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
Q12800	P67775	0	dephosphorylation	up-regulates	0.2	We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. This predominant cis conformation would also limit dephosphorylation of ser-291 and ser-309 by phosphatases such as pp2a	SIGNOR-167385
O60603	Q99836	2	binding	up-regulates activity	0.673	To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group	SIGNOR-266740
P04083	P17252	0	phosphorylation	up-regulates	0.2	The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization.	SIGNOR-202780
P26358	Q9H9S0	0	transcriptional regulation	up-regulates quantity by expression	0.432	Oct4 and Nanog upregulate Dnmt1 through direct binding to its promoter, thereby leading to the repressed expression of p16 and p21 and genes associated with development and lineage differentiation	SIGNOR-253157
P04629	P29350	0	dephosphorylation	down-regulates activity	0.476	Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675.	SIGNOR-248468
Q9NRJ5	Q96HN2	2	binding	down-regulates activity	0.2	Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation\|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner.	SIGNOR-268332
Q03113	O43613	2	binding	up-regulates activity	0.25	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-257404
Q96F24	P42345	0	phosphorylation	up-regulates activity	0.2	Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association.	SIGNOR-265875
P63092	P21728	2	binding	up-regulates activity	0.498	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-256796
Q5S007	P37840	1	phosphorylation	down-regulates activity	0.624	Here we show that full-length Lrrk2 or fragments containing its kinase domain have a significant capacity to phosphorylate recombinant alpha synuclein (Asyn) at serine 129. Such phosphorylated Asyn is the major component of pathological deposits in PD.	SIGNOR-249690
Q8WVD3	Q13315	0	phosphorylation	up-regulates activity	0.2	We further confirm that RNF138 is phosphorylated by ATM at Ser124.	SIGNOR-279505
Q13114	Q96RJ3	2	binding	down-regulates quantity by destabilization	0.758	Activation of br3 induces recruitment and degradation of traf3.	SIGNOR-168199
Q9Y4K3	Q9Y4K3	2	ubiquitination	up-regulates activity	0.2	Here we report that the ubiquitin ligase (e3) traf6 interacts with a consensus motif present in tbetari. The tbetari-traf6 interaction is required for tgf-beta-induced autoubiquitylation of traf6 and subsequent activation of the tak1-p38/jnk pathway, which leads to apoptosis.	SIGNOR-180562
P28482	Q13153	1	phosphorylation	down-regulates activity	0.402	We also show that ERK2 phosphorylates PAK1 on Thr(212) in vitro and that Thr(212) is phosphorylated in smooth muscle cells following PDGF-BB treatment in an adhesion- and MEK/ERK-dependent fashion. Expression of a phosphomimic variant, PAK-T212E, does not alter ERK association, but markedly attenuates downstream ERK signaling. Taken together, these data suggest that PAK1 may facilitate ERK signaling by serving as a scaffold to recruit Raf, MEK, and ERK to adhesion complexes, and that subsequent growth factor-stimulated phosphorylation of PAK-Thr(212) by ERK may serve to provide a negative feedback signal	SIGNOR-249432
P16519	P01178-PRO_0000020496	1	cleavage	up-regulates quantity	0.2	Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension.	SIGNOR-270337
Q02750	Q9Y2U5	0	phosphorylation	up-regulates	0.414	Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation	SIGNOR-107692
P08138	P01138	2	binding	up-regulates	0.836	The low affinity neurotrophin receptor p75ntr can mediate cell survival as well as cell death of neural cells by ngf and other neurotrophins.	SIGNOR-76832
Q07817	Q07812	2	binding	down-regulates	0.745	The presence of an anti-apoptotic molecule such as bcl-2 or bcl-xl can inhibit the activation of bax following a death signal.	SIGNOR-59141
Q8NG27	P15172	0	transcriptional regulation	up-regulates quantity	0.2	... chromatin immunoprecipitation (ChIP) analysis showed MYOD binds to a site upstream the Pja1 promoter preferentially in C2C12 cells induced to differentiate (Fig. 2c). In addition, over-expression of MyoD in human fibroblasts is sufficient to up-regulate Pja1 expression	SIGNOR-255718
P54764	P20827	2	binding	up-regulates	0.823	Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor	SIGNOR-52087
O95835	Q16635	1	phosphorylation	down-regulates activity	0.387	When the inhibitory Hippo kinase module is ' on ', LATS1 and LATS2 phosphorylate and inactivate YAP and TAZ, and the output gene production is therefore turned off.\|When the inhibitory Hippo kinase module is \u2018on\u2019, LATS1 and LATS2 phosphorylate and inactivate YAP and TAZ, and the output gene production is therefore turned off.	SIGNOR-279200
P27361	P05976	1	phosphorylation	up-regulates	0.287	Activation of raf/mek/erk cascade can also result in the phosphorylation of the antiapoptotic mcl-1 protein and the pro-apoptotic bim protein.	SIGNOR-148002
Q15759	Q06413	1	phosphorylation	up-regulates activity	0.538	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-280025
P35222	O60907	2	binding	up-regulates activity	0.659	TBL1 appears to serve two roles in regulating the activity of β-catenin. Besides the initially identified role of TBL1 in recruiting β-catenin to the SCF(TBL1) complex, it has also been shown to function as a transcriptional co-activator of β-catenin in recruiting it to the promoter site of Wnt target genes. Our results indicated that TBL1 can inhibit the polyubiquitination of β-catenin by Siah-1 in vitro (Fig. 3) and stabilize β-catenin in cells by protecting it from Siah-1-mediated ubiquitination and proteasomal degradation (Fig. 4).	SIGNOR-271954
O00418	O15264	0	phosphorylation	down-regulates activity	0.578	eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta. eEF2K[S359A] was phosphorylated (presumably at Ser396) by the high concentrations of SAPK4/p38 used in this experiment. However, the inhibition of eEF2K under these conditions was reduced from 82% in the wild-type enzyme to 19% in eEF2K[S359A]	SIGNOR-250089
O15264	Q6JBY9	1	phosphorylation	down-regulates activity	0.419	CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.	SIGNOR-263084
P16104	Q99504	0	dephosphorylation	down-regulates	0.2	Tyr142 is dephosphorylated by the tyr phosphatases eya1 and eya3.	SIGNOR-168927
