanced when USP13 interacts with its substrate Beclin1 or USP10.	SIGNOR-260296
P04150	P42229	1	binding	up-regulates	0.53	We show here that the glucocorticoid receptor can act as a transcriptional co-activator for stat5 and enhance stat5-dependent transcription. Stat5 forms a complex with the gluco-corticoid receptor which binds to dna independently of the gre. This complex formation between stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a gre-con-taining promoter.	SIGNOR-44376
Q9Y2N7	Q99814	1	transcriptional regulation	down-regulates quantity by repression	0.53	None of the long HIF-3α variants was capable of efficient induction of an HRE reporter in overexpression experiments, but instead inhibited the transcriptional activation of the reporter by HIF-1 and HIF-2.	SIGNOR-261616
Q02535	P15923	1	binding	down-regulates activity	0.53	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241134
P31751	P46527	1	phosphorylation	down-regulates	0.53	Akt-induced t157 phosphorylation causes retention of p27(kip1) in the cytoplasm, precluding p27(kip1)-induced g1 arrest.[__]Thus, cytoplasmic relocalization of p27(kip1), secondary to akt-mediated phosphorylation, is a novel mechanism whereby the growth inhibitory properties of p27(kip1) are functionally inactivated and the proliferation of breast cancer cells is sustained.	SIGNOR-93122
Q92560	Q9C0F0	1	binding	up-regulates activity	0.53	We report a critical link between BAP1 complex and BRD4, which is bridged by the physical interaction between ASXL3 and BRD4 in an SCLC subtype (SCLC-A), which expresses a high level of ASCL1. We further showed that ASXL3 functions as an adaptor protein, which directly interacts with BRD4's extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), and maintains chromatin occupancy of BRD4 to active enhancers.	SIGNOR-266761
P04626	Q15303	1	binding	up-regulates	0.53	Most breast, skin, lung, ovary, and gastrointestinal tract tumors express erbb-4, and heterodimerization of this receptor with erbb-2, may be involved in some cancer	SIGNOR-43844
Q9H4X1	P06493	1	binding	up-regulates activity	0.53	RGC-32 was physically associated with cyclin-dependent kinase p34CDC2 and increased the kinase activity in vivo and in vitro. In addition, RGC-32 was phosphorylated by p34CDC2-cyclin B1 in vitro. Mutation of RGC-32 protein at Thr-91 prevented the p34CDC2-mediated phosphorylation and resulted in loss of p34CDC2 kinase enhancing activity.	SIGNOR-262726
Q9NYA4	Q15796	1	dephosphorylation	down-regulates	0.53	Here we demonstrate that myotubularin-related protein 4 (mtmr4), a fyve domain-containing dual-specificity protein phosphatase (dsp), attenuates tgfbeta signaling by reducing the phosphorylation level of r-smads in early endosomes.	SIGNOR-163031
Q99705	P50148	1	binding	up-regulates activity	0.529	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-257302
P28482	P17535	1	phosphorylation	up-regulates	0.529	Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase.	SIGNOR-196030
P31751	O15111	1	phosphorylation	up-regulates	0.529	Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta	SIGNOR-187010
P00533	P15311	1	phosphorylation	up-regulates	0.529	Ezrin was initially identified as a substrate for tyrosine phosphorylation by egfr (bretscher, 1989) and phosphorylation of residues y145 and y353 were detected to high stoichiometry after egf treatment . Phosphorylation of ezrin at y353 has been delineated to signal survival during epithelial cell differentiation via the phosphatidylinositol 3-kinase (pi3k)/akt pathway.	SIGNOR-133215
Q2M1Z3	P61586	1	gtpase-activating protein	down-regulates activity	0.529	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-260488
Q15418	P23588	1	phosphorylation	up-regulates	0.529	S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function.	SIGNOR-123993
Q15418	P01100	1	phosphorylation	up-regulates activity	0.529	We now provide evidence that two growth-regulated, nucleus- and cytoplasm-localized protein kinases, 90-kda ribosomal s6 kinase (rsk) and mitogen-activated protein kinase (map kinase), contribute to the serum-induced phosphorylation of c-fos. The major phosphopeptides derived from biosynthetically labeled c-fos correspond to phosphopeptides generated after phosphorylation of c-fos in vitro with both rsk and map kinase. The phosphorylation sites identified for rsk (ser-362) and map kinase (ser-374) are in the transrepression domain. Cooperative phosphorylation at these sites by both enzymes was observed in vitro and reflected in vivo by the predominance of the peptide phosphorylated on both sites, as opposed to singly phosphorylated peptides. This study suggests a role for nuclear rsk and map kinase in modulating newly synthesized c-fos phosphorylation and downstream signaling.	SIGNOR-37154
Q7Z5H3	P63000	1	gtpase-activating protein	down-regulates activity	0.529	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-260477
O43541	P31273	1	binding	up-regulates activity	0.529	Smad6 interacts with hox transcription factors as part of the negative feedback circuit in the bmp signaling pathway	SIGNOR-75823
Q9HAU4	O95630	1	polyubiquitination	down-regulates quantity by destabilization	0.529	RNF11 recruits AMSH to Smurf2 E3 ligase. Smurf2 promotes ubiquitination of AMSH in the presence of wt RNF11. Previously, we have shown that RNF11 interacts with the HECT-type E3 ligases AIP4 and Smurf2. Here, we show that RNF11 binds to AMSH in mammalian cells and that this interaction is independent of the RNF11 RING-finger domain and the PY motif. Our results also demonstrate that AMSH is ubiquitinated by Smurf2 E3 ligase in the presence of RNF11 and that a consequent reduction in its steady-state level requires both RNF11 and Smurf2. RNF11 therefore recruits AMSH to Smurf2 for ubiquitination, leading to its degradation by the 26S proteasome.	SIGNOR-272951
Q99500	Q14344	1	binding	up-regulates	0.529	Edg-3 and edg-5 couple not only to gibut also to gqand g13.	SIGNOR-70710
Q8IWJ2	P11717	1	relocalization	up-regulates activity	0.529	Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector	SIGNOR-253085
P12931	Q06187	1	phosphorylation	up-regulates activity	0.529	This interaction of BTK with SRC kinases transphosphorylated BTK on tyrosine at residue 551, which led to BTK activation.	SIGNOR-251100
P27361	Q15797	1	phosphorylation	down-regulates	0.528	Ras signaling was shown previously to induce the phosphorylation of the bmp mediator smad1 at four erk consensus sites in the linker domain (kretzschmar et al. 1997a). Phosphorylation of these four sites inhibits smad1 accumulation in the nucleus	SIGNOR-66755
Q9NRM7	O95863	1	phosphorylation	up-regulates	0.528	Lats2 kinase potentiates snail1 activity by promoting nuclear retention upon phosphorylation. during tgf_-induced emt lats2 is activated and snail1 phosphorylated at t203.	SIGNOR-176647

