GleghornLab/Signor_3class · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels int64 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
Q9Y5H2	Q9Y5I2	2	binding	up-regulates activity	0.2	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265712
P56545	O95600	2	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
Q2TAL8	P54577	1	transcriptional regulation	up-regulates quantity by expression	0.2	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269412
Q04759	P35236	1	phosphorylation	up-regulates activity	0.2	PKC θ is required for HePTP translocation to the immune synapse. PKC θ phosphorylates HePTP at S225 in primary T cells.	SIGNOR-276045
P23769	Q8IX07	0	transcriptional regulation	down-regulates quantity by repression	0.746	GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1.	SIGNOR-256061
P51608	O43395	2	binding	up-regulates activity	0.267	MeCP2 interacts directly with Prpf3 and Sdccag1\|Notably, Mecp2308/Y mice, which produce a truncated form of MeCP2 and reproduce many of the classical features of RTT [43], have been shown to have multiple genes that are abnormally spliced in the brain [23]. This suggests the C-terminal portion of MeCP2, which we have identified as the putative Sdccag1 interaction domain, plays a critical role in regulating alternative splicing.	SIGNOR-277691
Q15173	O95235	1	dephosphorylation	up-regulates activity	0.2	We identify MKlp2 as an essential protein for promoting abscission, which may regulate tethering and stabilizing of the PM to the microtubule cytoskeleton. Aurora B phosphorylation of MKlp2 S878 in the LAM is a key inhibitory signal for abscission. Conversely, B56-PP2A promotes abscission by opposing Aurora B phosphorylation of MKlp2 S878.	SIGNOR-262660
Q04741	O14786	1	transcriptional regulation	up-regulates quantity by expression	0.2	EMX1 activates the transcription of Nrp1 in vitro.	SIGNOR-261593
Q13151	P49137	0	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
P06850	Q13324	2	binding	up-regulates activity	0.917	The actions of CRH are transduced through CRH receptors, which belong to the class II/secretin-like family of the G-protein coupled receptor (GPCR) superfamily (Martin et al. 2005). There are three types of CRH receptors – type 1 (CRHR1), type 2 (CRHR2) and type 3 (CRHR3). Among these, CRHR3 has not been identified in mammals. \|CRH is a high-affinity ligand of CRHR1. It also binds to CRHR2, but with lower affinity	SIGNOR-268611
Q13882	P60484	0	dephosphorylation	down-regulates activity	0.416	PTEN inhibits PTK6 activity and downstream signaling in prostate cancer cells.\|Using an in vitro phosphatase assay, we observed that PTEN was able to dephosphorylate PTK6 at tyrosine residue 342 in a dose dependent manner.	SIGNOR-276975
O95292	Q92953	0	relocalization	up-regulates quantity	0.2	Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays.\|As Kv2.1 accumulates on the surface it begins to bind ER VAPs and form the large and stable membrane junctions.	SIGNOR-262123
Q9UQL6	Q16566	0	phosphorylation	down-regulates	0.51	Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs.	SIGNOR-236571
Q99677	P38405	2	binding	up-regulates activity	0.385	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-256928
P11831	Q13976	0	phosphorylation	up-regulates	0.275	Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. \| Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha.	SIGNOR-188185
P0C0L4	O00187	0	cleavage	up-regulates activity	0.798	MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a).	SIGNOR-263431
Q9UM11	P24941	0	phosphorylation	down-regulates activity	0.745	A nuclear localization signal conserved in various species was identified in CDH1, and it sufficiently targets green fluorescent protein to the nucleus. Interestingly, a CDH1-4D mutant mimicking the hyperphosphorylated form was constitutively found in the cytoplasm. In further support of the notion that phosphorylation inhibits nuclear import, the nuclear localization signal of CDH1 with two phospho-accepting serine/threonine residues changed into aspartates was unable to drive heterologous protein into the nucleus.	SIGNOR-250732
Q14344	P30989	2	binding	up-regulates activity	0.25	Altogether, these results reveal for the first time the ability of hNTS1 to directly activate the Gαq-, Gαi1-, GαoA-, and Gα13-mediated signaling pathways	SIGNOR-278060
O43294	Q14289	0	phosphorylation	up-regulates activity	0.71	Hic-5 is a CAKbeta-binding protein localized at focal adhesions. Here we show that overexpression of CAKbeta or Fyn, but not FAK, enhanced the tyrosine phosphorylation of coexpressed Hic-5 in COS-7 cells. The Y60F mutant of Hic-5 was not phosphorylated, and Hic-5 phosphorylated on tyrosine 60 was bound specifically to the SH2 domain of Csk. Specific phosphorylation of Hic-5 by CAKbeta and Fyn may activate a signaling pathway mediated by Hic-5.	SIGNOR-262876
P63244	P05412	0	null	up-regulates quantity by expression	0.2	In turn, c-Jun induces expression of RACK1, which is required for JNK activation by PKC, pointing to a c-Jun/RACK1/PKC/JNK feedback loop.	SIGNOR-278066
O15084	Q13557	0	phosphorylation	down-regulates activity	0.2	We provide evidence for a dual kinase-mediated regulation of the PITK holoenzyme whereby PITK phosphorylation at S1017 is catalyzed by calcium/calmodulin-dependent kinase II-delta (CaMKIIdelta), promoting the subsequent phosphorylation of S1013 by glycogen synthase kinase-3 (GSK3) in vitro.\|the phosphorylation of PITK at these specific residues altered PP1 binding and subsequent PITK-directed dephosphorylation of hnRNP K	SIGNOR-264793
P00533	Q9Y6I3	0	relocalization	down-regulates	0.596	Epsin 1 is involved in recruitment of ubiquitinated egf receptors into clathrin-coated pits this supports the contention that epsin 1 promotes endocytosis of the ubiquitinated egfr.	SIGNOR-182562
Q9GZU7	P24928	1	dephosphorylation	up-regulates activity	0.431	Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. \| This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat.	SIGNOR-248785
O43293	Q13464	0	phosphorylation	up-regulates activity	0.306	ROCK1 phosphorylates and activates ZIPK suggesting that at least some of these physiological functions may require both enzymes.	SIGNOR-279102
O43474	P42226	0	transcriptional regulation	up-regulates quantity by expression	0.345	STAT6 coordinates and synergizes with both PPAR? and Krppel-like factor 4 (KLF4), a member of a family of proteins that contribute to macrophage function.	SIGNOR-249568
O15519	Q9UNE7	0	ubiquitination	down-regulates quantity by destabilization	0.356	Taken together, our data suggest that CHIP interacts with c-FLIP L in vivo and promotes the ubiquitination of c-FLIP L.\|When we knocked down CHIP, c-FLIP L degradation was inhibited after treatment with 17-AAG, which indicated that CHIP modulated c-FLIP L degradation in the NSCLC cell lines.	SIGNOR-278783
