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
Q7L590	O94761	2	binding	down-regulates	0.509	Mcm10 inhibits recq4 helicase activity.	SIGNOR-187701
O75581	Q9ULV1	2	binding	up-regulates activity	0.649	Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction.	SIGNOR-258964
P15172	P40424	2	binding	up-regulates activity	0.41	These domains are necessary for the stable binding of myod to the myogenin promoter through an interaction with an adjacent protein complex containing the homeodomain protein pbx, which appears to be constitutively bound at this site	SIGNOR-124834
Q9Y243	P55265	1	phosphorylation	down-regulates activity	0.2	AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively	SIGNOR-276191
P01024	P01024	2	cleavage	up-regulates activity	0.2	C3 autoactivates in a process known as “tick-over,” which is characterized by spontaneous hydrolysis of a reactive thiol-ester to generate C3(H2O). Although C3(H2O)Bb produces only relatively small amounts of C3b compared to the other C3 convertases, it nevertheless generates enough C3b to set the C3 convertase amplification loop in motion.	SIGNOR-263483
Q9HAW9	Q99626	0	transcriptional regulation	up-regulates quantity by expression	0.26	Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter.	SIGNOR-253969
Q96P20	Q6PJ69	0	ubiquitination	down-regulates activity	0.2	These results suggest that TRIM65 could inhibit the activation of the NLRP3 inflammasome in response to multiple agonists.\|Thus, TRIM65 deficiency impairs NLRP3 ubiquitination and enhances NLRP3 inflammasome activation, but has no effects on AIM2 or IPAF inflammasome activation.	SIGNOR-278566
P13498	P14598	2	binding	up-regulates activity	0.79	Stimulus-induced phosphorylation of p47phox causes a conformational change, by which both PX and SH3 domains become accessible to their membranous targets, phosphoinositides and p22phox, respectively. Cooperation of these two interactions, each being indispensable, enables p47phox to form a stable complex with cytochrome b558 (composed of the two subunit gp91phox and p22phox), leading to activation of the phagocyte NADPH oxidase.	SIGNOR-276625
P78352	Q7Z6G8	2	binding	up-regulates activity	0.45	The reversible removal of AIDA-1 from the PSD core under excitatory conditions is similar to the redistribution of another abundant PSD protein, SynGAP. Both SynGAP-alpha1 and AIDA-1 are known to bind PSD-95.	SIGNOR-264228
P04626	P22681	0	ubiquitination	down-regulates quantity by destabilization	0.601	Ligand binding to EGFR also leads to rapid internalization and proteosomal/lysosomal degradation of the receptors. This process results in a dramatic downregulation of both total and cell surface receptors. EGF-induced degradation of EGFR is thought to be initiated by phosphorylation of tyrosine 1045 of the receptor followed by binding of Cbl adaptor proteins and ubiquitination of the receptor. Internalized EGFR is transported to early endosomes where receptor-ligand complexes are sorted for either degradation or recycling to the cell surface.	SIGNOR-30794
O15444	P51686	2	binding	up-regulates	0.805	Ccr9 is a specific receptor for the beta-chemokine teck/ccl25.	SIGNOR-104902
O00429	Q14012	0	phosphorylation	up-regulates activity	0.333	For example, protein kinase A (PKA) phosphorylation of Drp1S600 has been reported to decrease Drp1 GTPase activity in vitro (23, 24), whereas phosphorylation of the same conserved serine residue by Ca2+-calmodulin–dependent protein kinase Iα (CaMKIα) in Drp1 isoform 3 has been reported to cause a significant increase in mitochondrial fission	SIGNOR-262552
Q16595	P12931	0	phosphorylation	down-regulates quantity by destabilization	0.2	We found that frataxin can be phosphorylated by Src. Phosphorylation occurs primarily on Y118 and promotes frataxin ubiquitination, a signal for degradation.	SIGNOR-275585
P45984	Q9UPT6	2	phosphorylation	up-regulates	0.663	Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro.	SIGNOR-134576