P53350

P60484

1

phosphorylation

down-regulates activity

0.534

Subsequently, Plk1 phosphorylation of PTEN was shown to be responsible for its inactivation.

SIGNOR-280070

Q9UPT9

Q96EB6

1

deubiquitination

up-regulates quantity by stabilization

0.534

USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells.

SIGNOR-261561

P00533

Q9UKV8

1

phosphorylation

up-regulates activity

0.534

Furthermore, AGO2 function is directly modulated by EGFR signaling in ERalpha negative breast cancer under states of hypoxic stress.|Here, EGFR can directly bind and phosphorylate residue Y393 of AGO2[ xref ].

SIGNOR-278931

P11161

P17676

1

transcriptional regulation

up-regulates quantity by expression

0.534

Ectopic expression of krox20 can transactivate the c/ebpbeta promoter and increase c/ebpbeta gene expression in 3t3-l1 preadipocytes

SIGNOR-139292

P31749

P06748

1

phosphorylation

down-regulates activity

0.534

We find that AKT phosphorylation of NPM-Ser48 prevents oligomerization that results in nucleoplasmic localization of ARF, constitutive MDM2 inhibition and stabilization of p53.

SIGNOR-276667

Q14680

P30305

1

phosphorylation

down-regulates activity

0.533

In the present study we show that the human pEg3 kinase is able to specifically phosphorylate CDC25B in vitro. One phosphorylation site was identified and corresponded to serine 323[Ä] Taken together these results suggest that pEg3 is a potential regulator of the G2/M progression and may act antagonistically to the CDC25B phosphatase

SIGNOR-255655

P28482

P55211

1

phosphorylation

down-regulates activity

0.533

ERK/MAPK phosphorylates caspase-9 at Thr(125), and this phosphorylation is crucial for caspase-9 inhibition

SIGNOR-148616

Q8N608

Q9NZV8

1

relocalization

up-regulates activity

0.533

Coexpression of DPP10 changes the subcellular localization of Kv4.2 expressed in COS-7 cells by promoting surface trafficking.DPP10 accelerates Kv4.2 inactivation at high and low voltages

SIGNOR-269006

O75469

P19793

1

binding

up-regulates

0.533

The constitutive androstane receptor (car, nr1i4), like fxr and pxr, binds dna as a heterodimer with rxr?