P05067	P53355	0	phosphorylation	up-regulates quantity	0.287	DAPK1, but not its kinase deficient mutant (K42A), significantly increased human AŒ≤ secretion in neuronal cell culture models. Moreover, knockdown of DAPK1 expression or inhibition of DAPK1 catalytic activity significantly decreased AŒ≤ secretion. Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of AŒ≤.\|Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of Abeta.	SIGNOR-279518
P42229	P36888	0	phosphorylation	up-regulates activity	0.605	FLT3-ITDs induced a strong activation of STAT5. FLT3-ITD mutants induce an autophosphorylation of the receptor, interleukin 3-independent growth in Ba/F3 cells, and a strong STAT5 and mitogen-activated protein kinase (MAPK) activation.	SIGNOR-261516
P49815	Q96BR1	0	phosphorylation	up-regulates activity	0.434	SGK3 phosphorylates six sites on TSC2 to activate mTORC1 in an AKT-independent manner.	SIGNOR-279284
Q13131	P06400	1	phosphorylation	down-regulates	0.2	Amp-activated protein kinase phosphorylates retinoblastoma protein. Rb phosphorylation sites, ser804 (ser811 in human), resembled the ampk consensus phosphorylation site.	SIGNOR-184052
P98177	O75874	1	transcriptional regulation	up-regulates quantity by expression	0.264	We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH.	SIGNOR-260102
P15514	P19544	0	transcriptional regulation	up-regulates quantity by expression	0.396	The Wilms Tumor Suppressor WT1 Encodes a Transcriptional Activator of amphiregulin	SIGNOR-251745
Q8NEV4	Q8NEV4	2	phosphorylation	down-regulates activity	0.2	We demonstrate by mass spectrometry that Thr-178 and Thr-184 in the kinase domain activation loop and two threonines in the loop 2 region of the motor domain are autophosphorylated (Thr-908 and Thr-919) \| Thus, the phosphorylation sites in loop 2 (Thr-908 and Thr-919) are likely responsible for the down-regulation of MYO3A motor activity observed in our current and previous work	SIGNOR-260923
Q7Z699	P00533	0	phosphorylation	down-regulates activity	0.272	We show that oncogenic EGFR(L858R) signaling leads to the phosphorylation of SPRED1 on serine 105, disrupting the SPRED1-neurofibromin complex. The structural, biochemical, and biological results provide new mechanistic insights about how SPRED1 interacts with neurofibromin and regulates active KRAS levels in normal and pathologic conditions.	SIGNOR-273638
Q8N8S7	Q9UQB8	2	binding	up-regulates activity	0.569	We conclude that the interaction of Cdc42 with the partial CRIB motif of IRSp53 relieves an intramolecular, autoinhibitory interaction with the N terminus, allowing the recruitment of Mena to the IRSp53 SH3 domain. This IRSp53:Mena complex initiates actin filament assembly into filopodia.	SIGNOR-268423
P26715	P17693	2	binding	up-regulates	0.631	Current models of nk cell function have supposed that the cd94/nkg2a heterodimer is interacting with an epitope common to classical hla class i	SIGNOR-56714
P61586	P10911	0	guanine nucleotide exchange factor	up-regulates activity	0.754	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-260556
P50148	P37288	2	binding	up-regulates activity	0.463	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-257077
P49841	Q9HB09	1	phosphorylation	up-regulates	0.338	Gsk3b phosphorylates bcl2l12 at s156. Ectopic expression of gfp-fused bcl2l12 or bcl2l12a in u87mg cells leads to repression of apoptotic markers and protects against staurosporine (sts) insults, indicating an antiapoptotic role for both bcl2l12 and bcl2l12a. In contrast, no anti-apoptotic ability was seen in bcl2l12(s156a)	SIGNOR-195512
O95997	O95155	0	polyubiquitination	down-regulates quantity by destabilization	0.2	We further demonstrate that Ufd2 directly and efficiently ubiquitylates securin in vitro and is required for securin polyubiquitylation in vivo. This is the first description of a physiologic substrate for Ufd2, establishing this E4 enzyme as an important regulator of chromosome condensation and separation during mitosis in human cells.	SIGNOR-271523
P11309	Q99814	1	phosphorylation	up-regulates quantity by stabilization	0.2	PIM1 kinase directly phosphorylates HIF-1α at threonine 455, a previously uncharacterized site within its oxygen-dependent degradation domain. This phosphorylation event disrupts the ability of prolyl hydroxylases to bind and hydroxylate HIF-1α, interrupting its canonical degradation pathway and promoting constitutive transcription of HIF-1 target genes. Moreover, phosphorylation of the analogous site in HIF-2α (S435) stabilizes the protein through the same mechanism, indicating post-translational modification within the oxygen-dependent degradation domain as a mechanism of regulating the HIF-α subunits.	SIGNOR-277310
O00548	Q8NES3	2	binding	up-regulates	0.447	The modification of notch by fringe would influence binding between the notch receptor and its ligand. It was reported previously that mfng and lfng inhibited notch1-mediated signaling triggered by jagged1 and enhanced that triggered by delta1, and either jagged1- or delta1-triggered notch2 signaling was enhanced by lfng	SIGNOR-107699
O60260	P49792	1	ubiquitination	down-regulates quantity by destabilization	0.2	Our findings suggested that the intracellular levels of RanBP2 and its functional activity may be modulated by Parkin-mediated ubiquitination and proteasomal pathways. Furthermore, Parkin controls the intracellular levels of sumoylated HDAC4, as a result of the ubiquitination and degradation of RanBP2.	SIGNOR-259116
O75582	P50549	1	phosphorylation	up-regulates activity	0.463	Activated, overexpressed MSK1 was able to phosphorylate ER81 at Ser191 and Ser216. Mutation of these residues strongly impairs ER81-responsive promoter activity.	SIGNOR-262987
O14920	Q07817	1	phosphorylation	down-regulates quantity	0.339	We present evidence for a signaling network that involves phosphorylation and reduction of Bcl-xL by IKKbeta, and subsequent activation of caspases, which can cleave Htt.\|We propose that IKKbeta reduces Bcl-xL levels by phosphorylation (XREF_FIG), a modification known to promote Bcl-xL degradation .	SIGNOR-279529
P17096	Q13315	0	phosphorylation	up-regulates activity	0.2	21 As shown in Fig. 2 b, ATM was able to phosphorylate in vitro the C-terminal peptide of HMGA1.	SIGNOR-279493
Q96ST3	Q9BXK1	2	binding	up-regulates activity	0.464	detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A.	SIGNOR-222460
P35368	P29992	2	binding	up-regulates activity	0.661	In this report, we demonstrate that in transfected cos-7 cells Gal4 and Ga16, like Gaq and Ga11, can activate PIPLC j3l and that all three al-ARs, alA, alB and alC, can activate endogenous PI-PLC by coupling to Gaq or Ga11.	SIGNOR-278122
Q99500	P63092	2	binding	up-regulates activity	0.2	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-256790
Q13315	Q8IW19	1	phosphorylation	up-regulates activity	0.4	We show that APLF undergoes ATM dependent hyperphosphorylation following IR and that APLF is directly phosphorylated by ATM in vitro.	SIGNOR-279492