P54646	Q13085	1	phosphorylation	down-regulates	0.697	Significant negative linear correlations between phospho-acc and acc activity were observed in all models (p < 0.01). The decline in acc activity was related to the decrease in pcr and the rise in amp. A relationship between phospho-ampk (threonine 172) and activity of ampk immunoprecipitated with anti-alpha(2) subunit antibody preparation was also observed.	SIGNOR-87583
Q13561	O43264	0	relocalization	up-regulates activity	0.685	ZW10 interacts with dynamitin, a subunit of the dynein-dynactin complex (Echeverri et al., 1996), thereby recruiting this motor to kinetochores	SIGNOR-265016
Q9BYB0	Q9P1A6	0	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-264591
P34925	O14640	2	binding	up-regulates	0.483	Ryk also binds to dishevelled, through which it activates the canonical wnt, providing a link between wnt and dishevelled.	SIGNOR-129568
Q13459	P60953	1	gtpase-activating protein	down-regulates activity	0.562	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-260511
P23443	Q13362	2	binding	down-regulates	0.341	The human homolog of pp2a-b', ppp2r5c, also counteracts s6k1 phosphorylation, indicating a conserved mechanism in mammals	SIGNOR-165224
P42575	Q96GD4	0	phosphorylation	up-regulates activity	0.244	Furthermore, in vitro phosphorylation using GST-Casp2 363-423 WT or S384A confirmed that S384 of caspase-2 is phosphorylated by AURKB.	SIGNOR-279496
P16066	P01160	2	binding	up-regulates	0.887	Natriuretic peptide receptor-a (npra) is the biological receptor of the peptide hormones atrial natriuretic peptide (anp) and brain natriuretic peptide (bnp)	SIGNOR-137600
P17612	Q15831	1	phosphorylation	up-regulates activity	0.502	Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell growth.	SIGNOR-250055
P43694	Q4G0P3	0	transcriptional regulation	up-regulates quantity by expression	0.2	HYDIN promotes expression of Gata4 in cardiomyocyte differentiation. HYDIN functions as a positive regulator of human cardiomyocyte differentiation and promotes expression of cardiac contractile genes in hESC cells. This is mediated through GATA4, a critical transcription factor in heart development. Cardiac-specific Hydin knockdown in vivo leads to Gata4 downregulation and enhanced atrial septal defect (ASD) risk in mice. GATA4 is a fundamental TF in embryonic heart development and cardiac differentiation, and reduction in GATA4 function results in a diverse range of CHDs	SIGNOR-265479
P17252	P46940	1	phosphorylation	up-regulates	0.258	Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth.	SIGNOR-128714
P09874	Q9UGL1	1	relocalization	up-regulates activity	0.354	The mechanism of KDM5B recruitment is quite specific and requires the presence of nucleosomes containing histone variant MacroH2A1.1 and PARylation by PARP1.	SIGNOR-271574
Q96B36	P31751	0	phosphorylation	down-regulates	0.674	Insulin-stimulated phosphorylation of pras40 by akt/pkb suppresses its mtorc1 inhibitory activity.	SIGNOR-153931
P48730	O14641	1	phosphorylation	up-regulates	0.534	Ck1_/__dependent phosphorylation of dvl2 at s143 and t224and that this event is critical to interact with plk1 in early stages of the cell cycle	SIGNOR-197547
Q9NR61	P46531	2	binding	up-regulates activity	0.644	Expression analysis of known notch ligands suggests that dll4 is the only ligand that exhibits spatial and temporal expression consistent with the activation of notch1 and notch4 during vascular development. The identification of dll4 reveals a candidate ligand for notch receptors involved in blood vessel biology	SIGNOR-112649
Q9UKM9	Q99873	1	post transcriptional regulation	up-regulates quantity	0.247	RALY binds poly-U rich elements within several RNAs and regulates the expression as well as the stability of specific transcripts. Here we show that RALY binds PRMT1 mRNA and regulates its expression.\|We demonstrate that RALY down-regulation decreases protein arginine N-methyltransferase 1 levels	SIGNOR-262273
Q6NUQ1	Q92878	2	binding	up-regulates activity	0.471	We propose that p130, forming a complex with Rad50 through RINT-1, blocks telomerase-independent telomere lengthening in normal cells.	SIGNOR-265030
P11678	P10153	1	post translational modification	up-regulates activity	0.476	Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism.	SIGNOR-261704
Q13315	P53350	1	phosphorylation	down-regulates activity	0.429	Indeed Chk2 mediates the degradation of Cdc25A to activate the S-phase checkpoint [5\u20137,18] , whereas ATM phosphorylates and inactivates Plk1, consolidating the delay in the entry into M phase [5\u201319] .\|Indeed Chk2 mediates the degradation of Cdc25A to activate the S-phase checkpoint [5-7,18], whereas ATM phosphorylates and inactivates Plk1, consolidating the delay in the entry into M phase [5-19].	SIGNOR-279793
P05067	P53779	0	phosphorylation	up-regulates	0.582	Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in sh-sy5y neuroblastoma cells. is regulated by jnk3 via phosphorylation of app at thr668	SIGNOR-204671
Q13077	P20333	2	binding	up-regulates	0.72	Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2.	SIGNOR-33133
O75602	Q92949	0	transcriptional regulation	up-regulates quantity by expression	0.447	FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).	SIGNOR-266935
O60486	Q86YJ5	0	ubiquitination	down-regulates quantity by destabilization	0.2	MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.	SIGNOR-271532
Q13887	P49841	0	phosphorylation	down-regulates	0.368	Stability of the klf5 is mediated by proteasomal degradation via phosphorylation by glycogen synthase kinase 3_ (gsk3_) and recognition by f-box and wd repeat domain-containing 7 (fbw7) of a phosphodegron sequence surrounding serine 303 in klf5	SIGNOR-203627
Q969T9	P12931	0	phosphorylation	up-regulates activity	0.297	Using dominant-negative, constitutively active mutants, RNAi, and pharmacological studies, we demonstrated that phosphorylation of WBP2 at Tyr192 and Tyr231 could be regulated by c-Src and c-Yes kinases.We further showed that abrogating WBP2 phosphorylation impaired >60% of ERα reporter activity, putatively by blocking nuclear entry of WBP2 and its interaction with ERα.	SIGNOR-273567
Q07889	P19174	2	binding	up-regulates	0.647	We provide evidence that sos1, a p21ras-specific guanine nucleotide exchange factor, directly binds to the sh3 domain of plc-gamma1, and that the sh3 domain of plc-gamma1 is involved in sos1-mediated p21ras activation.	SIGNOR-80024