SIGNOR-111624

Q13177

Q15746

1

phosphorylation

down-regulates activity

0.533

PAK2 can directly phosphorylate MLCK, inhibiting its activity and limiting the development of isometric tension. PAK2 catalyzes MLCK phosphorylation on serine residues 439 and 991.

SIGNOR-250223

P15509

O60674

2

binding

up-regulates activity

0.533

JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation.

SIGNOR-249502

Q9H0M0

P36897

1

ubiquitination

down-regulates

0.533

Similar to smurfs, wwp1 associated with smad7 and induced its nuclear export, and enhanced binding of smad7 to tgf-beta type i receptor to cause ubiquitination and degradation of the receptor. Consistent with these results, wwp1 inhibited phosphorylation of smad2 induced by tgf-beta. Wwp1 thus negatively regulates tgf-beta signaling in cooperation with smad7

SIGNOR-126581

P12931

P41743

1

phosphorylation

up-regulates

0.533

Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase c's via a src kinase pathway. tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain.

SIGNOR-111920

O60674

P15509

2

phosphorylation

up-regulates activity

0.533

JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation.

SIGNOR-249503

Q05655

P08913

1

phosphorylation

up-regulates activity

0.533

Taken together, these results indicate that S232 acts as a selective, PKC-sensitive, modulator of effector coupling of the alpha(2A)AR to inositol phosphate stimulation. This represents one mechanism by which cells route stimuli directed to multifunctional receptors to selected effectors so as to attain finely targeted signaling.

SIGNOR-249126

P31749

P28482

1

phosphorylation

up-regulates activity

0.533

AKT1 stimulated PLD activity via activation of ERK.|AKT1 actually phosphorylated ERK2 as a substrate (K(m) 1 \u03bcm).

SIGNOR-279136

P45983

Q14653

1

phosphorylation

up-regulates

0.533

In this study, we show that another kinase, c-jun-nh(2)-terminal kinase (jnk), phosphorylates irf3 on its n-terminal serine 173 residuejnk1 can synergize the action of irf3(5d), but not the s173a-irf3(5d) mutant

SIGNOR-183489

P11171

Q14980

1

relocalization

up-regulates activity

0.533

These results indicate that 4.1 proteins recruit NuMA and dynein to the anaphase cell cortex through their conserved CTD (Figure 2I).

SIGNOR-266012

P53350

P01106

1

phosphorylation

up-regulates activity

0.533

Here, we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces MYC phosphorylation and protein accumulation. We show that PDK1-PLK1-MYC signaling is critical for cancer cell growth and survival, and small-molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting of MYC dependency

SIGNOR-243522

Q8NG68

Q71U36

1

tyrosination

down-regulates

0.533

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

SIGNOR-176912

P49913

P25090

1

binding

up-regulates

0.533

Ll-37 may contribute to innate and adaptive immunity by recruiting neutrophils, monocytes, and t cells to sites of microbial invasion by interacting with fprl1.

SIGNOR-82701

O15379

Q13547

1

binding

up-regulates

0.533

Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes.

SIGNOR-199964

P37231

P25874

1

transcriptional regulation

up-regulates quantity by expression

0.533

NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog,

SIGNOR-263985

Q96GF1

Q12981

1

polyubiquitination

up-regulates activity

0.533

RNF185 functions as a ubiquitin E3 ligase, enabling BNIP1-p62 interaction. Here we show that human RNF185 is a mitochondrial ubiquitin E3 ligase that regulates selective mitochondrial autophagy in cultured cells. Human BNIP1 colocalizes with RNF185 at mitochondria and is polyubiquitinated by RNF185 through K63-based ubiquitin linkage in vivo. The polyubiquitinated BNIP1 is capable of recruiting autophagy receptor p62, which simultaneously binds both ubiquitin and LC3 to link ubiquitination and autophagy. RNF185 interacts with BNIP1 and ATG5

SIGNOR-271931

P00519

P15391

1

phosphorylation

up-regulates activity

0.533

The results revealed that only tyrosine (Y)490 of CD19 was phosphorylated by c-Abl.

SIGNOR-245283

Q15466

Q07869

1

binding

up-regulates

0.533

Surprisingly, shp potentiated transcription by pparalpha/rxralpha heterodimers from the hd-ppre. This is the first demonstration of positive transcriptional activity attributable to shp. Together, these results suggest that shp can modulate pparalpha/rxralpha-mediated transcription in a response element-specific manner.

