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
O95153	Q9UJD0	2	binding	down-regulates activity	0.2	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-264373
P53350	Q8NFH5	1	phosphorylation	down-regulates activity	0.415	Collectively, these data show that mitotic hyperphosphorylation of Nup53 by CDK1 and PLK1 contributes to its removal from NPCs.\|The combined mutation of the CDK1 and PLK1 sites to phosphomimetic residues almost completely abolished NPC integration of Nup53, indicating that hyperphosphorylation of Nup53 might be incompatible with its NPC association.	SIGNOR-279252
P49286	P08754	2	binding	up-regulates activity	0.452	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-256850
Q15796	P12757	2	binding	down-regulates activity	0.801	The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway	SIGNOR-236099
Q01726	Q8IUH4	0	palmitoylation	up-regulates activity	0.274	Collectively these results suggest that ZDHHC13 phosphorylation by ATR following UVB irradiation promotes its interaction with MC1R to stimulate MC1R palmitoylation.Activating MC1R palmitoylation rescues the defect of MC1R RHC variants	SIGNOR-273518
P46531	Q13233	0	phosphorylation	down-regulates activity	0.367	As a result, MEKK1 suppresses the Notch1 intracellular domain protein stability and transcriptional activity.\|We confirmed that MEKK1 binds to Notch1 intracellular domain and phosphorylates the Notch1 intracellular domain Threonine 2512 residue.	SIGNOR-279628
Q13114	P49674	0	phosphorylation	up-regulates activity	0.307	CK1ɛ interacted with and phosphorylated TRAF3 at Ser349, which thereby promoted the Lys63 (K63)-linked ubiquitination of TRAF3 and subsequent recruitment of the kinase TBK1 to TRAF3.	SIGNOR-277212
P54829	Q7L9L4	1	dephosphorylation	up-regulates activity	0.2	PTPN5 dephosphorylates\nMob1a at Y26 residue.	SIGNOR-277058
Q06124	P17612	0	phosphorylation	down-regulates activity	0.451	We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity.	SIGNOR-276891
O43312	P48730	0	phosphorylation	down-regulates quantity by destabilization	0.327	Mechanistically, we defined that Casein Kinase Iδ (CKIδ) phosphorylates Ser322 to trigger MTSS1's interaction with β-TRCP for subsequent ubiquitination and degradation.	SIGNOR-276611
P04637	P21675	0	phosphorylation	down-regulates	0.681	Phosphorylation on thr-55 by taf1 mediates degradation of p53	SIGNOR-123651
P60510	O15379	1	dephosphorylation	down-regulates activity	0.379	Here we demonstrate that, in addition to protein-protein interactions with NCoR/SMRT, the activity of HDAC3 is regulated by both phosphorylation and dephosphorylation. A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity.\|Significantly, both overexpression and siRNA knock-down approaches, and analysis of cells devoid of PP4c, unequivocally show that HDAC3 activity is inversely proportional to the cellular abundance of PP4(c).	SIGNOR-248548
Q8TD08	Q8TD08	2	phosphorylation	up-regulates	0.2	Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif.Our results suggest that the activity of erk8 in transfected hek-293 cells depends on the relative rates of erk8 autophosphorylation	SIGNOR-142969
P17612	P23677	1	phosphorylation	up-regulates activity	0.327	Two isoforms of the inositol 1,4,5-trisphosphate 3-kinase have been identified, the A form and the B form. phosphorylation of isoform A by the cyclic AMP-dependent protein kinase increased activity 1.5-fold, whereas phosphorylation of isoform B decreased activity by 45%. major phosphorylation sites in the protein are Ser119 for PKA. Ser119 in the A isoform is conserved in the B isoform as Ser328	SIGNOR-249994
Q9P219	P54792	2	binding	up-regulates	0.2	Daple binds to dvl and functions as a negative regulator of the wnt signalling pathway.	SIGNOR-199448
Q02750	P35568	1	phosphorylation	down-regulates	0.352	Thus, at least three kinases mediate phosphorylation of ser307, including jnk, serine kinases in the pi 3-kinase cascade that are activated byinsulinor igf-1, and mek1-sensitive kinase cascades during tnf-alfa stimulation.	SIGNOR-236611
Q13153	Q96P20	1	phosphorylation	up-regulates activity	0.2	Pak1 phosphorylates NLRP3 to promote inflammasome activation.	SIGNOR-277547
P01574	O15226	0	transcriptional regulation	down-regulates quantity by repression	0.358	Constitutive silencing of IFN-beta promoter is mediated by NRF (NF-kappaB-repressing factor), a nuclear inhibitor of NF-kappaB	SIGNOR-266227
O14757	Q13263	1	phosphorylation	up-regulates activity	0.282	These data suggested that KAP1 Ser473 phosphorylation by Chk1 and Chk2 does not take place predominantly at sites of DNA damage, and are consistent with previous work indicating that, following their DNA-damage-localized phosphorylation and activation by ATR and ATM, Chk1 and Chk2 dissociate from chromatin to phosphorylate their substrates , ].\|These results therefore indicated that both Chk1 and Chk2 can target KAP1 Ser473, and are in agreement with IR triggering both the ATM and Chk2 and ATR and Chk1 pathways .	SIGNOR-280226
Q16650	Q8WXX7	1	transcriptional regulation	up-regulates quantity by expression	0.359	Tbr1 implements frontal identity in part by direct promoter binding and activation of Auts2, a frontal cortex gene implicated in autism.	SIGNOR-266836
O95235	Q9HC98	0	phosphorylation	down-regulates activity	0.347	We show that Nek9, Nek6, and the kinesin Mklp2 form a signaling module, which is required for Mklp2 to localize to the central spindle in anaphase. Nek6 also phosphorylates Mklp2 at Ser244, inhibiting its bundling activity until anaphase onset.	SIGNOR-273891
P51787	Q13557	0	phosphorylation	down-regulates activity	0.2	CaMKII regulates KCNQ1 at S484 during sustained β-AR stimulation to inhibit IKs. The ability of CaMKII to inhibit IKs may contribute to arrhythmogenicity during HF.	SIGNOR-275479
P00558	O15530	2	phosphorylation	up-regulates activity	0.2	PGK1 is an important enzyme in the metabolic glycolysis pathway, but PGK1 also phosphorylates and activates PDK1 through its protein kinase activity ( xref ).\|PGK1 is an important enzyme in the metabolic glycolysis pathway, but PGK1 also phosphorylates and activates PDK1 through its protein kinase activity.	SIGNOR-280064
P84022	P24941	0	phosphorylation	down-regulates activity	0.743	In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity	SIGNOR-182971
Q09472	Q9HCU9	0	ubiquitination	down-regulates quantity by destabilization	0.363	BRMS1 suppresses lung cancer metastases through an E3 ligase function on histone acetyltransferase p300. BRMS1 induces polyubiquitination of p300, resulting in its proteasome-mediated degradation.	SIGNOR-266408