O15297	Q12888	1	dephosphorylation	down-regulates activity	0.392	In addition, WIP1 dephosphorylates 53BP1 at Threonine 543 that was previously implicated in mediating interaction with RIF1.	SIGNOR-277046
P42224	P00519	0	phosphorylation	up-regulates activity	0.343	Our study unexpectedly found that c-Abl, another kinase other than JAKs, also contributes to STAT1 Y701 phosphorylation independently (XREF_FIG).\|reported that c-Abl, but not Arg, could induce neuronal loss by prompting STAT1 activation and interferon production.	SIGNOR-279491
P49840	O75444	1	phosphorylation	up-regulates	0.2	We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity.	SIGNOR-159358
P78504	Q04721	2	binding	up-regulates	0.639	Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch.	SIGNOR-81364
Q9UQL6	P17252	0	phosphorylation	down-regulates activity	0.2	We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. \| Finally, we assessed the ability of PKD to phosphorylate HDAC5 in cells by employing an antibody that specifically recognizes HDAC5 that has been phosphorylated at serine 259. HDAC5 was basally phosphorylated at serine 259, and phosphorylation at this site was dramatically increased by coexpression of constitutively active PKD S/E	SIGNOR-249269
Q8N8N0	Q7L523	1	polyubiquitination	down-regulates activity	0.74	Here, we identified the lysosome-anchored E3 ubiquitin ligase RNF152 as an essential negative regulator of the mTORC1 pathway by targeting RagA for K63-linked ubiquitination. RNF152 interacts with and ubiquitinates RagA in an amino-acid-sensitive manner. The mutation of RagA ubiquitination sites abolishes this effect of RNF152 and enhances the RagA-mediated activation of mTORC1. Ubiquitination by RNF152 generates an anchor on RagA to recruit its inhibitor GATOR1, a GAP complex for Rag GTPases.	SIGNOR-272222
Q14119	P05305	1	transcriptional regulation	up-regulates quantity by expression	0.276	Vascular endothelial zinc finger 1 (Vezf1)/DB1 is a recently identified zinc finger-containing protein that is expressed specifically within endothelial cells during development. In this report, we demonstrate that Vezf1/DB1 is a nuclear localizing protein that potently and specifically activates transcription mediated by the human endothelin-1 promoter, in a Tax-independent manner, in transient transfection assays. Regulation of endothelin-1 promoter activity by Vezf1/DB1 provides a mechanism for endothelin-1 expression in the vascular endothelium during development and to maintain vascular tone	SIGNOR-266884
Q96E09	P63151	2	binding	down-regulates activity	0.2	We demonstrate that the highly conserved protein in mammals, designated FAM122A, directly interacts with PP2A-Aα and B55α rather than B56α subunits, and inhibits the phosphatase activity of PP2A-Aα/B55α/Cα complex.	SIGNOR-266379
Q9H3F6	P61586	2	binding	down-regulates quantity	0.269	BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex.	SIGNOR-264237
Q15831	P27361	0	phosphorylation	down-regulates activity	0.39	Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK.	SIGNOR-209880
P49736	P68400	0	phosphorylation	up-regulates	0.259	In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2	SIGNOR-144004
P27694	P09884	2	binding	up-regulates activity	0.687	In our studies, we have shown that T antigen, DNA polymerase R, and the activation domain of VP16 all interact with overlapping regions of the 70-kDa subunit of RPA.\| In the latter, both the direct protein-protein interaction and ssDNA-binding activities of RPA were needed for RPA to modulate polymerase processivity. We also found that SV40 T antigen inhibited the ability of RPA to increase processivity of DNA polymerase alpha, suggesting that this activity of RPA may be important for elongation but not during the initiation of DNA replication.	SIGNOR-261272
P53778	Q13884	2	binding	down-regulates	0.368	Basal localization of the p38g/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through b1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38g/b1-syntrophin interactions are abrogated, resulting in enhanced Carm1 phosphorylation	SIGNOR-255901
Q15398	Q9BYB0	1	relocalization	up-regulates activity	0.2	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264600
Q9NX09	Q9H3M7	2	binding	up-regulates quantity by stabilization	0.508	In the present study, we identify TXNIP that inhibits mTOR activity by binding to and stabilizing Redd1 protein.	SIGNOR-277470
Q9UQ26	A6NNM3	2	binding	down-regulates activity	0.358	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-264369
P24385	Q13627	0	phosphorylation	down-regulates	0.395	Dyrk1a controls the rate of cycd1 degradation by directly phosphorylating cycd1 at thr 286 and thereby regulates the fraction of cycling cells.	SIGNOR-202838
O60260	P62987	2	binding	up-regulates activity	0.2	The phosphorylation-dependent interaction between ubiquitin and parkin suggests that phosphorylated ubiquitin unlocks autoinhibition of the catalytic cysteine. Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator.	SIGNOR-270344
P25490	Q96GD4	0	phosphorylation	up-regulates	0.368	Aurora b kinase phosphorylates yy1 on serine 184 and to a lesser extent serine 180 at the g2/m stage of the cell cycle (fig. 7). We show that yy1 is rapidly dephosphorylated as the cells exit mitosis, likely by pp1. Also, our data indicates that phosphorylation at serine 180 and serine 184 can affect the dna binding activity of yy1	SIGNOR-200079
P13349	P68400	0	phosphorylation	up-regulates activity	0.307	Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity.	SIGNOR-250922
P53350	P35869	1	phosphorylation	down-regulates activity	0.251	In this study, we demonstrate that PLK1 phosphorylates AHR at S489 in LUAD, leading to epithelial-mesenchymal transition (EMT) and metastatic events.	SIGNOR-277885
Q9Y4D1	P61586	2	binding	up-regulates activity	0.822	B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1.	SIGNOR-185268
Q9NPF5	Q7Z553	2	binding	up-regulates quantity by stabilization	0.348	The anti-tumorigenic effect of MDGA2 was mediated through direct stabilising of DNA methyltransferase 1 associated protein 1 (DMAP1), which played a tumour suppressive role in gastric cancer. MDGA2 expression and MG132 treatment increased the level of DMAP1, suggesting that the MDGA2–DMAP1 interaction stabilises DMAP1 by inhibiting its ubiquitin-mediated degradation.	SIGNOR-264240
O00254	P00734	2	binding	up-regulates	0.653	as noted previously, the human form of par-3 activated phosphoinositide signaling in response to thrombin when overexpressed in cos-7 cells	SIGNOR-108225
Q9P1W9	P38936	1	phosphorylation	up-regulates quantity by stabilization	0.402	Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellsere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo	SIGNOR-164646