SIGNOR-108252

Q15759

Q02078

1

phosphorylation

up-regulates activity

0.533

In this study, we demonstrate that among the different Mitogen-activated protein kinases, the MADS-box transcription factors MEF2A and MEF2C are preferentially phosphorylated and activated by the p38 subfamily members p38alpha and p38beta2.

SIGNOR-280024

P31749

P48431

1

phosphorylation

up-regulates quantity by stabilization

0.532

In contrast, phosphorylation of Sox2 by AKT1 at T118 blocks K119me by Set7 and stabilizes Sox2.

SIGNOR-279003

P31749

Q8N6T7

1

phosphorylation

down-regulates activity

0.532

AKT1 interacts with and phosphorylates SIRT6 on Ser 338.|Because AKT1 suppresses SIRT6 protein abundance by decreasing its stability, we investigated whether MDM2 is involved in this process.

SIGNOR-278465

P43405

P37840

1

phosphorylation

down-regulates

0.532

Here, we show that alpha-synuclein (alpha-syn) is an outstanding substrate for the protein tyrosine kinase p72syk (syk), which phosphorylates three tyrosyl residues in its c-terminal domain (y-125, y-133, and y-136), here, we show that _-syn is an outstanding substrate for syk and that once it is tyrosine phosphorylated, it loses the ability to form oligomers.

SIGNOR-113065

P63000

Q96Q42

1

binding

up-regulates activity

0.532

Thus, in our system, activeRac1 may recruit ALS2 only at the very early stage ofmacropinocytosis including membrane rufﬂes, suggest-ing that ALS2 is retained by some other mechanismsuntil Rab conversion.

SIGNOR-277777

P27361

O95644

1

phosphorylation

down-regulates

0.532

We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats.

SIGNOR-74564

Q8IWJ2

P20645

1

relocalization

up-regulates activity

0.532

Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector

SIGNOR-253086

O15164

P04637

1

ubiquitination

down-regulates

0.532

New ring-domain e3-ubiquitin ligase trim24 that targets p53 for degradation

SIGNOR-188726

P19525

P25963

1

phosphorylation

down-regulates quantity by destabilization

0.532

As described for other stimuli, following pIC treatment, PKR phosphorylates the NF-kappa B inhibitor I kappa B alpha at serine 32 before degradation.

SIGNOR-249335

O00533

P16157

1

relocalization

up-regulates quantity

0.532

Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.

SIGNOR-266724

P29350

P14784

1

dephosphorylation

down-regulates

0.532

We have found that il-2 induces association of shp-1 with the il-2 receptor complex, and that once shp-1 is recruited to the activated receptor it is able to decrease tyrosine phosphorylation of il-2rbeta and the associated tyrosine kinases jak1 and jak3.

SIGNOR-55989

P62820

O75385

1

relocalization

up-regulates activity

0.532

C9orf72 acts as an effector of Rab1a that recruits active Rab1a to theULK1 complex to promote translocation of the ULK1 complex to thephagophore during autophagy initiation

SIGNOR-261299

Q13882

P23246

1

phosphorylation

down-regulates activity

0.531

BRK phosphorylates PSF promoting its cytoplasmic localization and cell cycle arrest.|These data suggest that BRK activity impedes the ability of PSF to bind RNA.To map the PSF tyrosine residues phosphorylated by BRK and assess if the PSF N-terminal is required for phosphorylation, we co-transfected HEK293 cells with various GFP-PSF deletion mutants in the presence or absence myc-BRK-YF.

SIGNOR-279754

P17252

P10721

1

phosphorylation

down-regulates

0.531

Phosphorylation of kit/scfr by pkc-_ in vitro: identification of ser-741 and ser-746 as the major phosphorylation sites for pkc / pkc, which acts in an scf-stimulated feedback loop, that negatively controls kit/scfr kinase activity

SIGNOR-28605

Q13153

O15143

1

phosphorylation

up-regulates

0.531

The formation of new branched actin filament networks at the cell cortex of migrating cells is choreographed by the actin-related protein (arp) 2/3 complex. Despite the fundamental role of the arp2/3 complex in actin nucleation and branching, upstream signals that control the functions of p41-arc, a putative regulatory component of the mammalian arp2/3 complex. Pak1 phosphorylation of p41-arc regulates its localization with the arp2/3 complex in the cortical nucleation regions of cells. Pak1 phosphorylates p41-arc on threonine 21

SIGNOR-121642

P04233

P61073

1

binding

up-regulates

0.531

Cd74 forms functional complexes with cxcr4 that mediate mif-specific signaling.