P05023	Q05513	0	phosphorylation	up-regulates activity	0.2	Na,K-ATPase alpha(1) subunit was phosphorylated by PKC in hypoxia-treated AEC. In AEC treated with a PKC-zeta antagonist peptide or with the Na,K-ATPase alpha(1) subunit lacking the PKC phosphorylation site (Ser-18), hypoxia failed to decrease Na,K-ATPase abundance and function.	SIGNOR-263181
P14598	P31749	0	phosphorylation	up-regulates	0.559	Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. A direct interaction between p47(phox) and akt was shown. Active recombinant akt phosphorylated recombinant p47(phox) in vitro. Mutation analysis indicated that 2 aa residues, ser(304) and ser(328), were phosphorylated by akt. Inhibition of akt activity also inhibited fmlp-stimulated neutrophil chemotaxis.	SIGNOR-252586
P51674	P17252	0	phosphorylation	up-regulates activity	0.324	In summary, a CNS neuron-specific membrane glycoprotein, M6a, could act as a novel NGF-gated Ca2+ channel through the phosphorylation with PKC and augments [Ca2+]i in M6a-S cells.	SIGNOR-263163
O15534	P48730	0	phosphorylation	down-regulates quantity by destabilization	0.807	Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2. We have now extended our previous studies to show that human casein kinase Idelta (hCKIdelta), the closest homologue to hCKIepsilon, associates with and phosphorylates hPER1 and causes protein instability. Furthermore, we observed that both hCKIdelta and hCKIepsilon phosphorylated and caused protein instability of human period 2 protein (hPER2).	SIGNOR-268001
Q9Y2H0	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-264597
P00533	Q9BV68	0	polyubiquitination	down-regulates quantity by destabilization	0.328	RNF126 and Rabring7 associate with the EGFR through a ubiquitin-binding zinc finger domain and both E3 ubiquitin ligases promote ubiquitylation of EGFR. In HeLa cells depleted of either RNF126 or Rabring7 the EGFR is retained in a late endocytic compartment and is inefficiently degraded.	SIGNOR-272103
P00533	Q04912	1	phosphorylation	up-regulates activity	0.334	This showed that EGFR activation transphosphorylated Ron.\|Together, these data suggested that (1) Ron activation transphosphorylated EGFR and vice versa and (2) activated Ron biochemically interacted with EGFR.	SIGNOR-280000
P45983	Q92934	1	phosphorylation	down-regulates	0.686	Jnk phosphorylates bad at threonine 201, thereby inhibiting bad association with the antiapoptotic molecule bcl-x(l)	SIGNOR-121940
Q96K19	Q14571	1	polyubiquitination	down-regulates activity	0.331	In summary, here we present evidence that RNF170 is an E3 ligase that mediates IP3 receptor ubiquitination and processing by the UPP and that it is recruited to activated IP3 receptors by the erlin1/2 complex to which it is constitutively bound.	SIGNOR-271914
Q00535	P04637	1	phosphorylation	up-regulates	0.732	We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 cdk5-stabilized p53 protein is transcriptionally active	SIGNOR-156422
Q9UHF4	Q9NPH9	2	binding	up-regulates	0.601	The mrna expression level of il10, il19, il20, il22, il24, il26, il28b, il29 and their receptors il10ra, il10rb, il20ra, il20rb, il22ra1, il22ra2, il28ra was compared in skin biopsies of children and adults and in childrens' skin cells by quantitative real-time pcr (qrt-pcr).	SIGNOR-151920
O15294	P46937	1	glycosylation	up-regulates activity	0.283	Mass spectrometry analysis showed that YAP was the effector protein modified by OGT. In details, YAP Ser109 O-GlcNAcylation promoted the malignant phenotypes in PTC cells by inducing YAP Ser127 dephosphorylation and activation.	SIGNOR-276942
P08648	Q9BTC0	0	transcriptional regulation	up-regulates quantity by expression	0.2	Dido1 upregulates the expression of Integrin αV, thereby influencing the attachment, apoptosis and migration of melanoma cells.	SIGNOR-261580
Q9H0K1	Q15078	1	phosphorylation	down-regulates	0.331	Sik2 phosphorylates p35 at ser 91, to trigger its ubiquitylation by pja2 and promote insulin secretion. _-cell knockout of sik2 leads to accumulation of p35 and impaired secretion	SIGNOR-204648
P35813	P27986	1	dephosphorylation	up-regulates activity	0.324	Protein phosphatase-2C alpha as a positive regulator of insulin sensitivity through direct activation of phosphatidylinositol 3-kinase in 3T3-L1 adipocytes\|PP2Cα dephosphorylates the p85 subunit of PI3K, and dephosphorylation of the p85 subunit of PI3K at Ser608 increases its activity	SIGNOR-248489
Q04759	P35568	1	phosphorylation	down-regulates activity	0.567	Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101).	SIGNOR-260906
P56279	P31749	2	binding	up-regulates	0.825	Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation	SIGNOR-81680
Q9Y458	P56178	1	transcriptional regulation	down-regulates quantity by repression	0.307	the main function of TBX22 as shown in misexpression experiments is to decrease proliferation. We subsequently uncovered three targets of TBX22, DLX5, MSX2, and TBX22 itself. All are downregulated in the presence of viral-derived hTBX22.	SIGNOR-265566
Q9UNE7	P06730	1	ubiquitination	down-regulates quantity by destabilization	0.332	This collaborative activity of cIAP1 and CHIP directs eIF4E toward degradation, controlling its levels and suppressing tumorigenesis.\|We next sought to investigate whether eIF4E ubiquitination is enhanced by the collaborative activity of cIAP1 and CHIP, which we define as both the E3 ligase activity of cIAP1 alone and the E3 ligase activity of cIAP1 and CHIP together.	SIGNOR-278669
P19429	P17252	0	phosphorylation	up-regulates activity	0.343	In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. \| Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation.	SIGNOR-249066
P06239	Q99704	1	phosphorylation	up-regulates activity	0.6	Phosphorylation of p56 dok and p62 dok is increased following CD2 stimulation and requires Lck. Phosphorylation of Dok proteins by Lck might provide a mechanism by which SH2-containing proteins can be recruited and co-localized with their substrates.	SIGNOR-251373
Q9Y5G5	Q9Y5H9	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-265680
P12755	P84022	2	binding	down-regulates activity	0.728	Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling.	SIGNOR-232123
O60729	Q15572	1	dephosphorylation	up-regulates activity	0.2	Consistent with prior studies showing that the phosphatase hCdc14B regulates progression through mitosis by counteracting mitotic phosphorylation by Cdk1/cyclin B [ ], hCdc14B dephosphorylates TAFI110, thus promoting its reactivation as cells exit mitosis.\|Here we show that hCdc14B, the phosphatase that regulates Cdk1/cyclin B activity and progression through mitosis, promotes reactivation of rDNA transcription by dephosphorylating TAFI110.	SIGNOR-277135