P30307	Q9H4B4	0	phosphorylation	up-regulates	0.731	Cdc25c phosphorylation on serine 191 by plk3 promotes its nuclear translocation	SIGNOR-122090
Q15382	Q9NZJ5	2	binding	down-regulates activity	0.2	Rheb GTPase directly binds and activates PERK in vitro	SIGNOR-260873
Q8TDJ6	Q15042	2	binding	up-regulates quantity	0.54	We isolated here a novel protein that was co-immunoprecipitated with Rab3 GEP and GAP by their respective antibodies from the crude synaptic vesicle fraction of rat brain. The protein, named rabconnectin-3, bound both Rab3 GEP and GAP. These results indicate that rabconnectin-3 serves as a scaffold molecule for both Rab3 GEP and GAP on synaptic vesicles.	SIGNOR-265582
O43306	P04899	2	binding	down-regulates activity	0.522	Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3	SIGNOR-278078
P38405	P25100	2	binding	up-regulates activity	0.278	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-256951
Q6P0Q8	P60484	1	phosphorylation	up-regulates	0.666	We further demonstrate that binding of pten to specific pdz domains diminishes its degradation rate and facilitates its phosphorylation by mast kinases. Our results suggest a regulatory role of pdz domain binding on pten function by controlling its stability and phosphorylation status.	SIGNOR-138051
P35241	Q13464	0	phosphorylation	up-regulates activity	0.68	A peak of the phosphopeptide, in which only T573 was phosphorylated, was not detected. Quantitative analyses revealed that _100% of T564, but at most _40% of T573, was phosphorylated when C-rad was incubated with Rho-Kc for 1 h. Then we concluded that the major and primary phosphorylation site of radixin by Rho-kinase was T564 and referred to the Rho-Kcphosphorylated C-rad as T564-phosphorylated C-rad. \| In this study, we found that the T564 phosphorylation of radixin markedly suppressed its head-to-tail association. This suggests that the T564-phosphorylation of radixin (and probably also the phosphorylation of ezrin T567 and moesin T558) keeps them open and active.	SIGNOR-248994
Q96F44	Q99453	1	ubiquitination	down-regulates	0.485	The e3 ubiquitin ligasetrim11mediates the degradation of congenital central hypoventilation syndrome-associated polyalanine-expandedphox2b.	SIGNOR-195878
Q15418	P67809	1	phosphorylation	up-regulates	0.543	We therefore conclude that rsk1/rsk2 are novel activators of yb-1, able to phosphorylate the serine 102 residue.	SIGNOR-182497
Q9UQF2	P45983	2	binding	down-regulates	0.879	The jip proteins function by aggregating components of a map kinase module (including mlk, mkk7, and jnk) and facilitate signal transmission by the protein kinase cascade. Overexpression of jip1 deactivates the jnk pathway selectively by cytoplasmic retention of jnk and thereby inhibits gene expression mediated by jnk, which occurs in the nucleus	SIGNOR-124727
O14939	P00533	0	phosphorylation	up-regulates activity	0.516	Using transiently transfected human embryonic kidney fibroblasts (HEK293), we demonstrate here that PLD1 activity, and to a lesser extent PLD2 activity, is stimulated in response to epidermal growth factor (EGF). PLD2, but not PLD1, associates with the EGF receptor in a ligand-independent manner and becomes tyrosine-phosphorylated upon EGF receptor activation. Tyrosine 11 (Tyr-11) of PLD2 was identified as the specific phosphorylation site. Mutation of this residue to phenylalanine enhanced basal activity almost 2-fold	SIGNOR-251095
P46527	P49792	0	relocalization	down-regulates quantity	0.2	RanBP2 can increase the sumoylation of p27kip1. In our study, the target protein p27kip1 mainly acts as a tumor-suppressor gene in the nucleus, RanBP2 and SUMO1 act as oncogenes by promoting the nuclear-cytoplasmic translocation and debilitate the G1-arrest brought by p27kip1 accumulation in the nucleus.	SIGNOR-259115
P06748	P53350	0	phosphorylation	up-regulates	0.425	Phosphorylated at ser-4 by plk1 and plk2. Phosphorylation at ser-4 by plk2 in s phase is required for centriole duplication and is sufficient to trigger centriole replication. Phosphorylation at ser-4 by plk1 takes place during mitosis.	SIGNOR-125666