SIGNOR-187461

P43403

P51452

1

phosphorylation

up-regulates activity

0.531

ZAP-70 and Syk also tyrosine-phosphorylated VHR in COS-1 cells (Fig. 2d), whereas other kinases (Csk, Lck, Fyn, Jak2, Bcr-Abl and Itk) had little effect. Finally, recombinant ZAP-70 readily phosphorylated VHR in vitro (Fig. 2f).

SIGNOR-276000

Q9BUB5

O43597

1

phosphorylation

down-regulates

0.531

The spry2/nedd4 association involves the ww domains of nedd4 and requires phosphorylation of the mnk2 kinase sites, ser(112) and ser(121), on spry2. mnk2 silencing decreased spry2-nedd4 interactions and also augmented the ability of spry2 to inhibit fibroblast growth factor signaling. endogenous and overexpressed nedd4 polyubiquitinate spry2 via lys(48) on ubiquitin and decrease its stability.

SIGNOR-188889

O14757

P38936

1

phosphorylation

down-regulates quantity by destabilization

0.531

Responsible for this degradation is the checkpoint kinase Chk1, which phosphorylates p21(Waf1) on T145 and S146 residues and induces its proteasome-dependent proteolysis.

SIGNOR-279325

Q15154

P41208

1

relocalization

up-regulates

0.531

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

SIGNOR-94990

P17252

P16144

1

phosphorylation

down-regulates

0.531

Egf stimulates a pkc-?-Dependent pathway that results in the phosphorylation of the ?4 Integrin subunit on serine residues and its redistribution to actin-rich structures together, these results highlight the importance of serine phosphorylation in regulating type ii hemidesmosome disassembly, implicate a cluster of serine residues within the connecting segment of ?4, and argue for a key role for pkc-? In regulating these structures

SIGNOR-124494

O15034

Q9UQ26

1

binding

down-regulates activity

0.531

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

SIGNOR-264366

Q8N0Z6

Q8N9B5

1

binding

up-regulates activity

0.531

DNA damage activates ATM kinase which then phosphorylates Strap at Ser 203 (red circles). Phosphorylated Strap is stabilized and undergoes nuclear accumulation where it assembles into a co-activator complex, which includes p300 and cofactors such as JMY

SIGNOR-262647

P04626

Q96N67

1

phosphorylation

up-regulates

0.531

We show that the nrg1 receptor erbb2 directly binds and activates dock7 by phosphorylating tyr-1118. thus, dock7 functions as an intracellular substrate for erbb2 to promote schwann cell migration. This provides an unanticipated mechanism through which ligand-dependent tyrosine phosphorylation can trigger the activation of rho gtpase-gefs of the dock180 family.

SIGNOR-178348

Q96P48

P60953

1

gtpase-activating protein

down-regulates activity

0.531

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-260452

P81133

P27540

1

binding

up-regulates activity

0.531

We demonstrate that both SIM1 and SIM2 can heterodimerize via their helix-loop-helix·PAS regions with ARNT, but not with AHR, and that they do not form homodimers. Furthermore, SIM1 may have a dual role, both negatively affecting AHR·ARNT binding to the XRE and also acting in concert with ARNT as a novel DNA-binding heterodimer.

SIGNOR-240759

Q9Y3C5

O95630

1

binding

down-regulates quantity by destabilization

0.531

RNF11 recruits AMSH to Smurf2 E3 ligase. Smurf2 promotes ubiquitination of AMSH in the presence of wt RNF11. Previously, we have shown that RNF11 interacts with the HECT-type E3 ligases AIP4 and Smurf2. Here, we show that RNF11 binds to AMSH in mammalian cells and that this interaction is independent of the RNF11 RING-finger domain and the PY motif. Our results also demonstrate that AMSH is ubiquitinated by Smurf2 E3 ligase in the presence of RNF11 and that a consequent reduction in its steady-state level requires both RNF11 and Smurf2. RNF11 therefore recruits AMSH to Smurf2 for ubiquitination, leading to its degradation by the 26S proteasome.

SIGNOR-272953

P49137

Q13151

1

phosphorylation

up-regulates activity

0.531

MAPKAP-K2 phosphorylated hnRNP A0 at Ser84 in vitro and this residue became phosphorylated in LPS-stimulated cells. The simplest explanation for these findings is that the phosphorylation of hnRNP A0 at Ser84 by MAPKAP-K2 enhances binding to the AREs of these mRNAs or allows hnRNP A0 to displace another protein(s) from the AREs.