Q9NQC7	O15111	0	phosphorylation	up-regulates activity	0.544	The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.	SIGNOR-204692
Q15797	Q13485	1	phosphorylation	up-regulates	0.671	Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common(co-Smad; Smad4 in mammals) and shuttle into the nucleus.	SIGNOR-168734
P30968	O95837	2	binding	up-regulates activity	0.478	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-257331
P38405	Q99677	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
P00533	P42224	1	phosphorylation	up-regulates	0.738	The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation	SIGNOR-235689
P01127	P09619	2	binding	up-regulates	0.906	Pdgf-b activates both pdgfr-alpha and pdgfr-beta	SIGNOR-107400
Q13535	O60934	1	phosphorylation	up-regulates	0.785	We demonstrate that mrn and atr/atr-interacting protein (trip) interact with each other, and the forkhead-associated/breast cancer c-terminal domains (fha/brct) of nbs1 play a significant role in mediating this interaction. Mutations in the fha/brct domains do not prevent atr activation but specifically impair atr-mediated nbs1 phosphorylation at ser-343, which results in a defect in the s-phase checkpoint.	SIGNOR-155214
P49281	O00308	0	ubiquitination	down-regulates quantity	0.299	Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2\|This promotes DMT1 ubiquitination and degradation by WWP2.	SIGNOR-268852
P51168	P28482	0	phosphorylation	down-regulates quantity by destabilization	0.29	Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4.	SIGNOR-249446
O43561	P06241	0	phosphorylation	up-regulates	0.749	Both lck and syk, phosphorylate the itam-like motifs on lat at y171y191, which is essential for induction of the interaction of lat with downstream signaling molecules such as grb2, plc-gamma1 and c-cbl, and for activation of mapk-erk.	SIGNOR-149174
Q13255	P17252	0	phosphorylation	down-regulates activity	0.385	Furthermore, we demonstrate that the selectivity of PKC action on receptor signaling rests on phosphorylation of a threonine residue located in the G protein-interacting domain of the receptor. Modification at Thr(695) selectively disrupts mGluR1alpha-G(q/11) interaction without affecting signaling through G(s).	SIGNOR-249043
Q9NQX3	O95166	2	binding	up-regulates activity	0.561	The GABA(A)R-associated protein GABARAP was found to bind to the gamma2 subunit of GABA(A)Rs. Here we show that GABARAP interacts with gephyrin in both biochemical assays and transfected cells. Our data indicate that GABARAP-gephyrin interactions are not important for postsynaptic GABA(A)R anchoring but may be implicated in receptor sorting and/or targeting mechanisms.	SIGNOR-264971
Q0VAM2	P01116	2	binding	up-regulates	0.297	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-183835
Q9Y5I3	P05556	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.	SIGNOR-265663
Q9BZL6	Q9UQL6	1	phosphorylation	up-regulates activity	0.295	Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67].	SIGNOR-275929
P63096	P28336	2	binding	up-regulates activity	0.268	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-257047
O75385	Q14457	1	phosphorylation	up-regulates activity	0.771	In the nucleation step of autophagy, The ULK1 complex phosphorylates and activates the Beclin-1-VPS34 complex.	SIGNOR-278503
Q15836	Q8NE79	2	binding	up-regulates activity	0.42	Taken together, these data demonstrate that Bves interacts with VAMP3 and facilitates receptor recycling both in vitro and during early development.	SIGNOR-237771
Q9UI95	Q9UM11	2	binding	down-regulates activity	0.544	The APC is activated in mitosis and G1 by CDC20 and CDH1, and inhibited by the checkpoint protein MAD2, a specific inhibitor of CDC20. We show here that a MAD2 homolog MAD2B also inhibits APC. MAD2B directly inhibits activation of APC by CDC20 and CDH1	SIGNOR-264902
P63096	Q15722	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-256691
Q9BY66	Q16695	1	demethylation	up-regulates activity	0.2	KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.	SIGNOR-264309
Q13627	O75688	0	dephosphorylation	down-regulates activity	0.236	In conclusion, our study demonstrates that DYRK1A autophosphorylates Ser258, the dephosphorylation target of PPM1B, and PPM1B negatively regulates DYRK1A activity.\|We found that PPM1B dephosphorylates DYRK1A at Ser258, contributing to the inhibition of DYRK1A activity.	SIGNOR-277108
P08559	Q9NTG7	0	deacetylation	down-regulates activity	0.48	SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells\|SIRT3 deacetylates PDHA1 lysine 321 (K321)	SIGNOR-267636
Q86UZ6	P15018	1	transcriptional regulation	up-regulates quantity by expression	0.2	ZBTB46 binds directly to the LIF regulatory sequence and enhances its transcription. Our study confirmed a novel positive association between ZBTB46 activity and LIF levels in prostate cancer tissues and cells. Under androgen regulation, low levels of ZBTB46 are an essential transcriptional factor for maintaining LIF-STAT3 signaling, while the loss of androgen signaling or inhibition of AR signaling causes LIF-enhanced therapeutic resistance and CRPC characteristics through the upregulation of ZBTB46. We also found that LIF activation drives malignant progression and NE-like reprogramming in prostate cancer by activating STAT3 signaling.	SIGNOR-277988
P40925	Q86X55	0	acetylation	down-regulates activity	0.355	Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer\|Arginine methylation at R248 negatively regulates MDH1 activity\|PRMT4/CARM1 methylates MDH1 at R248 and inhibits its dimerization	SIGNOR-267639
P49841	Q92837	2	phosphorylation	down-regulates activity	0.776	Protein kinase A (PKA) was found to phosphorylate Ser188 in vitro as well as in intact cells. Importantly, activation of endogenous cAMP-coupled beta-adrenergic receptors with norepinephrine stimulated the phosphorylation of FRAT1 at Ser188. GSK-3 was also able to phosphorylate FRAT1 at Ser188 and other residues in vitro or when overexpressed in intact cells. Phosphorylation of Ser188 by PKA inhibited the ability of FRAT1 to activate beta-catenin-dependent transcription.	SIGNOR-276057
P53350	P35568	1	phosphorylation	down-regulates activity	0.267	Phosphorylation of ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by mouse pelle-like kinase/interleukin-1 receptor-associated kinase\| irs-1 mutants s24d or s24e (mimicking phosphorylation at ser(24)) had impaired ability to associate with insulin receptors resulting in diminished tyrosine phosphorylation of irs-1 and impaired ability of irs-1 to bind and activate pi-3 kinase in response to insulin.	SIGNOR-135688