O75553	Q93034	0	polyubiquitination	down-regulates quantity by destabilization	0.327	SOCS7 promotes Dab1 polyubiquitylation and degradation. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SOCS7, a CRL5 substrate adaptor protein, is also required for neocortical layering. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1.	SIGNOR-272140
P07947	Q04760	1	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
Q9Y2I7	P31749	0	phosphorylation	up-regulates	0.491	Here we report that serine318 on the fyve domain-containing ptdins3p 5-kinase (pikfyve) is a novel substrate for pkb, and show that phosphorylation stimulates the ptdins3p 5-kinase activity of the enzyme.	SIGNOR-252474
Q14185	Q8WXX7	2	binding	up-regulates activity	0.2	Mutations in the Autism susceptibility candidate 2 gene (AUTS2), whose protein is believed to act in neuronal cell nuclei, have been associated with multiple psychiatric illnesses, including autism spectrum disorders, intellectual disability, and schizophrenia. Here we show that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development. AUTS2 activates Rac1 to induce lamellipodia but downregulates Cdc42 to suppress filopodia. Our loss-of-function and rescue experiments show that a cytoplasmic AUTS2-Rac1 pathway is involved in cortical neuronal migration and neuritogenesis in the developing brain. These results suggest that FL-AUTS2 can activate Rac1 via interaction with P-Rex1 and the Elmo2/Dock180 complex to regulate actin dynamics in N1E-115 cells.	SIGNOR-266820
P49137	Q00987	1	phosphorylation	up-regulates quantity by stabilization	0.364	Hdm2 phosphorylation by mapkap kinase 2 enhances hdm2 activity and promote the degradation of p53.	SIGNOR-133560
Q99523	P02647	2	binding	up-regulates quantity	0.331	Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/Aβ complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aβ in the brain and in aggravated plaque burden. Sortilin interacts with all human APOE isoforms.	SIGNOR-273722
Q92963	Q12967	2	binding	up-regulates activity	0.534	Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors.	SIGNOR-220859
P17813	O95393	2	binding	up-regulates activity	0.362	Soluble endoglin specifically binds bone morphogenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppresses tumor growth. We found that mouse and human endoglin ECD-Fc bound directly, specifically, and with high affinity to bone morphogenetic proteins 9 and 10 (BMP9 and BMP10) in surface plasmon resonance (Biacore) and cell-based assays.	SIGNOR-276657
P22694	P10644	2	binding	down-regulates activity	0.863	Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets	SIGNOR-258755
Q96EP1	Q93009	0	deubiquitination	up-regulates quantity by stabilization	0.432	In this study, we identified USP7 (also known as HAUSP), which is a member of a family of proteins that cleave polyubiquitin chains and/or ubiquitin precursors, as an interacting protein with Chfr by immunoaffinity purification and mass spectrometry, and their interaction greatly increases the stability of Chfr. In fact, USP7 can remove ubiquitin moiety from the autoubiquitinated Chfr both in vivo and in vitro, which results in the accumulation of Chfr in the cell. USP7 mediates deubiquitination of Chfr.	SIGNOR-271462
P41586	P18509	2	binding	up-regulates	0.877	Type i pacap receptors bind pacap-27 and -38. the potencies of the two forms of pacap are similar for adenylate cyclase stimulation, whereas pacap-38 is more potent than pacap-27 in phospholipase c activation.	SIGNOR-43225
Q9UD71	P68400	0	phosphorylation	up-regulates activity	0.34	Study of [Plphosphate release during manual Edman degradation confirmed that the phosphorylated residues in rat DARPP-32 were Ser45 and Ser102. \| Phosphorylation by casein kinase II did not affect the potency of DARPP-32 as an inhibitor of protein phosphatase-1, which depended only on phosphorylation of Thr34 by cAMP-dependent protein kinase. However, phosphorylation of DARPP-32 by casein kinase II facilitated phosphorylation of Thr34 by cAMP-dependent protein kinase	SIGNOR-250927