P31749	Q96QF0	1	phosphorylation	up-regulates activity	0.2	Rabin8 is phosphorylated and activated by Akt in cells grown on stiff ECM.	SIGNOR-277802
Q70E73	P50552	2	binding	up-regulates activity	0.578	Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins.	SIGNOR-268426
Q8IU81	P14316	2	binding	up-regulates activity	0.692	We have identified two novel proteins that interact specifically with the C-terminal repression domain of Interferon Regulatory Factor-2 (IRF-2). These proteins, which we term IRF-2 binding proteins 1 and 2 (IRF-2BP1 and IRF-2BP2, the latter having two splicing isoforms, A and B), are nuclear proteins, and have the properties of IRF-2-dependent transcriptional co-repressors that can inhibit both enhancer-activated and basal transcription in a manner that is not dependent upon histone deacetylation.	SIGNOR-224045
P23467	Q9UM73	1	dephosphorylation	down-regulates	0.334	Rptpbeta/zeta dephosphorylates alk at the site(s) in alk that is undergoing autophosphorylation through autoactivation.	SIGNOR-157175
Q9NS28	P17612	0	phosphorylation	up-regulates activity	0.2	Cyclic AMP- and cyclic GMP-dependent kinases (PKA, PKG) inhibit the interaction of RGS18 and 14-3-3 by phosphorylating S216.	SIGNOR-273786
Q13153	Q13352	1	phosphorylation	up-regulates	0.2	Serine 28 phosphorylation of nrif3 confers its co-activator function for estrogen receptor-alpha transactivation. p21-activated protein kinase 1 (pak1) phosphorylates eralpha at ser305 and this modification is important in eralpha transactivation function.	SIGNOR-178795
P63000	Q9H0H5	0	gtpase-activating protein	down-regulates activity	0.586	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-260512
P10586	Q9NT99	2	binding	up-regulates activity	0.617	The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively.	SIGNOR-264049
Q06124	P21802	1	dephosphorylation	down-regulates activity	0.622	In forming this heterotetrameric complex Grb2 inhibits both the dephosphorylation of FGFR2 by Shp2 and the phosphorylation of Shp2 by FGFR2 (XREF_FIG, respectively).\|Knockdown of Grb2 elevates Shp2 phosphorylation (XREF_FIG), strongly suggesting that the inability of Shp2 to interact directly with the receptor in the presence of Grb2 prevents FGFR2 kinase activity toward Shp2.	SIGNOR-277030
P45983	Q13469	1	phosphorylation	down-regulates	0.752	Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin jnk directly regulated nuclear factor of activated t-cell (nfat) activation in culture and in transgenic mice containing an nfat-dependent luciferase reporter.	SIGNOR-118217
P04035	Q86TM6	0	polyubiquitination	down-regulates quantity by destabilization	0.562	In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation.Human HRD1 appears to be involved in the basal degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase but not in the degradation that is regulated by sterols.	SIGNOR-272594
O00566	Q96G21	2	binding	up-regulates activity	0.818	Mpp10 represents a platform for the interaction of multiple factors within the 90S pre-ribosome. In eukaryotes, ribosome assembly is a highly complex process that involves more than 200 assembly factors that ensure the folding, modification and processing of the different rRNA species as well as the timely association of ribosomal proteins. One of these factors, Mpp10 associates with Imp3 and Imp4 to form a complex that is essential for the normal production of the 18S rRNA.	SIGNOR-261174
P09651	P01106	0	transcriptional regulation	up-regulates quantity by expression	0.456	We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2,	SIGNOR-268690
Q16539	Q14790	1	phosphorylation	down-regulates	0.55	P38-mapk can directly phosphorylate and inhibit the activities of caspase-8	SIGNOR-122103
Q07869	Q7Z6Z7	0	ubiquitination	down-regulates quantity by destabilization	0.2	Furthermore, the E3 ubiquitin ligase HUWE1 was identified to mediate PPARalpha polyubiquitination.\|This notion is also supported by our finding that Huwe1 knockdown up-regulated the expression of PPARalpha target genes at the cellular level.	SIGNOR-278814
Q86XI6	P13807	2	binding	up-regulates	0.714	In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2)	SIGNOR-271734
Q7Z6Z7	P04198	1	ubiquitination	down-regulates quantity by destabilization	0.423	HUWE1 ubiquitinates and directs MYCN degradation to the proteasome.	SIGNOR-278750
P49810	P55212	0	cleavage	up-regulates activity	0.363	In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329.	SIGNOR-261750
Q13761	Q00987	0	ubiquitination	down-regulates quantity by destabilization	0.579	RUNX3 protein is ubiquitinated by MDM2 at Lys-94 and Lys-148.\|RUNX3 protein is ubiquitinated by MDM2 at Lys 94 and Lys 148.\|MDM2 suppresses the transcriptional activity of RUNX3.	SIGNOR-278557
Q53HL2	P33981	0	phosphorylation	up-regulates	0.461	First, we confirmed that wild-type borealin is phosphorylated at the previously described sites t88, t94, t169, and t230 when present in complex with survivin borealin might be a substrate for mps1. In the case of wild-type borealin, the fast exchange between the monomeric and dimeric forms may allow mps1 to phosphorylate the monomer. In turn, mps1 may regulate borealin function by unfolding the c-terminal domain and/or shifting the population to the monomeric form.	SIGNOR-186151
P24941	P30291	2	null	down-regulates quantity by destabilization	0.666	PS123 primes CK2 to phosphorylate S121, resulting in creation of a β-TrCP phosphodegron (EEGFGpS121) that is responsible for the instability of Wee1A during interphase.	SIGNOR-276039
Q9UP95	Q9BYP7	0	phosphorylation	down-regulates activity	0.464	We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities\|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs	SIGNOR-264627
P40763	P16591	0	phosphorylation	up-regulates activity	0.402	Replacing the unique 43-amino acid-long N-terminal tail of p51 (ferT) with a parallel segment from the N-terminal tail of p94 (fer) did not change the subcellular localization of p51 (ferT) but enabled it to activate Stat3.\|When combined with immunoprecipitation analysis, this assay showed that p94 (fer) can lead to the tyrosine phosphorylation and activation of Stat3 but not of Stat1 or Stat2.	SIGNOR-279713