P04637	O15297	0	dephosphorylation	down-regulates activity	0.558	PPM1D binds Chk1 and dephosphorylates the ATR-targeted phospho-Ser 345, leading to decreased Chk1 kinase activity. PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair.	SIGNOR-248319
P25098	P12931	0	phosphorylation	up-regulates activity	0.2	Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq.	SIGNOR-266305
P17252	O60825	1	phosphorylation	up-regulates activity	0.439	The phosphorylation sites for both cAMP-dependent protein kinase and protein kinase C were located in a single peptide whose sequence was Arg-Arg-Asn-Ser-(P)-Phe-Thr-Pro-Leu-Ser-Ser-Ser-Asn-Thr(P)-Ile-Arg-Arg-Pro. The seryl residue nearest the N terminus was the residue specifically phosphorylated by cAMP-dependent protein kinase, whereas the threonine residue nearest the C terminus was phosphorylated by protein kinase C. \| Phosphorylation of bovine heart Fru-6-P,B-kinase by either protein kinase C or CAMP-dependent protein kinase results in activation of the enzyme.	SIGNOR-248844
Q86UZ6	P35558	1	transcriptional regulation	up-regulates quantity by expression	0.2	We identified LIF/ZBTB46 signalling as a key promoter of metabolic reprogramming and NE differentiation of PCa cells through interactions with PCK1. We showed that ZBTB46 directly upregulates the expression of PCK1 and NE marker gene through activation of LIF signalling.	SIGNOR-277987
Q9BUB5	Q9NP80	1	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
Q9HBW0	Q8WWY8	2	binding	up-regulates	0.293	When overexpressed in jurkat t cells, the edg4 protein mediated lpa-induced activation of a serum response element reporter gene with lpa concentration dependence (ec50 of 10 nm) and specificity.	SIGNOR-56093
P36888	Q06124	2	binding	up-regulates activity	0.525	Y599 was additionally found to interact with the protein tyrosine phosphatase SHP2 in a phosphorylation-dependent manner. As Y599F-Flt3-32D was unable to associate with and to phosphorylate SHP2 and since silencing of SHP2 in WT-Flt3-expressing cells mimicked the Y599F-Flt3 phenotype, we hypothesize that recruitment of SHP2 to pY599 contributes to FL-mediated Erk activation and proliferation.	SIGNOR-245057
Q9Y5I2	Q9Y5G4	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-265700
P05976	P27361	0	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
P61586	Q8N1W1	0	guanine nucleotide exchange factor	up-regulates activity	0.755	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-260546
P47900	P19086	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 ≥ -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-257273
Q08211	Q9ULX6	2	binding	up-regulates activity	0.544	We report evidence for a novel nuclear export signal in HAP95 and showed that the domains involved in RHA binding and nuclear localization are required for CTE activation. Finally, we showed that HAP95 synergizes significantly with RHA on CTE-mediated reporter gene expression and promotes nuclear export of unspliced mRNA in transfected cells. Taken together, these data support the proposal that HAP95 specifically facilitates CTE-mediated gene expression by directly binding to RHA.	SIGNOR-260950
Q15583	Q96J02	0	ubiquitination	up-regulates activity	0.2	Based on these observations, we suggest that a mechanism of protein stabilization might account for the accumulation of TGIF protein in response to TNF-alpha signaling.Next, we used three different approaches to investigate the possibility that Itch could contribute to the ability of TNF-alpha to promote TGIF stabilization.\|We also employed the experimental strategy combining the detection of monoubiquitinated and polyubiquitinated TGIF and found that mutation of K259 not only compromised monoubiquitination of TGIF by Itch but also enhanced its polyubiquitination.	SIGNOR-278817
P19544	O00592	1	transcriptional regulation	up-regulates quantity by expression	0.409	Binding of WT1 to conserved elements within the Podocalyxin gene promoter results in potent transcriptional activation, and the specific expression pattern of Podocalyxin in the developing kidney mirrors that of WT1 itself.	SIGNOR-252300
Q99873	Q9UKM9	0	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
Q8TE12	O14529	1	transcriptional regulation	up-regulates quantity by expression	0.285	Lmx1a drives Cux2 expression in the cortical hem through activation of a conserved intronic enhancer. Lmx1a knockdown abolishes activation of the Cux2 enhancer in the cortical hem	SIGNOR-263961
P63096	P25116	2	binding	up-regulates	0.402	Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13).	SIGNOR-196009
Q8WYQ5	Q13315	0	phosphorylation	up-regulates quantity by stabilization	0.27	Specifically, radiation-induced ATM-dependent phosphorylation of DGCR8 at serine 677 facilitates USP51 to bind, deubiquitinate, and stabilize DGCR8, which leads to the recruitment of DGCR8 and DGCR8's binding partner RNF168 to MDC1 and RNF8 at DSBs.	SIGNOR-277307
P24941	Q13416	1	phosphorylation	up-regulates	0.756	We also found that horc2p is phosphorylated in vitro by cyclin a/cdk2, specifically at residues thr116 and thr226. These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability.	SIGNOR-116364
P25098	P21731-2	1	phosphorylation	down-regulates activity	0.2	These data suggest a model whereby agonist-induced PKC phosphorylation of Ser(145) partially impairs TPbeta signalling while GRK2/3 phosphorylation at both Ser(239) and Ser(357) within its IC(3) and C-tail domains, respectively, sterically inhibits G-protein coupling, profoundly desensitizing signalling, and promotes beta-arrestin association and, in turn, facilitates TPbeta internalization.	SIGNOR-274088
P27448	Q05513	0	phosphorylation	down-regulates	0.2	Hpar-1a, t564, is phosphorylated in vivo and by apkc in vitro.This study establishes a novel functional link between two central determinants of cellular polarity, apkc and par-1, and suggests a model by which apkc may regulate par-1 in polarized cells	SIGNOR-124221
P12830	Q13363	0	transcriptional regulation	down-regulates quantity by repression	0.6	Carboxyl-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor with oncogenic potential. We found CtBP1 was recruited to the promoter regions of Brca1 and E-cadherin genes in breast cancer cells.	SIGNOR-259197
P27986	P01137	2	binding	up-regulates activity	0.258	While association of the TGF_RI receptor with p85 requires TGF-_ stimulation.	SIGNOR-217960
P68400	P18858	1	phosphorylation	up-regulates activity	0.34	Moreover, these data confirmed the occurrence of Ser66 phosphorylation, which was previously studied with a specific monoclonal antibody (23).	SIGNOR-103258