O14965	P00352	1	phosphorylation	up-regulates activity	0.372	AURKA phosphorylates ALDH1A1 at three critical residues which exert a multifaceted regulation over its level, enzymatic activity, and quaternary structure. While all three phosphorylation sites contribute to its increased stability, T267 phosphorylation primarily regulates ALDH1A1 activity. AURKA-mediated phosphorylation rapidly dissociates tetrameric ALDH1A1 into a highly active monomeric species.	SIGNOR-276748
P50570	O43586	2	binding	down-regulates	0.374	We show that pstpip1 associates with the regulator of endocytosis, dynamin 2, and pstpip1 expression impairs transferrin uptake and endocytosis	SIGNOR-178628
P15311	P00533	0	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
Q16539	P61244	1	phosphorylation	down-regulates	0.627	Mxi2 phosphorylates max both in vitro and in vivo. Phosphorylation by mxi2 may affect the ability of max to oligomerize with itself and its partners, bind dna, or regulate gene expression.	SIGNOR-26511
Q9Y6K9	O95999	2	ubiquitination	up-regulates activity	0.827	Here we show that Bcl10 targets NEMO for lysine-63-linked ubiquitination. Notably, a mutant form of NEMO that cannot be ubiquitinated inhibited Bcl10-induced NF-κB activation.	SIGNOR-274149
P49841	O43623	1	phosphorylation	down-regulates activity	0.423	GSK3beta controls epithelial-mesenchymal transition and tumor metastasis by CHIP mediated degradation of Slug.\|Phosphorylation of Slug by GSK3beta promotes CHIP binding and ubiquitin mediated proteolysis.	SIGNOR-279414
Q9UFD9	Q86UR5	2	binding	down-regulates activity	0.341	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-264360
Q9HBA0	Q96J02	0	ubiquitination	down-regulates activity	0.377	AIP4 ubiquitin ligase is involved in the ubiquitination of both TRPV4 and TRPC4.Ubiquitination of TRPV4 is dramatically increased by the HECT (homologous to E6-AP carboxyl terminus)-family ubiquitin ligase AIP4 without inducing degradation of this channel. Instead, AIP4 promotes the endocytosis of TRPV4 and decreases its amount at the plasma membrane.	SIGNOR-272625
P49840	P24723	0	phosphorylation	down-regulates	0.321	Furthermore, several pkc isotypes phosphorylate gsk-3 in vitro and in vivo. in the presence of atp, several isoforms (?, ___, _, ?, And of pkc phosphorylated both gsk-3? At ser 21 and gsk-3_ at ser 9	SIGNOR-115730
P20336	Q9UJD0	0	relocalization	up-regulates activity	0.282	N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle	SIGNOR-264379
P59635	Q07817	2	binding	down-regulates activity	0.2	In this study, we show that the overexpression of Bcl-XL, a prosurvival member of the Bcl-2 family, blocks 7a-induced apoptosis, suggesting that the mechanism for apoptosis induction by 7a is at the level of or upstream from the Bcl-2 family.	SIGNOR-261075
P23527	Q14493	0	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265379
Q9UQM7	P28329	1	phosphorylation	up-regulates	0.372	We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation.	SIGNOR-96628
P60953	Q96HP0	0	guanine nucleotide exchange factor	up-regulates activity	0.677	Dock6 is a guanine nucleotide exchange factor (GEF) that activates the Rho family guanosine triphosphatases Rac1 and Cdc42 to regulate the actin cytoskeleton.	SIGNOR-275671
P04637	Q6UB99	2	transcriptional regulation	up-regulates quantity by expression	0.308	Ankyrin repeat domain 11, ANKRD11 (also known as ANR11 or ANCO1), was found to be a novel p53-interacting protein that enhanced the transcriptional activity of p53. In addition, ANKRD11 itself was found to be a novel p53 target gene. These findings demonstrate a role for ANKRD11 as a p53 coactivator and suggest the involvement of ANKRD11 in a regulatory feedback loop with p53.	SIGNOR-266735
P56178	P31749	0	phosphorylation	up-regulates	0.264	Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5. akt interacts with and phosphorylates dlx5. In addition, we provide evidences that akt kinase activity is important for akt to enhance the protein stability and transcriptional activity of dlx5.	SIGNOR-252513
Q9UM47	O00548	2	binding	up-regulates	0.63	These results suggest that delta1, jagged1, and jagged2 are ligands for notch1 and notch3 receptors.	SIGNOR-82398
Q969Q1	P19237	1	polyubiquitination	down-regulates quantity by destabilization	0.36	We used MuRF1 as the E3 as it functions with all these E2s to ubiquitinate one of its typical substrates, troponin I Although UbcH1 and UbcH13/Uev1a support ubiquitination of troponin I by MuRF1, these E2s do not support ubiquitination of S5a, unlike Class I E2s.	SIGNOR-272736
O60858	Q00987	1	polyubiquitination	down-regulates quantity by destabilization	0.374	Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT. We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro.	SIGNOR-271851
Q13127	P53350	0	phosphorylation	down-regulates activity	0.309	Mass spectrometry revealed that PLK1 phosphorylates REST on serine-1030 ( xref and xref ).\|Notably, PLK1 depletion significantly increased REST protein half-life (XREF_FIG, XREF_SUPPLEMENTARY), indicating PLK1 antagonizes REST abundance by restraining REST protein stability.	SIGNOR-279380
O95382	Q16539	1	phosphorylation	up-regulates activity	0.2	These data indicate that MKK6 phosphorylates p38 MAP kinase on Thr-180 and Tyr-182, the sites of phosphorylation that activate p38 MAP kinase	SIGNOR-260916
P48729	P27348	1	phosphorylation	down-regulates activity	0.516	This protein kinase has been identified as casein kinase Ialpha (CKIalpha) by peptide mapping analysis and sequencing. Among mammalian 14-3-3, only 14-3-3 tau possesses a phosphorylatable residue at the same position (Ser-233), and we show that this residue is also phosphorylated by CKI. In addition, we show that 14-3-3 zeta is exclusively phosphorylated on Thr-233 in human embryonic kidney 293 cells. The residue 233 is located within a region shown to be important for the association of 14-3-3 to target proteins.	SIGNOR-250795
Q9HBH9	P42345	0	phosphorylation	down-regulates activity	0.274	MTOR phosphorylates MNK2a on Ser74. Here, we show that mTORC1, a key regulator of mRNA translation and oncogenesis, directly phosphorylates MNK2 on Ser74. This suppresses MNK2 activity and impairs binding of MNK2 to eIF4G.	SIGNOR-277516
Q08379	Q14789	2	binding	up-regulates activity	0.769	The “cis-golgin tether” is one of the most well-characterized golgin tether complexes. It is composed of the COPI vesicle-associated golgin giantin linked to Golgi membrane-associated GM130 via p115. GM130 is in turn linked to GRASP65 via a PDZ-like domain. GRASP65 is anchored to the Golgi membrane through N-terminal myristoylation as well as through binding to other Golgi proteins [10]. Together, these proteins appear to mediate vesicle tethering at the cis-Golgi membrane.	SIGNOR-261238
P68400	Q14676	1	phosphorylation	up-regulates	0.346	The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites.	SIGNOR-179887