P49023	P12931	0	phosphorylation	up-regulates activity	0.808	Here, we demonstrate that Src kinase directly phosphorylates Y88 paxillin\|In this study, we also show how pY88 paxillin transduces a signal to activate Akt	SIGNOR-263977
P05305	P24530	2	binding	up-regulates	0.946	Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors.	SIGNOR-145762
P11831	Q9UQM7	0	phosphorylation	up-regulates activity	0.369	Skeletal muscle CaMKII enriches in nuclei and phosphorylates myogenic factor SRF at multiple sites. \| Microsequencing of these phosphorylated peptides identified that both Ser-103 and a novel residue, Thr-160 in the MADS box of SRF, were sites of phosphorylation. \| The location of Thr-160 in the 3-D structure of SRF suggests that its phosphorylation by nuclear CaMKII may directly influence DNA binding of SRF and other MADS box factors.	SIGNOR-250639
Q00978	P48551	2	binding	up-regulates activity	0.727	By binding to IFNalphaR2 within the region where two adjacent proline boxes bear phospho-Ser364 and phospho-Ser384, CBP acetylates IFNalphaR2 on Lys399, which in turn serves as the docking site for interferon regulatory factor 9 (IRF9)RF9 interacts with the acetyl-Lys399 motif by means of its IRF homology2 (IH2) domain, leading to formation of the ISGF3 complex that includes IRF9, STAT1, and STAT2.	SIGNOR-217779
Q7L591	P07948	0	phosphorylation	up-regulates activity	0.409	An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling.	SIGNOR-268447
P09429	P31249	2	binding	up-regulates activity	0.298	We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein.	SIGNOR-219980
Q8TD08	P05412	1	phosphorylation	up-regulates	0.428	Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein. these data suggest that erks, rather than jnks, are required for c- jun up-regulation.	SIGNOR-91375
Q13490	O43353	1	polyubiquitination	up-regulates activity	0.652	CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.	SIGNOR-272712
P53350	P78527	2	phosphorylation	up-regulates activity	0.425	Moreover, PLK1 phosphorylates DNA-PKcs directly on Ser 3205 invitro, suggesting that DNA-PKcs Ser 3205 is a direct target of PLK1 in mitosis.	SIGNOR-278188
P67775	P05771	1	dephosphorylation	down-regulates activity	0.446	Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme.	SIGNOR-248620
O60315	P0C2W1	2	binding	down-regulates quantity by destabilization	0.362	One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively.	SIGNOR-272180
Q16236	Q13131	0	phosphorylation	up-regulates activity	0.2	MS-based analysis of immunoprecipitated Nrf2 revealed serine 374, 408 and 433 in human Nrf2 to be hyperphosphorylated as a function of activated AMPK. A direct phosphate-transfer by AMPK to those sites was indicated by in vitro kinase assays with recombinant proteins as well as interaction of AMPK and Nrf2 in cells, evident by co-immunoprecipitation. Mutation of serine 374, 408 and 433 to alanine did not markedly affect half-life, nuclear accumulation or induction of reporter gene expression upon Nrf2 activation with sulforaphane. However, some selected endogenous Nrf2 target genes responded with decreased induction when the identified phosphosites were mutated, whereas others remained unaffected.	SIGNOR-277496
P06493	Q15116	1	phosphorylation	down-regulates quantity by destabilization	0.2	We demonstrated that cyclin-dependent kinase 1-mediated phosphorylation of Ser261 residue primes PD-1 protein nucleus translocation and binding with FBW7.	SIGNOR-277605
O43464	P98170	2	binding	down-regulates	0.709	Here we report that a serine protease called htra2/omi is released from mitochondria and inhibits the function of xiap by direct binding in a similar way to diablo.	SIGNOR-110834
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
Q7Z5J4	O15516	1	transcriptional regulation	up-regulates quantity by expression	0.479	RAI1 Transcriptionally Activates CLOCK via an Intron 1 Enhancer Element. data suggest that RAI1 binds, directly or in a complex, to the first intron of CLOCK and enhances its transcriptional activity in vitro, supporting RAI1 as a positive regulator of CLOCK and an important part of the circadian loop of transcription. Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others.	SIGNOR-266839
Q9NP80	Q9BUB5	0	phosphorylation	up-regulates activity	0.2	Constitutively active MNK1 activates and phosphorylates iPLA2γ. Thus, complement-mediated activation of iPLA(2)γ is mediated via ERK and p38 pathways, and phosphorylation of Ser-511 and/or Ser-515 plays a key role in the catalytic activity and signaling of iPLA(2)γ.	SIGNOR-273677
P24071	P67775	0	dephosphorylation	up-regulates activity	0.323	Furthermore, FcalphaRI activation is induced by protein phosphatase 2A (PP2A) after it dephosphorylates a single serine residue (S263) in the FcalphaRI intracellular tail	SIGNOR-264858
Q99558	O15111	2	phosphorylation	up-regulates activity	0.698	Once activated by autophosphorylation, nik activates ikkalpha, which in turn phosphorylates nf-kb2. This stimulates limited proteasome-mediated proteolysis of nf-kb2 to p52. Removal of the carboxy-terminal ankyrin repeats from nf-kb2 releases the p52/RELB heterodimer, allowing its translocation to the nucleus where it instigates the expression of nf-kb target genes.	SIGNOR-167060
O14503	P48729	0	phosphorylation	down-regulates quantity by destabilization	0.2	CK1α-mediated phosphorylation of DEC1 on a conserved degron is required for DEC1 degradation.	SIGNOR-276851
Q9BT81	Q9HCK8	0	transcriptional regulation	down-regulates quantity	0.2	Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells	SIGNOR-268922
Q9HCE7	Q96AC1	1	ubiquitination	down-regulates quantity by destabilization	0.2	Smurf1 mediates Kindlin-2 proteasomal degradation.\|Smurf1 promotes polyubiquitination of Kindlin-2.	SIGNOR-278614
P49327	O15379	0	deacetylation	up-regulates quantity by stabilization	0.2	Overexpression of HA-HDAC3 decreased the acetylation level of endogenous FASN by 35% in HEK293T cells, while the expression of a catalytic inactive mutant HDAC3Y298H (38) failed to reduce FASN acetylation (Fig. 4C). Conversely, HDAC3 knockdown increased the acetylation level of endogenous FASN by >1.5-fold in HEK293T cells	SIGNOR-267367
Q04760	P07947	0	phosphorylation	up-regulates activity	0.2	We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).	SIGNOR-276185