O95153

Q9UJD0

2

binding

down-regulates activity

0.2

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-264373

P53350

Q8NFH5

1

phosphorylation

down-regulates activity

0.415

Collectively, these data show that mitotic hyperphosphorylation of Nup53 by CDK1 and PLK1 contributes to its removal from NPCs.|The combined mutation of the CDK1 and PLK1 sites to phosphomimetic residues almost completely abolished NPC integration of Nup53, indicating that hyperphosphorylation of Nup53 might be incompatible with its NPC association.

SIGNOR-279252

P49286

P08754

2

binding

up-regulates activity

0.452

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-256850

Q15796

P12757

2

binding

down-regulates activity

0.801

The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway

SIGNOR-236099

Q01726

Q8IUH4

0

palmitoylation

up-regulates activity

0.274

Collectively these results suggest that ZDHHC13 phosphorylation by ATR following UVB irradiation promotes its interaction with MC1R to stimulate MC1R palmitoylation.Activating MC1R palmitoylation rescues the defect of MC1R RHC variants

SIGNOR-273518

P46531

Q13233

0

phosphorylation

down-regulates activity

0.367

As a result, MEKK1 suppresses the Notch1 intracellular domain protein stability and transcriptional activity.|We confirmed that MEKK1 binds to Notch1 intracellular domain and phosphorylates the Notch1 intracellular domain Threonine 2512 residue.

SIGNOR-279628

Q13114

P49674

0

phosphorylation

up-regulates activity

0.307

CK1ɛ interacted with and phosphorylated TRAF3 at Ser349, which thereby promoted the Lys63 (K63)-linked ubiquitination of TRAF3 and subsequent recruitment of the kinase TBK1 to TRAF3.

SIGNOR-277212

P54829

Q7L9L4

1

dephosphorylation

up-regulates activity

0.2

PTPN5 dephosphorylates\nMob1a at Y26 residue.

SIGNOR-277058

Q06124

P17612

0

phosphorylation

down-regulates activity

0.451

We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity.

SIGNOR-276891

O43312

P48730

0

phosphorylation

down-regulates quantity by destabilization

0.327

Mechanistically, we defined that Casein Kinase Iδ (CKIδ) phosphorylates Ser322 to trigger MTSS1's interaction with β-TRCP for subsequent ubiquitination and degradation.

SIGNOR-276611

P04637

P21675

0

phosphorylation

down-regulates

0.681

Phosphorylation on thr-55 by taf1 mediates degradation of p53

SIGNOR-123651

P60510

O15379

1

dephosphorylation

down-regulates activity

0.379

Here we demonstrate that, in addition to protein-protein interactions with NCoR/SMRT, the activity of HDAC3 is regulated by both phosphorylation and dephosphorylation. A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity.|Significantly, both overexpression and siRNA knock-down approaches, and analysis of cells devoid of PP4c, unequivocally show that HDAC3 activity is inversely proportional to the cellular abundance of PP4(c).

SIGNOR-248548

Q8TD08

2

phosphorylation

up-regulates

0.2

Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif.Our results suggest that the activity of erk8 in transfected hek-293 cells depends on the relative rates of erk8 autophosphorylation

SIGNOR-142969

P17612

P23677

1

phosphorylation

up-regulates activity

0.327

Two isoforms of the inositol 1,4,5-trisphosphate 3-kinase have been identified, the A form and the B form. phosphorylation of isoform A by the cyclic AMP-dependent protein kinase increased activity 1.5-fold, whereas phosphorylation of isoform B decreased activity by 45%. major phosphorylation sites in the protein are Ser119 for PKA. Ser119 in the A isoform is conserved in the B isoform as Ser328

SIGNOR-249994

Q9P219

P54792

2

binding

up-regulates

0.2

Daple binds to dvl and functions as a negative regulator of the wnt signalling pathway.

SIGNOR-199448

Q02750

P35568

1

phosphorylation

down-regulates

0.352

Thus, at least three kinases mediate phosphorylation of ser307, including jnk, serine kinases in the pi 3-kinase cascade that are activated byinsulinor igf-1, and mek1-sensitive kinase cascades during tnf-alfa stimulation.

SIGNOR-236611

Q13153

Q96P20

1

phosphorylation

up-regulates activity

0.2

Pak1 phosphorylates NLRP3 to promote inflammasome activation.

SIGNOR-277547

P01574

O15226

0

transcriptional regulation

down-regulates quantity by repression

0.358

Constitutive silencing of IFN-beta promoter is mediated by NRF (NF-kappaB-repressing factor), a nuclear inhibitor of NF-kappaB

SIGNOR-266227

O14757

Q13263

1

phosphorylation

up-regulates activity

0.282

These data suggested that KAP1 Ser473 phosphorylation by Chk1 and Chk2 does not take place predominantly at sites of DNA damage, and are consistent with previous work indicating that, following their DNA-damage-localized phosphorylation and activation by ATR and ATM, Chk1 and Chk2 dissociate from chromatin to phosphorylate their substrates , ].|These results therefore indicated that both Chk1 and Chk2 can target KAP1 Ser473, and are in agreement with IR triggering both the ATM and Chk2 and ATR and Chk1 pathways .

SIGNOR-280226

Q16650

Q8WXX7

1

transcriptional regulation

up-regulates quantity by expression

0.359

Tbr1 implements frontal identity in part by direct promoter binding and activation of Auts2, a frontal cortex gene implicated in autism.

SIGNOR-266836

O95235

Q9HC98

0

phosphorylation

down-regulates activity

0.347

We show that Nek9, Nek6, and the kinesin Mklp2 form a signaling module, which is required for Mklp2 to localize to the central spindle in anaphase. Nek6 also phosphorylates Mklp2 at Ser244, inhibiting its bundling activity until anaphase onset.

SIGNOR-273891

P51787

Q13557

0

phosphorylation

down-regulates activity

0.2

CaMKII regulates KCNQ1 at S484 during sustained β-AR stimulation to inhibit IKs. The ability of CaMKII to inhibit IKs may contribute to arrhythmogenicity during HF.

SIGNOR-275479

P00558

O15530

2

phosphorylation

up-regulates activity

0.2

PGK1 is an important enzyme in the metabolic glycolysis pathway, but PGK1 also phosphorylates and activates PDK1 through its protein kinase activity ( xref ).|PGK1 is an important enzyme in the metabolic glycolysis pathway, but PGK1 also phosphorylates and activates PDK1 through its protein kinase activity.