SIGNOR-262951

P49761

Q07955

1

phosphorylation

up-regulates activity

0.531

In vitro, Clk/Sty efficiently phosphorylated the SR family member ASF/SF2 on serine residues located within its serine/arginine-rich region (the RS domain). Overexpression of the active Clk/Sty kinase caused a redistribution of SR proteins within the nucleus. These results suggest that Clk/Sty kinase directly regulates the activity and compartmentalization of SR splicing factors.

SIGNOR-273859

P68400

O15379

1

phosphorylation

up-regulates activity

0.531

A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity.

SIGNOR-250889

Q01105

P67775

1

binding

down-regulates

0.531

Here we report that both the amino terminal fragment (i(2ntf);aa 1-175) and the carboxy terminal fragment (i(2ctf);aa 176-277) of i(2)(pp2a) inhibit pp2a by binding to its catalytic subunit pp2ac

SIGNOR-175719

P46937

P35222

1

binding

up-regulates

0.531

Additionally, the hippo and wnts also cooperate in the nucleus, where yap interacts with beta-catenin and induces the expression of canonical wnt target genes, such as sox2 and snai2 in mouse heart tissue.

SIGNOR-201939

O15264

P10636

1

phosphorylation

down-regulates activity

0.531

Phosphorylation of tau by SAPK3 and SAPK4 resulted in a marked reduction in the ability of tau to promote microtubule assembly.

SIGNOR-278313

P02511

P07315

1

binding

up-regulates activity

0.531

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-253622

P51608

P16220

1

post transcriptional regulation

up-regulates quantity by expression

0.531

Interestingly, Creb1 was one of the activated MeCP2 targets that we validated by quantitative real-time RT-PCR (Fig. 1C), and using ChIP analysis we found that in vivo MeCP2 binds to the promoter region of Creb1, with significantly enhanced binding in MECP2-Tg samples compared to WT (p < 0.05) | In addition, Sst and CREB1 protein levels were increased in MECP2-Tg hypothalami compared to WT, indicating that MeCP2 indeed enhances expression of Sst and Creb1

SIGNOR-264682

P06744

Q9UKV5

2

binding

up-regulates

0.53

Pgi is a housekeeping gene encoding phosphoglucose isomerase (pgi) a glycolytic enzyme that also functions as a cytokine (autocrine motility factor (amf)/neuroleukin/maturation factor) upon secretion from the cell and binding to its 78 kda seven-transmembrane domain receptor (gp78/amf-r)

SIGNOR-97270

Q8IXJ6

Q92831

1

binding

down-regulates

0.53

Sir2 forms a complex with the acetyltransferase pcaf and myod and, when overexpressed, retards muscle differentiation.

SIGNOR-104248

P04637

P14921

1

binding

down-regulates activity

0.53

We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and inter-related manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription. We show that ets-1 and p53 associate physically in vitro and in vivo and that their interaction, rather than a direct binding of p53 to the TXSA promoter, is required for transcriptional repression of TXSA by wild-type p53.

SIGNOR-254087

Q8IWV8

O94761

1

binding

up-regulates

0.53

The isolated recql4, assayed as a complex with ubr1 and ubr2, exhibited dna-stimulated atpase activity but was inactive as either dna helicase or dna translocase / the discovery, in the present work, that these ub ligases, ubr1 and ubr2, interact with the putative helicase recql4 (fig. 2), and that recql4 is a long-lived, non-ubiquitylated protein in hela cells

SIGNOR-128214

Q01484

P11532

1

relocalization

up-regulates quantity

0.53

We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4.

SIGNOR-266712

Q92995

Q14457

2

deubiquitination

up-regulates quantity by stabilization

0.53

Similarly, the overexpression of USP13 reduced the levels of ubiquitinated Beclin1 which was inhibited by spautin-1 (Figure 4E)

SIGNOR-260295

Q6SZW1

Q8IUC6

1

binding

down-regulates

0.53

SARM utilizes its TIR domain to negatively regulate TRIF

SIGNOR-252068

O95136

P50148

1

binding

up-regulates activity

0.53

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-257215

Q12959

P43403

1

phosphorylation

up-regulates activity

0.53

Immunoblot analysis showed that phosphorylation of the activating ZAP70 kinase domain residue Tyr 493 was decreased in the DLG1 KD cells. Similarly, the Tyr 319 residue of ZAP70 and Tyr 83 residue of TCR- ζ also showed reduced phosphorylation.