Q12800

P67775

0

dephosphorylation

up-regulates

0.2

We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. This predominant cis conformation would also limit dephosphorylation of ser-291 and ser-309 by phosphatases such as pp2a

SIGNOR-167385

O60603

Q99836

2

binding

up-regulates activity

0.673

To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group

SIGNOR-266740

P04083

P17252

0

phosphorylation

up-regulates

0.2

The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization.

SIGNOR-202780

P26358

Q9H9S0

0

transcriptional regulation

up-regulates quantity by expression

0.432

Oct4 and Nanog upregulate Dnmt1 through direct binding to its promoter, thereby leading to the repressed expression of p16 and p21 and genes associated with development and lineage differentiation

SIGNOR-253157

P04629

P29350

0

dephosphorylation

down-regulates activity

0.476

Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675.

SIGNOR-248468

Q9NRJ5

Q96HN2

2

binding

down-regulates activity

0.2

Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner.

SIGNOR-268332

Q03113

O43613

2

binding

up-regulates activity

0.25

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-257404

Q96F24

P42345

0

phosphorylation

up-regulates activity

0.2

Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association.

SIGNOR-265875

P63092

P21728

2

binding

up-regulates activity

0.498

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-256796

Q5S007

P37840

1

phosphorylation

down-regulates activity

0.624

Here we show that full-length Lrrk2 or fragments containing its kinase domain have a significant capacity to phosphorylate recombinant alpha synuclein (Asyn) at serine 129. Such phosphorylated Asyn is the major component of pathological deposits in PD.

SIGNOR-249690

Q8WVD3

Q13315

0

phosphorylation

up-regulates activity

0.2

We further confirm that RNF138 is phosphorylated by ATM at Ser124.

SIGNOR-279505

Q13114

Q96RJ3

2

binding

down-regulates quantity by destabilization

0.758

Activation of br3 induces recruitment and degradation of traf3.

SIGNOR-168199

Q9Y4K3

2

ubiquitination

up-regulates activity

0.2

Here we report that the ubiquitin ligase (e3) traf6 interacts with a consensus motif present in tbetari. The tbetari-traf6 interaction is required for tgf-beta-induced autoubiquitylation of traf6 and subsequent activation of the tak1-p38/jnk pathway, which leads to apoptosis.

SIGNOR-180562

P28482

Q13153

1

phosphorylation

down-regulates activity

0.402

We also show that ERK2 phosphorylates PAK1 on Thr(212) in vitro and that Thr(212) is phosphorylated in smooth muscle cells following PDGF-BB treatment in an adhesion- and MEK/ERK-dependent fashion. Expression of a phosphomimic variant, PAK-T212E, does not alter ERK association, but markedly attenuates downstream ERK signaling. Taken together, these data suggest that PAK1 may facilitate ERK signaling by serving as a scaffold to recruit Raf, MEK, and ERK to adhesion complexes, and that subsequent growth factor-stimulated phosphorylation of PAK-Thr(212) by ERK may serve to provide a negative feedback signal

SIGNOR-249432

P16519

P01178-PRO_0000020496

1

cleavage

up-regulates quantity

0.2

Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension.

SIGNOR-270337

Q02750

Q9Y2U5

0

phosphorylation

up-regulates

0.414

Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation

SIGNOR-107692

P08138

P01138

2

binding

up-regulates

0.836

The low affinity neurotrophin receptor p75ntr can mediate cell survival as well as cell death of neural cells by ngf and other neurotrophins.

SIGNOR-76832

Q07817

Q07812

2

binding

down-regulates

0.745

The presence of an anti-apoptotic molecule such as bcl-2 or bcl-xl can inhibit the activation of bax following a death signal.

SIGNOR-59141

Q8NG27

P15172

0

transcriptional regulation

up-regulates quantity

0.2

... chromatin immunoprecipitation (ChIP) analysis showed MYOD binds to a site upstream the Pja1 promoter preferentially in C2C12 cells induced to differentiate (Fig. 2c). In addition, over-expression of MyoD in human fibroblasts is sufficient to up-regulate Pja1 expression

SIGNOR-255718

P54764

P20827

2

binding

up-regulates

0.823

Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor

SIGNOR-52087

O95835

Q16635

1

phosphorylation

down-regulates activity

0.387

When the inhibitory Hippo kinase module is ' on ', LATS1 and LATS2 phosphorylate and inactivate YAP and TAZ, and the output gene production is therefore turned off.|When the inhibitory Hippo kinase module is \u2018on\u2019, LATS1 and LATS2 phosphorylate and inactivate YAP and TAZ, and the output gene production is therefore turned off.

SIGNOR-279200

P27361

P05976

1

phosphorylation

up-regulates

0.287

Activation of raf/mek/erk cascade can also result in the phosphorylation of the antiapoptotic mcl-1 protein and the pro-apoptotic bim protein.

SIGNOR-148002

Q15759

Q06413

1

phosphorylation

up-regulates activity

0.538

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-280025

P35222

O60907

2

binding

up-regulates activity

0.659

TBL1 appears to serve two roles in regulating the activity of β-catenin. Besides the initially identified role of TBL1 in recruiting β-catenin to the SCF(TBL1) complex, it has also been shown to function as a transcriptional co-activator of β-catenin in recruiting it to the promoter site of Wnt target genes. Our results indicated that TBL1 can inhibit the polyubiquitination of β-catenin by Siah-1 in vitro (Fig. 3) and stabilize β-catenin in cells by protecting it from Siah-1-mediated ubiquitination and proteasomal degradation (Fig. 4).

SIGNOR-271954

O00418

O15264

0

phosphorylation

down-regulates activity

0.578

eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta. eEF2K[S359A] was phosphorylated (presumably at Ser396) by the high concentrations of SAPK4/p38 used in this experiment. However, the inhibition of eEF2K under these conditions was reduced from 82% in the wild-type enzyme to 19% in eEF2K[S359A]

SIGNOR-250089

O15264

Q6JBY9

1

phosphorylation

down-regulates activity

0.419

CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.

SIGNOR-263084

P16104

Q99504

0

dephosphorylation

down-regulates

0.2

Tyr142 is dephosphorylated by the tyr phosphatases eya1 and eya3.