SIGNOR-280064

P84022

P24941

0

phosphorylation

down-regulates activity

0.743

In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity

SIGNOR-182971

Q09472

Q9HCU9

0

ubiquitination

down-regulates quantity by destabilization

0.363

BRMS1 suppresses lung cancer metastases through an E3 ligase function on histone acetyltransferase p300. BRMS1 induces polyubiquitination of p300, resulting in its proteasome-mediated degradation.

SIGNOR-266408

P05023

Q05513

0

phosphorylation

up-regulates activity

0.2

Na,K-ATPase alpha(1) subunit was phosphorylated by PKC in hypoxia-treated AEC. In AEC treated with a PKC-zeta antagonist peptide or with the Na,K-ATPase alpha(1) subunit lacking the PKC phosphorylation site (Ser-18), hypoxia failed to decrease Na,K-ATPase abundance and function.

SIGNOR-263181

P14598

P31749

0

phosphorylation

up-regulates

0.559

Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. A direct interaction between p47(phox) and akt was shown. Active recombinant akt phosphorylated recombinant p47(phox) in vitro. Mutation analysis indicated that 2 aa residues, ser(304) and ser(328), were phosphorylated by akt. Inhibition of akt activity also inhibited fmlp-stimulated neutrophil chemotaxis.

SIGNOR-252586

P51674

P17252

0

phosphorylation

up-regulates activity

0.324

In summary, a CNS neuron-specific membrane glycoprotein, M6a, could act as a novel NGF-gated Ca2+ channel through the phosphorylation with PKC and augments [Ca2+]i in M6a-S cells.

SIGNOR-263163

O15534

P48730

0

phosphorylation

down-regulates quantity by destabilization

0.807

Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2. We have now extended our previous studies to show that human casein kinase Idelta (hCKIdelta), the closest homologue to hCKIepsilon, associates with and phosphorylates hPER1 and causes protein instability. Furthermore, we observed that both hCKIdelta and hCKIepsilon phosphorylated and caused protein instability of human period 2 protein (hPER2).

SIGNOR-268001

Q9Y2H0

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-264597

P00533

Q9BV68

0

polyubiquitination

down-regulates quantity by destabilization

0.328

RNF126 and Rabring7 associate with the EGFR through a ubiquitin-binding zinc finger domain and both E3 ubiquitin ligases promote ubiquitylation of EGFR. In HeLa cells depleted of either RNF126 or Rabring7 the EGFR is retained in a late endocytic compartment and is inefficiently degraded.

SIGNOR-272103

P00533

Q04912

1

phosphorylation

up-regulates activity

0.334

This showed that EGFR activation transphosphorylated Ron.|Together, these data suggested that (1) Ron activation transphosphorylated EGFR and vice versa and (2) activated Ron biochemically interacted with EGFR.

SIGNOR-280000

P45983

Q92934

1

phosphorylation

down-regulates

0.686

Jnk phosphorylates bad at threonine 201, thereby inhibiting bad association with the antiapoptotic molecule bcl-x(l)

SIGNOR-121940

Q96K19

Q14571

1

polyubiquitination

down-regulates activity

0.331

In summary, here we present evidence that RNF170 is an E3 ligase that mediates IP3 receptor ubiquitination and processing by the UPP and that it is recruited to activated IP3 receptors by the erlin1/2 complex to which it is constitutively bound.

SIGNOR-271914

Q00535

P04637

1

phosphorylation

up-regulates

0.732

We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 cdk5-stabilized p53 protein is transcriptionally active

SIGNOR-156422

Q9UHF4

Q9NPH9

2

binding

up-regulates

0.601

The mrna expression level of il10, il19, il20, il22, il24, il26, il28b, il29 and their receptors il10ra, il10rb, il20ra, il20rb, il22ra1, il22ra2, il28ra was compared in skin biopsies of children and adults and in childrens' skin cells by quantitative real-time pcr (qrt-pcr).

SIGNOR-151920

O15294

P46937

1

glycosylation

up-regulates activity

0.283

Mass spectrometry analysis showed that YAP was the effector protein modified by OGT. In details, YAP Ser109 O-GlcNAcylation promoted the malignant phenotypes in PTC cells by inducing YAP Ser127 dephosphorylation and activation.

SIGNOR-276942

P08648

Q9BTC0

0

transcriptional regulation

up-regulates quantity by expression

0.2

Dido1 upregulates the expression of Integrin αV, thereby influencing the attachment, apoptosis and migration of melanoma cells.

SIGNOR-261580

Q9H0K1

Q15078

1

phosphorylation

down-regulates

0.331

Sik2 phosphorylates p35 at ser 91, to trigger its ubiquitylation by pja2 and promote insulin secretion. _-cell knockout of sik2 leads to accumulation of p35 and impaired secretion

SIGNOR-204648

P35813

P27986

1

dephosphorylation

up-regulates activity

0.324

Protein phosphatase-2C alpha as a positive regulator of insulin sensitivity through direct activation of phosphatidylinositol 3-kinase in 3T3-L1 adipocytes|PP2Cα dephosphorylates the p85 subunit of PI3K, and dephosphorylation of the p85 subunit of PI3K at Ser608 increases its activity

SIGNOR-248489

Q04759

P35568

1

phosphorylation

down-regulates activity

0.567

Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101).

SIGNOR-260906

P56279

P31749

2

binding

up-regulates

0.825

Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation

SIGNOR-81680

Q9Y458

P56178

1

transcriptional regulation

down-regulates quantity by repression

0.307

the main function of TBX22 as shown in misexpression experiments is to decrease proliferation. We subsequently uncovered three targets of TBX22, DLX5, MSX2, and TBX22 itself. All are downregulated in the presence of viral-derived hTBX22.

SIGNOR-265566

Q9UNE7

P06730

1

ubiquitination

down-regulates quantity by destabilization

0.332

This collaborative activity of cIAP1 and CHIP directs eIF4E toward degradation, controlling its levels and suppressing tumorigenesis.|We next sought to investigate whether eIF4E ubiquitination is enhanced by the collaborative activity of cIAP1 and CHIP, which we define as both the E3 ligase activity of cIAP1 alone and the E3 ligase activity of cIAP1 and CHIP together.

SIGNOR-278669

P19429

P17252

0

phosphorylation

up-regulates activity

0.343

In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation.

SIGNOR-249066

P06239

Q99704

1

phosphorylation

up-regulates activity

0.6

Phosphorylation of p56 dok and p62 dok is increased following CD2 stimulation and requires Lck. Phosphorylation of Dok proteins by Lck might provide a mechanism by which SH2-containing proteins can be recruited and co-localized with their substrates.