Q9Y5H2

Q9Y5I2

2

binding

up-regulates activity

0.2

The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.

SIGNOR-265712

P56545

O95600

2

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

Q2TAL8

P54577

1

transcriptional regulation

up-regulates quantity by expression

0.2

QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.

SIGNOR-269412

Q04759

P35236

1

phosphorylation

up-regulates activity

0.2

PKC θ is required for HePTP translocation to the immune synapse. PKC θ phosphorylates HePTP at S225 in primary T cells.

SIGNOR-276045

P23769

Q8IX07

0

transcriptional regulation

down-regulates quantity by repression

0.746

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

SIGNOR-256061

P51608

O43395

2

binding

up-regulates activity

0.267

MeCP2 interacts directly with Prpf3 and Sdccag1|Notably, Mecp2308/Y mice, which produce a truncated form of MeCP2 and reproduce many of the classical features of RTT [43], have been shown to have multiple genes that are abnormally spliced in the brain [23]. This suggests the C-terminal portion of MeCP2, which we have identified as the putative Sdccag1 interaction domain, plays a critical role in regulating alternative splicing.

SIGNOR-277691

Q15173

O95235

1

dephosphorylation

up-regulates activity

0.2

We identify MKlp2 as an essential protein for promoting abscission, which may regulate tethering and stabilizing of the PM to the microtubule cytoskeleton. Aurora B phosphorylation of MKlp2 S878 in the LAM is a key inhibitory signal for abscission. Conversely, B56-PP2A promotes abscission by opposing Aurora B phosphorylation of MKlp2 S878.

SIGNOR-262660

Q04741

O14786

1

transcriptional regulation

up-regulates quantity by expression

0.2

EMX1 activates the transcription of Nrp1 in vitro.

SIGNOR-261593

Q13151

P49137

0

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

P06850

Q13324

2

binding

up-regulates activity

0.917

The actions of CRH are transduced through CRH receptors, which belong to the class II/secretin-like family of the G-protein coupled receptor (GPCR) superfamily (Martin et al. 2005). There are three types of CRH receptors – type 1 (CRHR1), type 2 (CRHR2) and type 3 (CRHR3). Among these, CRHR3 has not been identified in mammals. |CRH is a high-affinity ligand of CRHR1. It also binds to CRHR2, but with lower affinity

SIGNOR-268611

Q13882

P60484

0

dephosphorylation

down-regulates activity

0.416

PTEN inhibits PTK6 activity and downstream signaling in prostate cancer cells.|Using an in vitro phosphatase assay, we observed that PTEN was able to dephosphorylate PTK6 at tyrosine residue 342 in a dose dependent manner.

SIGNOR-276975

O95292

Q92953

0

relocalization

up-regulates quantity

0.2

Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays.|As Kv2.1 accumulates on the surface it begins to bind ER VAPs and form the large and stable membrane junctions.

SIGNOR-262123

Q9UQL6

Q16566

0

phosphorylation

down-regulates

0.51

Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs.

SIGNOR-236571

Q99677

P38405

2

binding

up-regulates activity

0.385

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-256928

P11831

Q13976

0

phosphorylation

up-regulates

0.275

Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. | Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha.

SIGNOR-188185

P0C0L4

O00187

0

cleavage

up-regulates activity

0.798

MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a).

SIGNOR-263431

Q9UM11

P24941

0

phosphorylation

down-regulates activity

0.745

A nuclear localization signal conserved in various species was identified in CDH1, and it sufficiently targets green fluorescent protein to the nucleus. Interestingly, a CDH1-4D mutant mimicking the hyperphosphorylated form was constitutively found in the cytoplasm. In further support of the notion that phosphorylation inhibits nuclear import, the nuclear localization signal of CDH1 with two phospho-accepting serine/threonine residues changed into aspartates was unable to drive heterologous protein into the nucleus.

SIGNOR-250732

Q14344

P30989

2

binding

up-regulates activity

0.25

Altogether, these results reveal for the first time the ability of hNTS1 to directly activate the Gαq-, Gαi1-, GαoA-, and Gα13-mediated signaling pathways

SIGNOR-278060

O43294

Q14289

0

phosphorylation

up-regulates activity

0.71

Hic-5 is a CAKbeta-binding protein localized at focal adhesions. Here we show that overexpression of CAKbeta or Fyn, but not FAK, enhanced the tyrosine phosphorylation of coexpressed Hic-5 in COS-7 cells. The Y60F mutant of Hic-5 was not phosphorylated, and Hic-5 phosphorylated on tyrosine 60 was bound specifically to the SH2 domain of Csk. Specific phosphorylation of Hic-5 by CAKbeta and Fyn may activate a signaling pathway mediated by Hic-5.

SIGNOR-262876

P63244

P05412

0

null

up-regulates quantity by expression

0.2

In turn, c-Jun induces expression of RACK1, which is required for JNK activation by PKC, pointing to a c-Jun/RACK1/PKC/JNK feedback loop.

SIGNOR-278066

O15084

Q13557

0

phosphorylation

down-regulates activity

0.2

We provide evidence for a dual kinase-mediated regulation of the PITK holoenzyme whereby PITK phosphorylation at S1017 is catalyzed by calcium/calmodulin-dependent kinase II-delta (CaMKIIdelta), promoting the subsequent phosphorylation of S1013 by glycogen synthase kinase-3 (GSK3) in vitro.|the phosphorylation of PITK at these specific residues altered PP1 binding and subsequent PITK-directed dephosphorylation of hnRNP K

SIGNOR-264793

P00533

Q9Y6I3

0

relocalization

down-regulates

0.596

Epsin 1 is involved in recruitment of ubiquitinated egf receptors into clathrin-coated pits this supports the contention that epsin 1 promotes endocytosis of the ubiquitinated egfr.

SIGNOR-182562

Q9GZU7

P24928

1

dephosphorylation

up-regulates activity

0.431

Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat.

SIGNOR-248785

O43293

Q13464

0

phosphorylation

up-regulates activity

0.306

ROCK1 phosphorylates and activates ZIPK suggesting that at least some of these physiological functions may require both enzymes.

SIGNOR-279102

O43474

P42226

0

transcriptional regulation

up-regulates quantity by expression

0.345

STAT6 coordinates and synergizes with both PPAR? and Krppel-like factor 4 (KLF4), a member of a family of proteins that contribute to macrophage function.

SIGNOR-249568

O15519

Q9UNE7

0

ubiquitination

down-regulates quantity by destabilization

0.356

Taken together, our data suggest that CHIP interacts with c-FLIP L in vivo and promotes the ubiquitination of c-FLIP L.|When we knocked down CHIP, c-FLIP L degradation was inhibited after treatment with 17-AAG, which indicated that CHIP modulated c-FLIP L degradation in the NSCLC cell lines.

SIGNOR-278783

P05067

P53355

0

phosphorylation

up-regulates quantity

0.287

DAPK1, but not its kinase deficient mutant (K42A), significantly increased human AŒ≤ secretion in neuronal cell culture models. Moreover, knockdown of DAPK1 expression or inhibition of DAPK1 catalytic activity significantly decreased AŒ≤ secretion. Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of AŒ≤.|Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of Abeta.