SIGNOR-274142

P06493

P10275

1

phosphorylation

up-regulates

0.53

At first, the data show that cdk5 enables phosphorylation of ar at ser-81 site through direct biochemical interaction and, therefore, results in the stabilization of ar proteins although ar was reported as substrates for cdk9 (5) as well as cdk1

SIGNOR-175692

P43119

P63092

1

binding

up-regulates activity

0.53

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-256806

O95600

P56545

1

binding

up-regulates activity

0.53

Here we report the characterisation of KLF8/ZNF741/BKLF3 (KLF8). We demonstrate that this protein is able to bind CACCC-boxes in DNA and can repress gene expression by associating with CtBP co-repressors.

SIGNOR-236962

Q13237

Q03393

1

phosphorylation

up-regulates

0.53

Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps. Addition of cgmp stimulated phosphotransferase activity 2-fold. Extracts from transfected cos-1 cells overexpressing cgkii stimulated ser(19) phosphorylation more than 100-fold.In assays with purified enzymes, wild-type but not ptps-s19a was a specific substrate for the cgmp-dependent protein kinase (cgk) type i and ii. Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps

SIGNOR-71751

Q9BXW4

Q14596

1

binding

down-regulates

0.53

We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family. . downregulation of either lc3 or gabarap (or both) family members leads to stabilization and p62-dependent aggregation of nbr1.

SIGNOR-184258

Q9UKV5

P06744

2

polyubiquitination

down-regulates quantity by destabilization

0.53

Gp78 is a ubiquitin ligase that plays a vital role in endoplasmic reticulum (ER)-associated degradation (ERAD). Here we report that autocrine motility factor (AMF), also known as phosphoglucose isomerase (PGI), is a novel substrate of gp78. We show that polyubiquitylation of AMF requires cooperative interaction between gp78 and the ubiquitin ligase TRIM25 (tripartite motif-containing protein 25). While TRIM25 mediates the initial round of ubiquitylation, gp78 catalyzes polyubiquitylation of AMF.

SIGNOR-272177

Q14457

Q92995

2

deubiquitination

up-regulates quantity by stabilization

0.53

We found that endogenous Beclin1 can interact with USP13 and the interaction was reduced in the presence of spautin-1 (Figure 5C). Interestingly, the DUB activities were significantly increased when USP13 and USP10 coincubated together or with Beclin1 or all 3 proteins together, suggesting the DUB activity can be significantly enhanced when USP13 interacts with its substrate Beclin1 or USP10.

SIGNOR-260296

P04150

P42229

1

binding

up-regulates

0.53

We show here that the glucocorticoid receptor can act as a transcriptional co-activator for stat5 and enhance stat5-dependent transcription. Stat5 forms a complex with the gluco-corticoid receptor which binds to dna independently of the gre. This complex formation between stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a gre-con-taining promoter.

SIGNOR-44376

Q9Y2N7

Q99814

1

transcriptional regulation

down-regulates quantity by repression

0.53

None of the long HIF-3α variants was capable of efficient induction of an HRE reporter in overexpression experiments, but instead inhibited the transcriptional activation of the reporter by HIF-1 and HIF-2.

SIGNOR-261616

Q02535

P15923

1

binding

down-regulates activity

0.53

All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.

SIGNOR-241134

P31751

P46527

1

phosphorylation

down-regulates

0.53

Akt-induced t157 phosphorylation causes retention of p27(kip1) in the cytoplasm, precluding p27(kip1)-induced g1 arrest.[__]Thus, cytoplasmic relocalization of p27(kip1), secondary to akt-mediated phosphorylation, is a novel mechanism whereby the growth inhibitory properties of p27(kip1) are functionally inactivated and the proliferation of breast cancer cells is sustained.

SIGNOR-93122

Q92560

Q9C0F0

1

binding

up-regulates activity

0.53

We report a critical link between BAP1 complex and BRD4, which is bridged by the physical interaction between ASXL3 and BRD4 in an SCLC subtype (SCLC-A), which expresses a high level of ASCL1. We further showed that ASXL3 functions as an adaptor protein, which directly interacts with BRD4's extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), and maintains chromatin occupancy of BRD4 to active enhancers.

SIGNOR-266761

P04626

Q15303

1

binding

up-regulates

0.53

Most breast, skin, lung, ovary, and gastrointestinal tract tumors express erbb-4, and heterodimerization of this receptor with erbb-2, may be involved in some cancer

SIGNOR-43844

Q9H4X1

P06493

1

binding

up-regulates activity

0.53

RGC-32 was physically associated with cyclin-dependent kinase p34CDC2 and increased the kinase activity in vivo and in vitro. In addition, RGC-32 was phosphorylated by p34CDC2-cyclin B1 in vitro. Mutation of RGC-32 protein at Thr-91 prevented the p34CDC2-mediated phosphorylation and resulted in loss of p34CDC2 kinase enhancing activity.