SIGNOR-251373

Q9Y5G5

Q9Y5H9

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-265680

P12755

P84022

2

binding

down-regulates activity

0.728

Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling.

SIGNOR-232123

O60729

Q15572

1

dephosphorylation

up-regulates activity

0.2

Consistent with prior studies showing that the phosphatase hCdc14B regulates progression through mitosis by counteracting mitotic phosphorylation by Cdk1/cyclin B [ ], hCdc14B dephosphorylates TAFI110, thus promoting its reactivation as cells exit mitosis.|Here we show that hCdc14B, the phosphatase that regulates Cdk1/cyclin B activity and progression through mitosis, promotes reactivation of rDNA transcription by dephosphorylating TAFI110.

SIGNOR-277135

Q9NQC7

O15111

0

phosphorylation

up-regulates activity

0.544

The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.

SIGNOR-204692

Q15797

Q13485

1

phosphorylation

up-regulates

0.671

Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common(co-Smad; Smad4 in mammals) and shuttle into the nucleus.

SIGNOR-168734

P30968

O95837

2

binding

up-regulates activity

0.478

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-257331

P38405

Q99677

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

P00533

P42224

1

phosphorylation

up-regulates

0.738

The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation

SIGNOR-235689

P01127

P09619

2

binding

up-regulates

0.906

Pdgf-b activates both pdgfr-alpha and pdgfr-beta

SIGNOR-107400

Q13535

O60934

1

phosphorylation

up-regulates

0.785

We demonstrate that mrn and atr/atr-interacting protein (trip) interact with each other, and the forkhead-associated/breast cancer c-terminal domains (fha/brct) of nbs1 play a significant role in mediating this interaction. Mutations in the fha/brct domains do not prevent atr activation but specifically impair atr-mediated nbs1 phosphorylation at ser-343, which results in a defect in the s-phase checkpoint.

SIGNOR-155214

P49281

O00308

0

ubiquitination

down-regulates quantity

0.299

Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2|This promotes DMT1 ubiquitination and degradation by WWP2.

SIGNOR-268852

P51168

P28482

0

phosphorylation

down-regulates quantity by destabilization

0.29

Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4.

SIGNOR-249446

O43561

P06241

0

phosphorylation

up-regulates

0.749

Both lck and syk, phosphorylate the itam-like motifs on lat at y171y191, which is essential for induction of the interaction of lat with downstream signaling molecules such as grb2, plc-gamma1 and c-cbl, and for activation of mapk-erk.

SIGNOR-149174

Q13255

P17252

0

phosphorylation

down-regulates activity

0.385

Furthermore, we demonstrate that the selectivity of PKC action on receptor signaling rests on phosphorylation of a threonine residue located in the G protein-interacting domain of the receptor. Modification at Thr(695) selectively disrupts mGluR1alpha-G(q/11) interaction without affecting signaling through G(s).

SIGNOR-249043

Q9NQX3

O95166

2

binding

up-regulates activity

0.561

The GABA(A)R-associated protein GABARAP was found to bind to the gamma2 subunit of GABA(A)Rs. Here we show that GABARAP interacts with gephyrin in both biochemical assays and transfected cells. Our data indicate that GABARAP-gephyrin interactions are not important for postsynaptic GABA(A)R anchoring but may be implicated in receptor sorting and/or targeting mechanisms.

SIGNOR-264971

Q0VAM2

P01116

2

binding

up-regulates

0.297

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

SIGNOR-183835

Q9Y5I3

P05556

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.

SIGNOR-265663

Q9BZL6

Q9UQL6

1

phosphorylation

up-regulates activity

0.295

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

SIGNOR-275929

P63096

P28336

2

binding

up-regulates activity

0.268

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-257047

O75385

Q14457

1

phosphorylation

up-regulates activity

0.771

In the nucleation step of autophagy, The ULK1 complex phosphorylates and activates the Beclin-1-VPS34 complex.

SIGNOR-278503

Q15836

Q8NE79

2

binding

up-regulates activity

0.42

Taken together, these data demonstrate that Bves interacts with VAMP3 and facilitates receptor recycling both in vitro and during early development.

SIGNOR-237771

Q9UI95

Q9UM11

2

binding

down-regulates activity

0.544

The APC is activated in mitosis and G1 by CDC20 and CDH1, and inhibited by the checkpoint protein MAD2, a specific inhibitor of CDC20. We show here that a MAD2 homolog MAD2B also inhibits APC. MAD2B directly inhibits activation of APC by CDC20 and CDH1

SIGNOR-264902

P63096

Q15722

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-256691

Q9BY66

Q16695

1

demethylation

up-regulates activity

0.2

KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.

SIGNOR-264309

Q13627

O75688

0

dephosphorylation

down-regulates activity

0.236

In conclusion, our study demonstrates that DYRK1A autophosphorylates Ser258, the dephosphorylation target of PPM1B, and PPM1B negatively regulates DYRK1A activity.|We found that PPM1B dephosphorylates DYRK1A at Ser258, contributing to the inhibition of DYRK1A activity.

SIGNOR-277108

P08559

Q9NTG7

0

deacetylation

down-regulates activity

0.48

SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells|SIRT3 deacetylates PDHA1 lysine 321 (K321)

SIGNOR-267636

Q86UZ6

P15018

1

transcriptional regulation

up-regulates quantity by expression

0.2

ZBTB46 binds directly to the LIF regulatory sequence and enhances its transcription. Our study confirmed a novel positive association between ZBTB46 activity and LIF levels in prostate cancer tissues and cells. Under androgen regulation, low levels of ZBTB46 are an essential transcriptional factor for maintaining LIF-STAT3 signaling, while the loss of androgen signaling or inhibition of AR signaling causes LIF-enhanced therapeutic resistance and CRPC characteristics through the upregulation of ZBTB46. We also found that LIF activation drives malignant progression and NE-like reprogramming in prostate cancer by activating STAT3 signaling.

SIGNOR-277988

P40925

Q86X55

0

acetylation

down-regulates activity

0.355

Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer|Arginine methylation at R248 negatively regulates MDH1 activity|PRMT4/CARM1 methylates MDH1 at R248 and inhibits its dimerization

SIGNOR-267639

P49841

Q92837

2

phosphorylation

down-regulates activity

0.776

Protein kinase A (PKA) was found to phosphorylate Ser188 in vitro as well as in intact cells. Importantly, activation of endogenous cAMP-coupled beta-adrenergic receptors with norepinephrine stimulated the phosphorylation of FRAT1 at Ser188. GSK-3 was also able to phosphorylate FRAT1 at Ser188 and other residues in vitro or when overexpressed in intact cells. Phosphorylation of Ser188 by PKA inhibited the ability of FRAT1 to activate beta-catenin-dependent transcription.