SIGNOR-279518

P42229

P36888

0

phosphorylation

up-regulates activity

0.605

FLT3-ITDs induced a strong activation of STAT5. FLT3-ITD mutants induce an autophosphorylation of the receptor, interleukin 3-independent growth in Ba/F3 cells, and a strong STAT5 and mitogen-activated protein kinase (MAPK) activation.

SIGNOR-261516

P49815

Q96BR1

0

phosphorylation

up-regulates activity

0.434

SGK3 phosphorylates six sites on TSC2 to activate mTORC1 in an AKT-independent manner.

SIGNOR-279284

Q13131

P06400

1

phosphorylation

down-regulates

0.2

Amp-activated protein kinase phosphorylates retinoblastoma protein. Rb phosphorylation sites, ser804 (ser811 in human), resembled the ampk consensus phosphorylation site.

SIGNOR-184052

P98177

O75874

1

transcriptional regulation

up-regulates quantity by expression

0.264

We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH.

SIGNOR-260102

P15514

P19544

0

transcriptional regulation

up-regulates quantity by expression

0.396

The Wilms Tumor Suppressor WT1 Encodes a Transcriptional Activator of amphiregulin

SIGNOR-251745

Q8NEV4

2

phosphorylation

down-regulates activity

0.2

We demonstrate by mass spectrometry that Thr-178 and Thr-184 in the kinase domain activation loop and two threonines in the loop 2 region of the motor domain are autophosphorylated (Thr-908 and Thr-919) | Thus, the phosphorylation sites in loop 2 (Thr-908 and Thr-919) are likely responsible for the down-regulation of MYO3A motor activity observed in our current and previous work

SIGNOR-260923

Q7Z699

P00533

0

phosphorylation

down-regulates activity

0.272

We show that oncogenic EGFR(L858R) signaling leads to the phosphorylation of SPRED1 on serine 105, disrupting the SPRED1-neurofibromin complex. The structural, biochemical, and biological results provide new mechanistic insights about how SPRED1 interacts with neurofibromin and regulates active KRAS levels in normal and pathologic conditions.

SIGNOR-273638

Q8N8S7

Q9UQB8

2

binding

up-regulates activity

0.569

We conclude that the interaction of Cdc42 with the partial CRIB motif of IRSp53 relieves an intramolecular, autoinhibitory interaction with the N terminus, allowing the recruitment of Mena to the IRSp53 SH3 domain. This IRSp53:Mena complex initiates actin filament assembly into filopodia.

SIGNOR-268423

P26715

P17693

2

binding

up-regulates

0.631

Current models of nk cell function have supposed that the cd94/nkg2a heterodimer is interacting with an epitope common to classical hla class i

SIGNOR-56714

P61586

P10911

0

guanine nucleotide exchange factor

up-regulates activity

0.754

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-260556

P50148

P37288

2

binding

up-regulates activity

0.463

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-257077

P49841

Q9HB09

1

phosphorylation

up-regulates

0.338

Gsk3b phosphorylates bcl2l12 at s156. Ectopic expression of gfp-fused bcl2l12 or bcl2l12a in u87mg cells leads to repression of apoptotic markers and protects against staurosporine (sts) insults, indicating an antiapoptotic role for both bcl2l12 and bcl2l12a. In contrast, no anti-apoptotic ability was seen in bcl2l12(s156a)

SIGNOR-195512

O95997

O95155

0

polyubiquitination

down-regulates quantity by destabilization

0.2

We further demonstrate that Ufd2 directly and efficiently ubiquitylates securin in vitro and is required for securin polyubiquitylation in vivo. This is the first description of a physiologic substrate for Ufd2, establishing this E4 enzyme as an important regulator of chromosome condensation and separation during mitosis in human cells.

SIGNOR-271523

P11309

Q99814

1

phosphorylation

up-regulates quantity by stabilization

0.2

PIM1 kinase directly phosphorylates HIF-1α at threonine 455, a previously uncharacterized site within its oxygen-dependent degradation domain. This phosphorylation event disrupts the ability of prolyl hydroxylases to bind and hydroxylate HIF-1α, interrupting its canonical degradation pathway and promoting constitutive transcription of HIF-1 target genes. Moreover, phosphorylation of the analogous site in HIF-2α (S435) stabilizes the protein through the same mechanism, indicating post-translational modification within the oxygen-dependent degradation domain as a mechanism of regulating the HIF-α subunits.

SIGNOR-277310

O00548

Q8NES3

2

binding

up-regulates

0.447

The modification of notch by fringe would influence binding between the notch receptor and its ligand. It was reported previously that mfng and lfng inhibited notch1-mediated signaling triggered by jagged1 and enhanced that triggered by delta1, and either jagged1- or delta1-triggered notch2 signaling was enhanced by lfng

SIGNOR-107699

O60260

P49792

1

ubiquitination

down-regulates quantity by destabilization

0.2

Our findings suggested that the intracellular levels of RanBP2 and its functional activity may be modulated by Parkin-mediated ubiquitination and proteasomal pathways. Furthermore, Parkin controls the intracellular levels of sumoylated HDAC4, as a result of the ubiquitination and degradation of RanBP2.

SIGNOR-259116

O75582

P50549

1

phosphorylation

up-regulates activity

0.463

Activated, overexpressed MSK1 was able to phosphorylate ER81 at Ser191 and Ser216. Mutation of these residues strongly impairs ER81-responsive promoter activity.

SIGNOR-262987

O14920

Q07817

1

phosphorylation

down-regulates quantity

0.339

We present evidence for a signaling network that involves phosphorylation and reduction of Bcl-xL by IKKbeta, and subsequent activation of caspases, which can cleave Htt.|We propose that IKKbeta reduces Bcl-xL levels by phosphorylation (XREF_FIG), a modification known to promote Bcl-xL degradation .

SIGNOR-279529

P17096

Q13315

0

phosphorylation

up-regulates activity

0.2

21 As shown in Fig. 2 b, ATM was able to phosphorylate in vitro the C-terminal peptide of HMGA1.

SIGNOR-279493

Q96ST3

Q9BXK1

2

binding

up-regulates activity

0.464

detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A.

SIGNOR-222460

P35368

P29992

2

binding

up-regulates activity

0.661

In this report, we demonstrate that in transfected cos-7 cells Gal4 and Ga16, like Gaq and Ga11, can activate PIPLC j3l and that all three al-ARs, alA, alB and alC, can activate endogenous PI-PLC by coupling to Gaq or Ga11.

SIGNOR-278122

Q99500

P63092

2

binding

up-regulates activity

0.2

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-256790

Q13315

Q8IW19

1

phosphorylation

up-regulates activity

0.4

We show that APLF undergoes ATM dependent hyperphosphorylation following IR and that APLF is directly phosphorylated by ATM in vitro.