SIGNOR-168927

P54646

Q13085

1

phosphorylation

down-regulates

0.697

Significant negative linear correlations between phospho-acc and acc activity were observed in all models (p < 0.01). The decline in acc activity was related to the decrease in pcr and the rise in amp. A relationship between phospho-ampk (threonine 172) and activity of ampk immunoprecipitated with anti-alpha(2) subunit antibody preparation was also observed.

SIGNOR-87583

Q13561

O43264

0

relocalization

up-regulates activity

0.685

ZW10 interacts with dynamitin, a subunit of the dynein-dynactin complex (Echeverri et al., 1996), thereby recruiting this motor to kinetochores

SIGNOR-265016

Q9BYB0

Q9P1A6

0

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-264591

P34925

O14640

2

binding

up-regulates

0.483

Ryk also binds to dishevelled, through which it activates the canonical wnt, providing a link between wnt and dishevelled.

SIGNOR-129568

Q13459

P60953

1

gtpase-activating protein

down-regulates activity

0.562

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-260511

P23443

Q13362

2

binding

down-regulates

0.341

The human homolog of pp2a-b', ppp2r5c, also counteracts s6k1 phosphorylation, indicating a conserved mechanism in mammals

SIGNOR-165224

P42575

Q96GD4

0

phosphorylation

up-regulates activity

0.244

Furthermore, in vitro phosphorylation using GST-Casp2 363-423 WT or S384A confirmed that S384 of caspase-2 is phosphorylated by AURKB.

SIGNOR-279496

P16066

P01160

2

binding

up-regulates

0.887

Natriuretic peptide receptor-a (npra) is the biological receptor of the peptide hormones atrial natriuretic peptide (anp) and brain natriuretic peptide (bnp)

SIGNOR-137600

P17612

Q15831

1

phosphorylation

up-regulates activity

0.502

Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell growth.

SIGNOR-250055

P43694

Q4G0P3

0

transcriptional regulation

up-regulates quantity by expression

0.2

HYDIN promotes expression of Gata4 in cardiomyocyte differentiation. HYDIN functions as a positive regulator of human cardiomyocyte differentiation and promotes expression of cardiac contractile genes in hESC cells. This is mediated through GATA4, a critical transcription factor in heart development. Cardiac-specific Hydin knockdown in vivo leads to Gata4 downregulation and enhanced atrial septal defect (ASD) risk in mice. GATA4 is a fundamental TF in embryonic heart development and cardiac differentiation, and reduction in GATA4 function results in a diverse range of CHDs

SIGNOR-265479

P17252

P46940

1

phosphorylation

up-regulates

0.258

Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth.

SIGNOR-128714

P09874

Q9UGL1

1

relocalization

up-regulates activity

0.354

The mechanism of KDM5B recruitment is quite specific and requires the presence of nucleosomes containing histone variant MacroH2A1.1 and PARylation by PARP1.

SIGNOR-271574

Q96B36

P31751

0

phosphorylation

down-regulates

0.674

Insulin-stimulated phosphorylation of pras40 by akt/pkb suppresses its mtorc1 inhibitory activity.

SIGNOR-153931

P48730

O14641

1

phosphorylation

up-regulates

0.534

Ck1_/__dependent phosphorylation of dvl2 at s143 and t224and that this event is critical to interact with plk1 in early stages of the cell cycle

SIGNOR-197547

Q9NR61

P46531

2

binding

up-regulates activity

0.644

Expression analysis of known notch ligands suggests that dll4 is the only ligand that exhibits spatial and temporal expression consistent with the activation of notch1 and notch4 during vascular development. The identification of dll4 reveals a candidate ligand for notch receptors involved in blood vessel biology

SIGNOR-112649

Q9UKM9

Q99873

1

post transcriptional regulation

up-regulates quantity

0.247

RALY binds poly-U rich elements within several RNAs and regulates the expression as well as the stability of specific transcripts. Here we show that RALY binds PRMT1 mRNA and regulates its expression.|We demonstrate that RALY down-regulation decreases protein arginine N-methyltransferase 1 levels

SIGNOR-262273

Q6NUQ1

Q92878

2

binding

up-regulates activity

0.471

We propose that p130, forming a complex with Rad50 through RINT-1, blocks telomerase-independent telomere lengthening in normal cells.

SIGNOR-265030

P11678

P10153

1

post translational modification

up-regulates activity

0.476

Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism.

SIGNOR-261704

Q13315

P53350

1

phosphorylation

down-regulates activity

0.429

Indeed Chk2 mediates the degradation of Cdc25A to activate the S-phase checkpoint [5\u20137,18] , whereas ATM phosphorylates and inactivates Plk1, consolidating the delay in the entry into M phase [5\u201319] .|Indeed Chk2 mediates the degradation of Cdc25A to activate the S-phase checkpoint [5-7,18], whereas ATM phosphorylates and inactivates Plk1, consolidating the delay in the entry into M phase [5-19].

SIGNOR-279793

P05067

P53779

0

phosphorylation

up-regulates

0.582

Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in sh-sy5y neuroblastoma cells. is regulated by jnk3 via phosphorylation of app at thr668

SIGNOR-204671

Q13077

P20333

2

binding

up-regulates

0.72

Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2.

SIGNOR-33133

O75602

Q92949

0

transcriptional regulation

up-regulates quantity by expression

0.447

FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).

SIGNOR-266935

O60486

Q86YJ5

0

ubiquitination

down-regulates quantity by destabilization

0.2

MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.

SIGNOR-271532

Q13887

P49841

0

phosphorylation

down-regulates

0.368

Stability of the klf5 is mediated by proteasomal degradation via phosphorylation by glycogen synthase kinase 3_ (gsk3_) and recognition by f-box and wd repeat domain-containing 7 (fbw7) of a phosphodegron sequence surrounding serine 303 in klf5

SIGNOR-203627

Q969T9

P12931

0

phosphorylation

up-regulates activity

0.297

Using dominant-negative, constitutively active mutants, RNAi, and pharmacological studies, we demonstrated that phosphorylation of WBP2 at Tyr192 and Tyr231 could be regulated by c-Src and c-Yes kinases.We further showed that abrogating WBP2 phosphorylation impaired >60% of ERα reporter activity, putatively by blocking nuclear entry of WBP2 and its interaction with ERα.

SIGNOR-273567

Q07889

P19174

2

binding

up-regulates

0.647

We provide evidence that sos1, a p21ras-specific guanine nucleotide exchange factor, directly binds to the sh3 domain of plc-gamma1, and that the sh3 domain of plc-gamma1 is involved in sos1-mediated p21ras activation.