Q8IZD2	P10276	2	binding	up-regulates activity	0.334	MLL5 binds to retinoic acid receptor α (RARα) and induces transcriptional activation of RARα target genes by methylation of lysine residues of histone H3.	SIGNOR-260041
P00533	Q16539	0	phosphorylation	down-regulates	0.508	In conclusion, the use of pharmacological agents suggests that p38 mapk is the enzyme involved in egfr phosphorylation, as well as internalization, following exposure of cells to various stress-inducing conditions.	SIGNOR-149089
P35580	Q06413	0	transcriptional regulation	up-regulates quantity by expression	0.345	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238769
Q86YJ5	Q96LA5	1	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-271543
P10145	P25024	2	binding	up-regulates	0.78	Il-8 activates both the cxcr1 and the cxcr2 on microvascular endothelial cells, using different signal transduction cascades.	SIGNOR-107920
P36897	O95405	2	binding	up-regulates activity	0.631	Sara functions to recruit smad2 to the tgfbeta receptor by controlling the subcellular localization of smad2 and by interacting with the tgfbeta receptor complex	SIGNOR-62868
P07947	P30530	0	phosphorylation	up-regulates activity	0.2	Here, we show that EphA2, YES1, and ANXA2 form a signal axis, in which YES1 activated by EphA2 phosphorylates ANXA2 at Tyr24 site, leading to ANXA2 activation and increased ANXA2 nuclear distribution in gastric cancer (GC) cells.	SIGNOR-277555
O95297	Q06124	0	dephosphorylation	down-regulates	0.522	In vitro, tyrosine-phosphorylated pzr was efficiently dephosphorylated by the full-length form of shp-2 but not by its sh2 domain-truncated form. The coexisting binding and dephosphorylation of pzr by shp-2 may function to terminate signal transduction initiated by pzr and shp-2 and to set a threshold for the signal transduction to be initiated.	SIGNOR-75220
P84243	O75151	0	demethylation	up-regulates activity	0.2	PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark.	SIGNOR-264518
P51003	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-268330
Q9NRI5	P33176	2	binding	up-regulates activity	0.2	We identified Kinesin-1, a microtubule-dependent and plus-end directed motor, as a DISC1-interacting molecule. Our results show that DISC1 links Kinesin-1 to the NUDEL/LIS1/14-3-3ε complex, serves as the cargo receptor, and regulates the transport of the complex to axons, leading to axon elongation. DISC1 directly interacted with kinesin heavy chain of Kinesin-1. Kinesin-1 interacted with the NUDEL/LIS1/14-3-3ε complex through DISC1	SIGNOR-252161
E9PAV3	Q13418	0	phosphorylation	up-regulates	0.426	The inactivation of gsk3? In response to adhesion and ilk activation (6) would then result in a thr-159-hypophosphorylated ?-Nac that would become unavailable for proteasome degradation but would become a substrate for the ilk kinase activity on residue ser-43. The ser-43-phosphorylated ?-Nac would preferentially interact with c-jun (30), translocate to the nucleus, and potentiate transcription	SIGNOR-127631
Q99704	Q13882	0	phosphorylation	down-regulates activity	0.494	BRK downregulates Dok1 via proteasomal degradation.\|BRK phosphorylates Dok1 at tyrosine 362.	SIGNOR-278301
Q9NZQ7	Q9Y4X5	0	polyubiquitination	down-regulates quantity by destabilization	0.2	We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal degradation following GSK3α-mediated phosphorylation of Ser279/Ser283. We identify ARIH1 as the E3 ubiquitin ligase responsible for targeting PD-L1 to degradation.	SIGNOR-277553
P12931	P56945	1	phosphorylation	up-regulates activity	0.803	Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src\|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs	SIGNOR-246393
P05204	P17252	0	phosphorylation	down-regulates	0.29	Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools.	SIGNOR-76320