SIGNOR-279492

O15297

Q12888

1

dephosphorylation

down-regulates activity

0.392

In addition, WIP1 dephosphorylates 53BP1 at Threonine 543 that was previously implicated in mediating interaction with RIF1.

SIGNOR-277046

P42224

P00519

0

phosphorylation

up-regulates activity

0.343

Our study unexpectedly found that c-Abl, another kinase other than JAKs, also contributes to STAT1 Y701 phosphorylation independently (XREF_FIG).|reported that c-Abl, but not Arg, could induce neuronal loss by prompting STAT1 activation and interferon production.

SIGNOR-279491

P49840

O75444

1

phosphorylation

up-regulates

0.2

We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity.

SIGNOR-159358

P78504

Q04721

2

binding

up-regulates

0.639

Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch.

SIGNOR-81364

Q9UQL6

P17252

0

phosphorylation

down-regulates activity

0.2

We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. | Finally, we assessed the ability of PKD to phosphorylate HDAC5 in cells by employing an antibody that specifically recognizes HDAC5 that has been phosphorylated at serine 259. HDAC5 was basally phosphorylated at serine 259, and phosphorylation at this site was dramatically increased by coexpression of constitutively active PKD S/E

SIGNOR-249269

Q8N8N0

Q7L523

1

polyubiquitination

down-regulates activity

0.74

Here, we identified the lysosome-anchored E3 ubiquitin ligase RNF152 as an essential negative regulator of the mTORC1 pathway by targeting RagA for K63-linked ubiquitination. RNF152 interacts with and ubiquitinates RagA in an amino-acid-sensitive manner. The mutation of RagA ubiquitination sites abolishes this effect of RNF152 and enhances the RagA-mediated activation of mTORC1. Ubiquitination by RNF152 generates an anchor on RagA to recruit its inhibitor GATOR1, a GAP complex for Rag GTPases.

SIGNOR-272222

Q14119

P05305

1

transcriptional regulation

up-regulates quantity by expression

0.276

Vascular endothelial zinc finger 1 (Vezf1)/DB1 is a recently identified zinc finger-containing protein that is expressed specifically within endothelial cells during development. In this report, we demonstrate that Vezf1/DB1 is a nuclear localizing protein that potently and specifically activates transcription mediated by the human endothelin-1 promoter, in a Tax-independent manner, in transient transfection assays. Regulation of endothelin-1 promoter activity by Vezf1/DB1 provides a mechanism for endothelin-1 expression in the vascular endothelium during development and to maintain vascular tone

SIGNOR-266884

Q96E09

P63151

2

binding

down-regulates activity

0.2

We demonstrate that the highly conserved protein in mammals, designated FAM122A, directly interacts with PP2A-Aα and B55α rather than B56α subunits, and inhibits the phosphatase activity of PP2A-Aα/B55α/Cα complex.

SIGNOR-266379

Q9H3F6

P61586

2

binding

down-regulates quantity

0.269

BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex.

SIGNOR-264237

Q15831

P27361

0

phosphorylation

down-regulates activity

0.39

Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK.

SIGNOR-209880

P49736

P68400

0

phosphorylation

up-regulates

0.259

In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2

SIGNOR-144004

P27694

P09884

2

binding

up-regulates activity

0.687

In our studies, we have shown that T antigen, DNA polymerase R, and the activation domain of VP16 all interact with overlapping regions of the 70-kDa subunit of RPA.| In the latter, both the direct protein-protein interaction and ssDNA-binding activities of RPA were needed for RPA to modulate polymerase processivity. We also found that SV40 T antigen inhibited the ability of RPA to increase processivity of DNA polymerase alpha, suggesting that this activity of RPA may be important for elongation but not during the initiation of DNA replication.

SIGNOR-261272

P53778

Q13884

2

binding

down-regulates

0.368

Basal localization of the p38g/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through b1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38g/b1-syntrophin interactions are abrogated, resulting in enhanced Carm1 phosphorylation

SIGNOR-255901

Q15398

Q9BYB0

1

relocalization

up-regulates activity

0.2

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

SIGNOR-264600

Q9NX09

Q9H3M7

2

binding

up-regulates quantity by stabilization

0.508

In the present study, we identify TXNIP that inhibits mTOR activity by binding to and stabilizing Redd1 protein.

SIGNOR-277470

Q9UQ26

A6NNM3

2

binding

down-regulates activity

0.358

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-264369

P24385

Q13627

0

phosphorylation

down-regulates

0.395

Dyrk1a controls the rate of cycd1 degradation by directly phosphorylating cycd1 at thr 286 and thereby regulates the fraction of cycling cells.

SIGNOR-202838

O60260

P62987

2

binding

up-regulates activity

0.2

The phosphorylation-dependent interaction between ubiquitin and parkin suggests that phosphorylated ubiquitin unlocks autoinhibition of the catalytic cysteine. Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator.

SIGNOR-270344

P25490

Q96GD4

0

phosphorylation

up-regulates

0.368

Aurora b kinase phosphorylates yy1 on serine 184 and to a lesser extent serine 180 at the g2/m stage of the cell cycle (fig. 7). We show that yy1 is rapidly dephosphorylated as the cells exit mitosis, likely by pp1. Also, our data indicates that phosphorylation at serine 180 and serine 184 can affect the dna binding activity of yy1

SIGNOR-200079

P13349

P68400

0

phosphorylation

up-regulates activity

0.307

Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity.

SIGNOR-250922

P53350

P35869

1

phosphorylation

down-regulates activity

0.251

In this study, we demonstrate that PLK1 phosphorylates AHR at S489 in LUAD, leading to epithelial-mesenchymal transition (EMT) and metastatic events.

SIGNOR-277885

Q9Y4D1

P61586

2

binding

up-regulates activity

0.822

B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1.

SIGNOR-185268

Q9NPF5

Q7Z553

2

binding

up-regulates quantity by stabilization

0.348

The anti-tumorigenic effect of MDGA2 was mediated through direct stabilising of DNA methyltransferase 1 associated protein 1 (DMAP1), which played a tumour suppressive role in gastric cancer. MDGA2 expression and MG132 treatment increased the level of DMAP1, suggesting that the MDGA2–DMAP1 interaction stabilises DMAP1 by inhibiting its ubiquitin-mediated degradation.

SIGNOR-264240

O00254

P00734

2

binding

up-regulates

0.653

as noted previously, the human form of par-3 activated phosphoinositide signaling in response to thrombin when overexpressed in cos-7 cells

SIGNOR-108225

Q9P1W9

P38936

1

phosphorylation

up-regulates quantity by stabilization

0.402

Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellsere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo

SIGNOR-164646

O14965

P00352

1

phosphorylation

up-regulates activity

0.372

AURKA phosphorylates ALDH1A1 at three critical residues which exert a multifaceted regulation over its level, enzymatic activity, and quaternary structure. While all three phosphorylation sites contribute to its increased stability, T267 phosphorylation primarily regulates ALDH1A1 activity. AURKA-mediated phosphorylation rapidly dissociates tetrameric ALDH1A1 into a highly active monomeric species.