SIGNOR-80024

P31749

Q96QF0

1

phosphorylation

up-regulates activity

0.2

Rabin8 is phosphorylated and activated by Akt in cells grown on stiff ECM.

SIGNOR-277802

Q70E73

P50552

2

binding

up-regulates activity

0.578

Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins.

SIGNOR-268426

Q8IU81

P14316

2

binding

up-regulates activity

0.692

We have identified two novel proteins that interact specifically with the C-terminal repression domain of Interferon Regulatory Factor-2 (IRF-2). These proteins, which we term IRF-2 binding proteins 1 and 2 (IRF-2BP1 and IRF-2BP2, the latter having two splicing isoforms, A and B), are nuclear proteins, and have the properties of IRF-2-dependent transcriptional co-repressors that can inhibit both enhancer-activated and basal transcription in a manner that is not dependent upon histone deacetylation.

SIGNOR-224045

P23467

Q9UM73

1

dephosphorylation

down-regulates

0.334

Rptpbeta/zeta dephosphorylates alk at the site(s) in alk that is undergoing autophosphorylation through autoactivation.

SIGNOR-157175

Q9NS28

P17612

0

phosphorylation

up-regulates activity

0.2

Cyclic AMP- and cyclic GMP-dependent kinases (PKA, PKG) inhibit the interaction of RGS18 and 14-3-3 by phosphorylating S216.

SIGNOR-273786

Q13153

Q13352

1

phosphorylation

up-regulates

0.2

Serine 28 phosphorylation of nrif3 confers its co-activator function for estrogen receptor-alpha transactivation. p21-activated protein kinase 1 (pak1) phosphorylates eralpha at ser305 and this modification is important in eralpha transactivation function.

SIGNOR-178795

P63000

Q9H0H5

0

gtpase-activating protein

down-regulates activity

0.586

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-260512

P10586

Q9NT99

2

binding

up-regulates activity

0.617

The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively.

SIGNOR-264049

Q06124

P21802

1

dephosphorylation

down-regulates activity

0.622

In forming this heterotetrameric complex Grb2 inhibits both the dephosphorylation of FGFR2 by Shp2 and the phosphorylation of Shp2 by FGFR2 (XREF_FIG, respectively).|Knockdown of Grb2 elevates Shp2 phosphorylation (XREF_FIG), strongly suggesting that the inability of Shp2 to interact directly with the receptor in the presence of Grb2 prevents FGFR2 kinase activity toward Shp2.

SIGNOR-277030

P45983

Q13469

1

phosphorylation

down-regulates

0.752

Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin jnk directly regulated nuclear factor of activated t-cell (nfat) activation in culture and in transgenic mice containing an nfat-dependent luciferase reporter.

SIGNOR-118217

P04035

Q86TM6

0

polyubiquitination

down-regulates quantity by destabilization

0.562

In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation.Human HRD1 appears to be involved in the basal degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase but not in the degradation that is regulated by sterols.

SIGNOR-272594

O00566

Q96G21

2

binding

up-regulates activity

0.818

Mpp10 represents a platform for the interaction of multiple factors within the 90S pre-ribosome. In eukaryotes, ribosome assembly is a highly complex process that involves more than 200 assembly factors that ensure the folding, modification and processing of the different rRNA species as well as the timely association of ribosomal proteins. One of these factors, Mpp10 associates with Imp3 and Imp4 to form a complex that is essential for the normal production of the 18S rRNA.

SIGNOR-261174

P09651

P01106

0

transcriptional regulation

up-regulates quantity by expression

0.456

We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2,

SIGNOR-268690

Q16539

Q14790

1

phosphorylation

down-regulates

0.55

P38-mapk can directly phosphorylate and inhibit the activities of caspase-8

SIGNOR-122103

Q07869

Q7Z6Z7

0

ubiquitination

down-regulates quantity by destabilization

0.2

Furthermore, the E3 ubiquitin ligase HUWE1 was identified to mediate PPARalpha polyubiquitination.|This notion is also supported by our finding that Huwe1 knockdown up-regulated the expression of PPARalpha target genes at the cellular level.

SIGNOR-278814

Q86XI6

P13807

2

binding

up-regulates

0.714

In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2)

SIGNOR-271734

Q7Z6Z7

P04198

1

ubiquitination

down-regulates quantity by destabilization

0.423

HUWE1 ubiquitinates and directs MYCN degradation to the proteasome.

SIGNOR-278750

P49810

P55212

0

cleavage

up-regulates activity

0.363

In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329.

SIGNOR-261750

Q13761

Q00987

0

ubiquitination

down-regulates quantity by destabilization

0.579

RUNX3 protein is ubiquitinated by MDM2 at Lys-94 and Lys-148.|RUNX3 protein is ubiquitinated by MDM2 at Lys 94 and Lys 148.|MDM2 suppresses the transcriptional activity of RUNX3.

SIGNOR-278557

Q53HL2

P33981

0

phosphorylation

up-regulates

0.461

First, we confirmed that wild-type borealin is phosphorylated at the previously described sites t88, t94, t169, and t230 when present in complex with survivin borealin might be a substrate for mps1. In the case of wild-type borealin, the fast exchange between the monomeric and dimeric forms may allow mps1 to phosphorylate the monomer. In turn, mps1 may regulate borealin function by unfolding the c-terminal domain and/or shifting the population to the monomeric form.

SIGNOR-186151

P24941

P30291

2

null

down-regulates quantity by destabilization

0.666

PS123 primes CK2 to phosphorylate S121, resulting in creation of a β-TrCP phosphodegron (EEGFGpS121) that is responsible for the instability of Wee1A during interphase.

SIGNOR-276039

Q9UP95

Q9BYP7

0

phosphorylation

down-regulates activity

0.464

We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs

SIGNOR-264627

P40763

P16591

0

phosphorylation

up-regulates activity

0.402

Replacing the unique 43-amino acid-long N-terminal tail of p51 (ferT) with a parallel segment from the N-terminal tail of p94 (fer) did not change the subcellular localization of p51 (ferT) but enabled it to activate Stat3.|When combined with immunoprecipitation analysis, this assay showed that p94 (fer) can lead to the tyrosine phosphorylation and activation of Stat3 but not of Stat1 or Stat2.