P29474	P17252	0	phosphorylation	down-regulates activity	0.3	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251620
O75030	P49840	0	phosphorylation	up-regulates	0.294	Glycogen synthase kinase 3 (gsk3) was found to phosphorylate ser298 in vitro, thereby enhancing the binding of mitf to the tyrosinase promoter	SIGNOR-72878
Q9NX18	P21912	2	binding	up-regulates	0.617	Sdh5 is required for sdh activity and stability / the sdh1-sdh5 interaction is likely to be functionally important because the sdh5_ mutant lacks sdh activity	SIGNOR-187239
P49757	P46531	1	ubiquitination	down-regulates quantity by destabilization	0.798	Mammalian numb proteins promote notch1 receptor ubiquitination and degradation of the notch1 intracellular domain	SIGNOR-99762
P16220	Q92911	1	transcriptional regulation	up-regulates quantity by expression	0.267	CREB recognized and bound to the promoter of SLC5A5 to facilitate its transcription.	SIGNOR-267137
Q92889	Q8IY92	2	binding	up-regulates	0.755	Slx4 is a tumor suppressor that stimulates the activity of the nuclease xpf-ercc1 in dna crosslink repair.	SIGNOR-204890
Q13043	P04406	1	phosphorylation	up-regulates activity	0.279	Interestingly, GAPDH is phosphorylated by Mst1 to a comparable extent as its known substrate MBP, suggesting that GAPDH is a good substrate of Mst1 at least in vitro.\|Moreover, interaction of Mst1 with GAPDH caused a robust phosphorylation of GAPDH and markedly increased the Mst1 activity in cells.	SIGNOR-279295
P17252	P15382	1	phosphorylation	down-regulates activity	0.307	Inhibition of the current was not seen in channels in which Ser103 was replaced by Ala, although other properties of the current were unchanged. These results indicate that inhibition of the potassium current results from direct phosphorylation of the channel subunit protein at Ser103.	SIGNOR-248852
P20366	P21452	2	binding	up-regulates	0.874	The mammalian tachykinins include substance p, neurokinin a and neurokinin b, which exert their effects by binding to specific receptors. These tachykinin receptors are divided into three types, designated nk1, nk2 and nk3, respectively. The interaction of tachykinin with its receptor activates gq, which in turn activates phospholipase c to break down phosphatidyl inositol bisphosphate into inositol trisphosphate (ip3) and diacylglycerol (dag).	SIGNOR-44773
P09086	P07947	0	phosphorylation	up-regulates activity	0.2	These data suggest that Yes1 is the TKI-sensitive kinase that can directly phosphorylate OCT2.	SIGNOR-279664
P01344	P08069	2	binding	up-regulates activity	0.821	These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients.	SIGNOR-251495
P35222	Q9Y3M2	2	binding	down-regulates	0.693	Here we report a conserved nuclear protein, named chibby, which was identified in a screen for proteins that directly interact with the c-terminal region of beta-catenin. In mammalian cultured cells we demonstrate that chibby inhibits beta-catenin-mediated transcriptional activation by competing with lef-1 to bind to beta-catenin.	SIGNOR-100835
P12931	P23469	0	dephosphorylation	up-regulates activity	0.402	PTPepsilonM activated c-Src kinase probably by directly dephosphorylating phospho-Tyr527, a negative regulatory site of c-Src.	SIGNOR-238074
P60953	Q6XZF7	0	guanine nucleotide exchange factor	up-regulates activity	0.572	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-260547
O43318	P53805	1	phosphorylation	up-regulates activity	0.2	Here we showed that TAK1 directly phosphorylated RCAN1 at two novel sites (serine 94 and -136), resulting in activation of calcineurin-NFAT signaling.\|Indeed, low doses of RCAN1 facilitated calcineurin-nuclear factor of activated T cells signaling in the presence of TGF-\u03b2-activated kinase 1+TAB1 ( ), suggesting that TGF-\u03b2-activated kinase 1 augments calcineurin-nuclear factor of activated T cells signaling through RCAN1.	SIGNOR-279535