SIGNOR-276748

P50570

O43586

2

binding

down-regulates

0.374

We show that pstpip1 associates with the regulator of endocytosis, dynamin 2, and pstpip1 expression impairs transferrin uptake and endocytosis

SIGNOR-178628

P15311

P00533

0

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

Q16539

P61244

1

phosphorylation

down-regulates

0.627

Mxi2 phosphorylates max both in vitro and in vivo. Phosphorylation by mxi2 may affect the ability of max to oligomerize with itself and its partners, bind dna, or regulate gene expression.

SIGNOR-26511

Q9Y6K9

O95999

2

ubiquitination

up-regulates activity

0.827

Here we show that Bcl10 targets NEMO for lysine-63-linked ubiquitination. Notably, a mutant form of NEMO that cannot be ubiquitinated inhibited Bcl10-induced NF-κB activation.

SIGNOR-274149

P49841

O43623

1

phosphorylation

down-regulates activity

0.423

GSK3beta controls epithelial-mesenchymal transition and tumor metastasis by CHIP mediated degradation of Slug.|Phosphorylation of Slug by GSK3beta promotes CHIP binding and ubiquitin mediated proteolysis.

SIGNOR-279414

Q9UFD9

Q86UR5

2

binding

down-regulates activity

0.341

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-264360

Q9HBA0

Q96J02

0

ubiquitination

down-regulates activity

0.377

AIP4 ubiquitin ligase is involved in the ubiquitination of both TRPV4 and TRPC4.Ubiquitination of TRPV4 is dramatically increased by the HECT (homologous to E6-AP carboxyl terminus)-family ubiquitin ligase AIP4 without inducing degradation of this channel. Instead, AIP4 promotes the endocytosis of TRPV4 and decreases its amount at the plasma membrane.

SIGNOR-272625

P49840

P24723

0

phosphorylation

down-regulates

0.321

Furthermore, several pkc isotypes phosphorylate gsk-3 in vitro and in vivo. in the presence of atp, several isoforms (?, ___, _, ?, And of pkc phosphorylated both gsk-3? At ser 21 and gsk-3_ at ser 9

SIGNOR-115730

P20336

Q9UJD0

0

relocalization

up-regulates activity

0.282

N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle

SIGNOR-264379

P59635

Q07817

2

binding

down-regulates activity

0.2

In this study, we show that the overexpression of Bcl-XL, a prosurvival member of the Bcl-2 family, blocks 7a-induced apoptosis, suggesting that the mechanism for apoptosis induction by 7a is at the level of or upstream from the Bcl-2 family.

SIGNOR-261075

P23527

Q14493

0

translation regulation

up-regulates quantity by expression

0.2

Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.

SIGNOR-265379

Q9UQM7

P28329

1

phosphorylation

up-regulates

0.372

We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation.

SIGNOR-96628

P60953

Q96HP0

0

guanine nucleotide exchange factor

up-regulates activity

0.677

Dock6 is a guanine nucleotide exchange factor (GEF) that activates the Rho family guanosine triphosphatases Rac1 and Cdc42 to regulate the actin cytoskeleton.

SIGNOR-275671

P04637

Q6UB99

2

transcriptional regulation

up-regulates quantity by expression

0.308

Ankyrin repeat domain 11, ANKRD11 (also known as ANR11 or ANCO1), was found to be a novel p53-interacting protein that enhanced the transcriptional activity of p53. In addition, ANKRD11 itself was found to be a novel p53 target gene. These findings demonstrate a role for ANKRD11 as a p53 coactivator and suggest the involvement of ANKRD11 in a regulatory feedback loop with p53.

SIGNOR-266735

P56178

P31749

0

phosphorylation

up-regulates

0.264

Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5. akt interacts with and phosphorylates dlx5. In addition, we provide evidences that akt kinase activity is important for akt to enhance the protein stability and transcriptional activity of dlx5.

SIGNOR-252513

Q9UM47

O00548

2

binding

up-regulates

0.63

These results suggest that delta1, jagged1, and jagged2 are ligands for notch1 and notch3 receptors.

SIGNOR-82398

Q969Q1

P19237

1

polyubiquitination

down-regulates quantity by destabilization

0.36

We used MuRF1 as the E3 as it functions with all these E2s to ubiquitinate one of its typical substrates, troponin I Although UbcH1 and UbcH13/Uev1a support ubiquitination of troponin I by MuRF1, these E2s do not support ubiquitination of S5a, unlike Class I E2s.

SIGNOR-272736

O60858

Q00987

1

polyubiquitination

down-regulates quantity by destabilization

0.374

Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT. We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro.

SIGNOR-271851

Q13127

P53350

0

phosphorylation

down-regulates activity

0.309

Mass spectrometry revealed that PLK1 phosphorylates REST on serine-1030 ( xref and xref ).|Notably, PLK1 depletion significantly increased REST protein half-life (XREF_FIG, XREF_SUPPLEMENTARY), indicating PLK1 antagonizes REST abundance by restraining REST protein stability.

SIGNOR-279380

O95382

Q16539

1

phosphorylation

up-regulates activity

0.2

These data indicate that MKK6 phosphorylates p38 MAP kinase on Thr-180 and Tyr-182, the sites of phosphorylation that activate p38 MAP kinase

SIGNOR-260916

P48729

P27348

1

phosphorylation

down-regulates activity

0.516

This protein kinase has been identified as casein kinase Ialpha (CKIalpha) by peptide mapping analysis and sequencing. Among mammalian 14-3-3, only 14-3-3 tau possesses a phosphorylatable residue at the same position (Ser-233), and we show that this residue is also phosphorylated by CKI. In addition, we show that 14-3-3 zeta is exclusively phosphorylated on Thr-233 in human embryonic kidney 293 cells. The residue 233 is located within a region shown to be important for the association of 14-3-3 to target proteins.

SIGNOR-250795

Q9HBH9

P42345

0

phosphorylation

down-regulates activity

0.274

MTOR phosphorylates MNK2a on Ser74. Here, we show that mTORC1, a key regulator of mRNA translation and oncogenesis, directly phosphorylates MNK2 on Ser74. This suppresses MNK2 activity and impairs binding of MNK2 to eIF4G.

SIGNOR-277516

Q08379

Q14789

2

binding

up-regulates activity

0.769

The “cis-golgin tether” is one of the most well-characterized golgin tether complexes. It is composed of the COPI vesicle-associated golgin giantin linked to Golgi membrane-associated GM130 via p115. GM130 is in turn linked to GRASP65 via a PDZ-like domain. GRASP65 is anchored to the Golgi membrane through N-terminal myristoylation as well as through binding to other Golgi proteins [10]. Together, these proteins appear to mediate vesicle tethering at the cis-Golgi membrane.

SIGNOR-261238

P68400

Q14676

1

phosphorylation

up-regulates

0.346

The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites.

SIGNOR-179887