SIGNOR-276057

P53350

P35568

1

phosphorylation

down-regulates activity

0.267

Phosphorylation of ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by mouse pelle-like kinase/interleukin-1 receptor-associated kinase| irs-1 mutants s24d or s24e (mimicking phosphorylation at ser(24)) had impaired ability to associate with insulin receptors resulting in diminished tyrosine phosphorylation of irs-1 and impaired ability of irs-1 to bind and activate pi-3 kinase in response to insulin.

SIGNOR-135688

P04637

O15297

0

dephosphorylation

down-regulates activity

0.558

PPM1D binds Chk1 and dephosphorylates the ATR-targeted phospho-Ser 345, leading to decreased Chk1 kinase activity. PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair.

SIGNOR-248319

P25098

P12931

0

phosphorylation

up-regulates activity

0.2

Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq.

SIGNOR-266305

P17252

O60825

1

phosphorylation

up-regulates activity

0.439

The phosphorylation sites for both cAMP-dependent protein kinase and protein kinase C were located in a single peptide whose sequence was Arg-Arg-Asn-Ser-(P)-Phe-Thr-Pro-Leu-Ser-Ser-Ser-Asn-Thr(P)-Ile-Arg-Arg-Pro. The seryl residue nearest the N terminus was the residue specifically phosphorylated by cAMP-dependent protein kinase, whereas the threonine residue nearest the C terminus was phosphorylated by protein kinase C. | Phosphorylation of bovine heart Fru-6-P,B-kinase by either protein kinase C or CAMP-dependent protein kinase results in activation of the enzyme.

SIGNOR-248844

Q86UZ6

P35558

1

transcriptional regulation

up-regulates quantity by expression

0.2

We identified LIF/ZBTB46 signalling as a key promoter of metabolic reprogramming and NE differentiation of PCa cells through interactions with PCK1. We showed that ZBTB46 directly upregulates the expression of PCK1 and NE marker gene through activation of LIF signalling.

SIGNOR-277987

Q9BUB5

Q9NP80

1

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

Q9HBW0

Q8WWY8

2

binding

up-regulates

0.293

When overexpressed in jurkat t cells, the edg4 protein mediated lpa-induced activation of a serum response element reporter gene with lpa concentration dependence (ec50 of 10 nm) and specificity.

SIGNOR-56093

P36888

Q06124

2

binding

up-regulates activity

0.525

Y599 was additionally found to interact with the protein tyrosine phosphatase SHP2 in a phosphorylation-dependent manner. As Y599F-Flt3-32D was unable to associate with and to phosphorylate SHP2 and since silencing of SHP2 in WT-Flt3-expressing cells mimicked the Y599F-Flt3 phenotype, we hypothesize that recruitment of SHP2 to pY599 contributes to FL-mediated Erk activation and proliferation.

SIGNOR-245057

Q9Y5I2

Q9Y5G4

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-265700

P05976

P27361

0

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

P61586

Q8N1W1

0

guanine nucleotide exchange factor

up-regulates activity

0.755

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-260546

P47900

P19086

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 ≥ -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-257273

Q08211

Q9ULX6

2

binding

up-regulates activity

0.544

We report evidence for a novel nuclear export signal in HAP95 and showed that the domains involved in RHA binding and nuclear localization are required for CTE activation. Finally, we showed that HAP95 synergizes significantly with RHA on CTE-mediated reporter gene expression and promotes nuclear export of unspliced mRNA in transfected cells. Taken together, these data support the proposal that HAP95 specifically facilitates CTE-mediated gene expression by directly binding to RHA.

SIGNOR-260950

Q15583

Q96J02

0

ubiquitination

up-regulates activity

0.2

Based on these observations, we suggest that a mechanism of protein stabilization might account for the accumulation of TGIF protein in response to TNF-alpha signaling.Next, we used three different approaches to investigate the possibility that Itch could contribute to the ability of TNF-alpha to promote TGIF stabilization.|We also employed the experimental strategy combining the detection of monoubiquitinated and polyubiquitinated TGIF and found that mutation of K259 not only compromised monoubiquitination of TGIF by Itch but also enhanced its polyubiquitination.

SIGNOR-278817

P19544

O00592

1

transcriptional regulation

up-regulates quantity by expression

0.409

Binding of WT1 to conserved elements within the Podocalyxin gene promoter results in potent transcriptional activation, and the specific expression pattern of Podocalyxin in the developing kidney mirrors that of WT1 itself.

SIGNOR-252300

Q99873

Q9UKM9

0

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

Q8TE12

O14529

1

transcriptional regulation

up-regulates quantity by expression

0.285

Lmx1a drives Cux2 expression in the cortical hem through activation of a conserved intronic enhancer. Lmx1a knockdown abolishes activation of the Cux2 enhancer in the cortical hem

SIGNOR-263961

P63096

P25116

2

binding

up-regulates

0.402

Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13).

SIGNOR-196009

Q8WYQ5

Q13315

0

phosphorylation

up-regulates quantity by stabilization

0.27

Specifically, radiation-induced ATM-dependent phosphorylation of DGCR8 at serine 677 facilitates USP51 to bind, deubiquitinate, and stabilize DGCR8, which leads to the recruitment of DGCR8 and DGCR8's binding partner RNF168 to MDC1 and RNF8 at DSBs.

SIGNOR-277307

P24941

Q13416

1

phosphorylation

up-regulates

0.756

We also found that horc2p is phosphorylated in vitro by cyclin a/cdk2, specifically at residues thr116 and thr226. These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability.

SIGNOR-116364

P25098

P21731-2

1

phosphorylation

down-regulates activity

0.2

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

SIGNOR-274088

P27448

Q05513

0

phosphorylation

down-regulates

0.2

Hpar-1a, t564, is phosphorylated in vivo and by apkc in vitro.This study establishes a novel functional link between two central determinants of cellular polarity, apkc and par-1, and suggests a model by which apkc may regulate par-1 in polarized cells

SIGNOR-124221

P12830

Q13363

0

transcriptional regulation

down-regulates quantity by repression

0.6

Carboxyl-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor with oncogenic potential. We found CtBP1 was recruited to the promoter regions of Brca1 and E-cadherin genes in breast cancer cells.

SIGNOR-259197

P27986

P01137

2

binding

up-regulates activity

0.258

While association of the TGF_RI receptor with p85 requires TGF-_ stimulation.

SIGNOR-217960

P68400

P18858

1

phosphorylation

up-regulates activity

0.34

Moreover, these data confirmed the occurrence of Ser66 phosphorylation, which was previously studied with a specific monoclonal antibody (23).

SIGNOR-103258