P49840	P17612	0	phosphorylation	down-regulates	0.372	Phosphorylation of ser21 and inactivation of glycogen synthase kinase 3 by protein kinase a.	SIGNOR-83221
Q9ULJ6	P46531	2	binding	up-regulates activity	0.452	The N-terminal domain (NTD) is critical for Zmiz1 to function as a Notch collaborator. Zmiz1 and Notch1 cooperatively recruit each other to chromatin through the TPR domain. The N-terminal domain (NTD) of Zmiz1 is important for enhancing Notch reporter activity and contains tetratricopeptide repeats (TPR) that mediate protein-protein interactions	SIGNOR-263936
O75385	Q6ZNE5	1	phosphorylation	up-regulates activity	0.651	ULK1 phosphorylates ATG14 at serine 29.	SIGNOR-278433
Q13950	P31749	0	phosphorylation	down-regulates activity	0.446	Here we show that Akt kinase directly phosphorylates Runx2 to regulate invasive properties of breast cancer cells.	SIGNOR-280176
P48775	P43694	0	transcriptional regulation	down-regulates quantity by repression	0.252	GATA4 inhibits expression of the tryptophan oxygenase gene by binding to the TATA box in fetal hepatocytes.	SIGNOR-268994
Q9UMX1	P51955	0	phosphorylation	up-regulates activity	0.2	Intriguingly, Nek2A is found to stabilize SuFu at least partly depending on its kinase activity, thereby triggering phosphorylation of the SuFu protein.\|Nek2A phosphorylates and stabilizes SuFu: A new strategy of Gli2/Hedgehog signaling regulatory mechanism.	SIGNOR-279235
Q9BRS8	P31749	0	phosphorylation	up-regulates activity	0.353	Akt dependent phosphorylation of LARP6. We provide the first description that LARP6 is phosphorylated at multiple sites and that phosphorylation of S451 is critical to activate the protein in type I collagen biosynthesis.	SIGNOR-277213
P16220	P51812	0	phosphorylation	up-regulates activity	0.726	MAPK activates CREB kinase, which in turn phosphorylates and activates CREB. Purification, sequencing, and biochemical characterization of CREB kinase revealed that it is identical to a member of the pp90(RSK) family, RSK2. RSK2 was shown to mediate growth factor induction of CREB serine-133 phosphorylation both in vitro and in vivo. These findings identify a cellular function for RSK2 and define a mechanism whereby growth factor signals mediated by RAS and MAPK are transmitted to the nucleus to activate gene expression	SIGNOR-248951
P14784	P29353	2	binding	up-regulates	0.558	The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival	SIGNOR-204975
P19784	P41236	1	phosphorylation	up-regulates activity	0.307	Recombinant wild-type I-2 and the Ala-120/121 mutant were phosphorylated synergistically by GSK-3 and casein kinase II. The Thr-72 and Ser-86 mutants, however, did not undergo this synergistic phosphorylation. Our studies indicate that Thr-72 is the only GSK-3 site and that Ser-86 is the casein kinase II site required for the potentiation of GSK-3 action.	SIGNOR-251021
Q9Y6Y8	Q15436	2	binding	up-regulates activity	0.572	The results showed that the N-terminal region of p125 is important for the interaction with Sec23p. We confirmed the interaction between the two proteins by a yeast two-hybrid assay. Overexpression of p125, like that of mammalian Sec23p, caused disorganization of the endoplasmic reticulum-Golgi intermediate compartment and Golgi apparatus, suggesting its role in the early secretory pathway.	SIGNOR-265307
Q9NTG7	P36888	0	phosphorylation	down-regulates activity	0.2	We also hypothesize that, besides activating ACAT1 through Y407 phosphorylation (Fan et al., 2016), FLT3 might simultaneously phosphorylate and regulate SIRT3. Our mutational studies on all of the seven tyrosine sites of SIRT3 revealed that purified rFLT3 directly phosphorylated purified rSIRT3 in an in vitro kinase assay, leading to decreased SIRT3 deacetylase activity that was assessed by ability to deacetylate K413 of mIDH2 (Figure 4H, first three samples in left, middle, and right panels), whereas replacement of Y226 completely abolished inhibition of SIRT3 by FLT3 (Figure 4H, right).	SIGNOR-267631