SIGNOR-262726

Q9NYA4

Q15796

1

dephosphorylation

down-regulates

0.53

Here we demonstrate that myotubularin-related protein 4 (mtmr4), a fyve domain-containing dual-specificity protein phosphatase (dsp), attenuates tgfbeta signaling by reducing the phosphorylation level of r-smads in early endosomes.

SIGNOR-163031

Q99705

P50148

1

binding

up-regulates activity

0.529

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-257302

P28482

P17535

1

phosphorylation

up-regulates

0.529

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

SIGNOR-196030

P31751

O15111

1

phosphorylation

up-regulates

0.529

Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta

SIGNOR-187010

P00533

P15311

1

phosphorylation

up-regulates

0.529

Ezrin was initially identified as a substrate for tyrosine phosphorylation by egfr (bretscher, 1989) and phosphorylation of residues y145 and y353 were detected to high stoichiometry after egf treatment . Phosphorylation of ezrin at y353 has been delineated to signal survival during epithelial cell differentiation via the phosphatidylinositol 3-kinase (pi3k)/akt pathway.

SIGNOR-133215

Q2M1Z3

P61586

1

gtpase-activating protein

down-regulates activity

0.529

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-260488

Q15418

P23588

1

phosphorylation

up-regulates

0.529

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

SIGNOR-123993

Q15418

P01100

1

phosphorylation

up-regulates activity

0.529

We now provide evidence that two growth-regulated, nucleus- and cytoplasm-localized protein kinases, 90-kda ribosomal s6 kinase (rsk) and mitogen-activated protein kinase (map kinase), contribute to the serum-induced phosphorylation of c-fos. The major phosphopeptides derived from biosynthetically labeled c-fos correspond to phosphopeptides generated after phosphorylation of c-fos in vitro with both rsk and map kinase. The phosphorylation sites identified for rsk (ser-362) and map kinase (ser-374) are in the transrepression domain. Cooperative phosphorylation at these sites by both enzymes was observed in vitro and reflected in vivo by the predominance of the peptide phosphorylated on both sites, as opposed to singly phosphorylated peptides. This study suggests a role for nuclear rsk and map kinase in modulating newly synthesized c-fos phosphorylation and downstream signaling.

SIGNOR-37154

Q7Z5H3

P63000

1

gtpase-activating protein

down-regulates activity

0.529

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-260477

O43541

P31273

1

binding

up-regulates activity

0.529

Smad6 interacts with hox transcription factors as part of the negative feedback circuit in the bmp signaling pathway

SIGNOR-75823

Q9HAU4

O95630

1

polyubiquitination

down-regulates quantity by destabilization

0.529

RNF11 recruits AMSH to Smurf2 E3 ligase. Smurf2 promotes ubiquitination of AMSH in the presence of wt RNF11. Previously, we have shown that RNF11 interacts with the HECT-type E3 ligases AIP4 and Smurf2. Here, we show that RNF11 binds to AMSH in mammalian cells and that this interaction is independent of the RNF11 RING-finger domain and the PY motif. Our results also demonstrate that AMSH is ubiquitinated by Smurf2 E3 ligase in the presence of RNF11 and that a consequent reduction in its steady-state level requires both RNF11 and Smurf2. RNF11 therefore recruits AMSH to Smurf2 for ubiquitination, leading to its degradation by the 26S proteasome.

SIGNOR-272951

Q99500

Q14344

1

binding

up-regulates

0.529

Edg-3 and edg-5 couple not only to gibut also to gqand g13.

SIGNOR-70710

Q8IWJ2

P11717

1

relocalization

up-regulates activity

0.529

Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector

SIGNOR-253085

P12931

Q06187

1

phosphorylation

up-regulates activity

0.529

This interaction of BTK with SRC kinases transphosphorylated BTK on tyrosine at residue 551, which led to BTK activation.

SIGNOR-251100

P27361

Q15797

1

phosphorylation

down-regulates

0.528

Ras signaling was shown previously to induce the phosphorylation of the bmp mediator smad1 at four erk consensus sites in the linker domain (kretzschmar et al. 1997a). Phosphorylation of these four sites inhibits smad1 accumulation in the nucleus

SIGNOR-66755

Q9NRM7

O95863

1

phosphorylation

up-regulates

0.528

Lats2 kinase potentiates snail1 activity by promoting nuclear retention upon phosphorylation. during tgf_-induced emt lats2 is activated and snail1 phosphorylated at t203.

SIGNOR-176647