SIGNOR-279713

P49023

P12931

0

phosphorylation

up-regulates activity

0.808

Here, we demonstrate that Src kinase directly phosphorylates Y88 paxillin|In this study, we also show how pY88 paxillin transduces a signal to activate Akt

SIGNOR-263977

P05305

P24530

2

binding

up-regulates

0.946

Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors.

SIGNOR-145762

P11831

Q9UQM7

0

phosphorylation

up-regulates activity

0.369

Skeletal muscle CaMKII enriches in nuclei and phosphorylates myogenic factor SRF at multiple sites. | Microsequencing of these phosphorylated peptides identified that both Ser-103 and a novel residue, Thr-160 in the MADS box of SRF, were sites of phosphorylation. | The location of Thr-160 in the 3-D structure of SRF suggests that its phosphorylation by nuclear CaMKII may directly influence DNA binding of SRF and other MADS box factors.

SIGNOR-250639

Q00978

P48551

2

binding

up-regulates activity

0.727

By binding to IFNalphaR2 within the region where two adjacent proline boxes bear phospho-Ser364 and phospho-Ser384, CBP acetylates IFNalphaR2 on Lys399, which in turn serves as the docking site for interferon regulatory factor 9 (IRF9)RF9 interacts with the acetyl-Lys399 motif by means of its IRF homology2 (IH2) domain, leading to formation of the ISGF3 complex that includes IRF9, STAT1, and STAT2.

SIGNOR-217779

Q7L591

P07948

0

phosphorylation

up-regulates activity

0.409

An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling.

SIGNOR-268447

P09429

P31249

2

binding

up-regulates activity

0.298

We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein.

SIGNOR-219980

Q8TD08

P05412

1

phosphorylation

up-regulates

0.428

Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein. these data suggest that erks, rather than jnks, are required for c- jun up-regulation.

SIGNOR-91375

Q13490

O43353

1

polyubiquitination

up-regulates activity

0.652

CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.

SIGNOR-272712

P53350

P78527

2

phosphorylation

up-regulates activity

0.425

Moreover, PLK1 phosphorylates DNA-PKcs directly on Ser 3205 invitro, suggesting that DNA-PKcs Ser 3205 is a direct target of PLK1 in mitosis.

SIGNOR-278188

P67775

P05771

1

dephosphorylation

down-regulates activity

0.446

Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme.

SIGNOR-248620

O60315

P0C2W1

2

binding

down-regulates quantity by destabilization

0.362

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

SIGNOR-272180

Q16236

Q13131

0

phosphorylation

up-regulates activity

0.2

MS-based analysis of immunoprecipitated Nrf2 revealed serine 374, 408 and 433 in human Nrf2 to be hyperphosphorylated as a function of activated AMPK. A direct phosphate-transfer by AMPK to those sites was indicated by in vitro kinase assays with recombinant proteins as well as interaction of AMPK and Nrf2 in cells, evident by co-immunoprecipitation. Mutation of serine 374, 408 and 433 to alanine did not markedly affect half-life, nuclear accumulation or induction of reporter gene expression upon Nrf2 activation with sulforaphane. However, some selected endogenous Nrf2 target genes responded with decreased induction when the identified phosphosites were mutated, whereas others remained unaffected.

SIGNOR-277496

P06493

Q15116

1

phosphorylation

down-regulates quantity by destabilization

0.2

We demonstrated that cyclin-dependent kinase 1-mediated phosphorylation of Ser261 residue primes PD-1 protein nucleus translocation and binding with FBW7.

SIGNOR-277605

O43464

P98170

2

binding

down-regulates

0.709

Here we report that a serine protease called htra2/omi is released from mitochondria and inhibits the function of xiap by direct binding in a similar way to diablo.

SIGNOR-110834

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

Q7Z5J4

O15516

1

transcriptional regulation

up-regulates quantity by expression

0.479

RAI1 Transcriptionally Activates CLOCK via an Intron 1 Enhancer Element. data suggest that RAI1 binds, directly or in a complex, to the first intron of CLOCK and enhances its transcriptional activity in vitro, supporting RAI1 as a positive regulator of CLOCK and an important part of the circadian loop of transcription. Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others.

SIGNOR-266839

Q9NP80

Q9BUB5

0

phosphorylation

up-regulates activity

0.2

Constitutively active MNK1 activates and phosphorylates iPLA2γ. Thus, complement-mediated activation of iPLA(2)γ is mediated via ERK and p38 pathways, and phosphorylation of Ser-511 and/or Ser-515 plays a key role in the catalytic activity and signaling of iPLA(2)γ.

SIGNOR-273677

P24071

P67775

0

dephosphorylation

up-regulates activity

0.323

Furthermore, FcalphaRI activation is induced by protein phosphatase 2A (PP2A) after it dephosphorylates a single serine residue (S263) in the FcalphaRI intracellular tail

SIGNOR-264858

Q99558

O15111

2

phosphorylation

up-regulates activity

0.698

Once activated by autophosphorylation, nik activates ikkalpha, which in turn phosphorylates nf-kb2. This stimulates limited proteasome-mediated proteolysis of nf-kb2 to p52. Removal of the carboxy-terminal ankyrin repeats from nf-kb2 releases the p52/RELB heterodimer, allowing its translocation to the nucleus where it instigates the expression of nf-kb target genes.

SIGNOR-167060

O14503

P48729

0

phosphorylation

down-regulates quantity by destabilization

0.2

CK1α-mediated phosphorylation of DEC1 on a conserved degron is required for DEC1 degradation.

SIGNOR-276851

Q9BT81

Q9HCK8

0

transcriptional regulation

down-regulates quantity

0.2

Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells

SIGNOR-268922

Q9HCE7

Q96AC1

1

ubiquitination

down-regulates quantity by destabilization

0.2

Smurf1 mediates Kindlin-2 proteasomal degradation.|Smurf1 promotes polyubiquitination of Kindlin-2.

SIGNOR-278614

P49327

O15379

0

deacetylation

up-regulates quantity by stabilization

0.2

Overexpression of HA-HDAC3 decreased the acetylation level of endogenous FASN by 35% in HEK293T cells, while the expression of a catalytic inactive mutant HDAC3Y298H (38) failed to reduce FASN acetylation (Fig. 4C). Conversely, HDAC3 knockdown increased the acetylation level of endogenous FASN by >1.5-fold in HEK293T cells

SIGNOR-267367

Q04760

P07947

0

phosphorylation

up-regulates activity

0.2

We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).

SIGNOR-276185