Q9UQ13	P62136	2	binding	up-regulates activity	0.596	Using a proteomics approach, we have identified a complex comprised of Shoc2/Sur-8 and the catalytic subunit of protein phosphatase 1 (PP1c) as a highly specific M-Ras effector. M-Ras targets Shoc2-PP1c to stimulate Raf activity by dephosphorylating the S259 inhibitory site	SIGNOR-251647
P67809	P28482	0	phosphorylation	up-regulates activity	0.47	ERK2 may also directly phosphorylate YB-1 and therefore promotes its ability to transactivate target genes.	SIGNOR-279227
P05106	P31749	0	phosphorylation	down-regulates activity	0.613	A survey of several protein kinases revealed that Thr-753 was avidly phosphorylated by PDK1 and Akt/PKB in vitro. These observations suggest that activation of PDK1 and/or Akt/PKB in platelets may modulate the binding activity and/or specificity of beta(3) for signaling molecules.	SIGNOR-252552
Q14980	Q13885	2	binding	up-regulates	0.2	Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.	SIGNOR-116936
Q96PU5	P35240	1	ubiquitination	up-regulates activity	0.261	Merlin ubiquitination is mediated by the E3 ubiquitin ligase, NEDD4L, which requires a scaffold protein, AMOTL1, to approach Merlin. Several NF2-patient-derived Merlin mutations disrupt its binding to AMOTL1 and its regulation by the AMOTL1-NEDD4L apparatus. Lysine (K) 396 is the major ubiquitin conjugation residue. Disruption of Merlin ubiquitination by the K396R mutation or NEDD4L depletion diminishes its binding to Lats1 and inhibits Lats1 activation. These effects are also accompanied by loss of Merlin's anti-mitogenic and tumor suppressive properties. Thus, we propose that dephosphorylation and ubiquitination compose an intramolecular relay to activate Merlin functions in activating the Hippo pathway during growth control.	SIGNOR-263662
P17252	P48050	1	phosphorylation	down-regulates activity	0.2	These results therefore indicate that Kir2.3 is directly modulated by PKC phosphorylation of its channel protein and threonine 53 is the PKC phosphorylation site in Kir2.3.	SIGNOR-275965
P84022	Q9UNE7	0	ubiquitination	down-regulates quantity by destabilization	0.57	These results suggest that Smad3 could be easily ubiquitinated and degraded by CHIP when Hsp90 activity was inhibited.To demonstrate the role of Hsp70 and Hsp90 on the regulation of Smad3 by CHIP, we over-expressed Hsp70 and Hsp90 in mammalian cells.	SIGNOR-278785
P17655	P28482	0	phosphorylation	up-regulates	0.628	Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo.	SIGNOR-123079
P29803	Q16654	0	phosphorylation	down-regulates	0.547	Pyruvate dehydrogenase (pdh) activity (pdha) controls the entry of carbohydrate into the tricarboxylic cycle and is regulated by pdh kinase (pdk), which phosphorylates and inactivates the enzyme, and pdh phosphatase, which dephosphorylates the enzyme to the active form	SIGNOR-121936
P15924	P17612	0	phosphorylation	down-regulates activity	0.328	HeLa cells treated with forskolin indicated that stimulation of protein kinase A in transfected cells could decrease the interaction of DP.AN.SerC23 with keratin IF networks. phosphorylation of Ser-C23 could destabilize interactions that occur either directly through this 20 residue sequence or that are dependent on its correct conformation	SIGNOR-250353
P63096	P35414	2	binding	up-regulates activity	0.437	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-256681
Q05655	P10588	1	phosphorylation	down-regulates	0.2	Ser-83 on recombinant nr2f6is a pkc substrate site;mutation of ser-83 (but not ser-89) to alanine strongly reduced pkc-mediated nr2f6 phosphorylation, confirming ser-83 as the major pkc phosphorylation site in nr2f6;the dna-binding capacity of nr2f6 is antagonized by a (p)ser-83 switch on nr2f6.	SIGNOR-180017
P05771	Q8NER1	2	phosphorylation	up-regulates activity	0.2	PKCβII causes the downregulation of TRPV1 by phosphorylating the channel. The increased threonine phosphorylation was substantially reduced by mutating Thr705, showing that Thr705 is indeed a major PKCβII phosphorylation site.	SIGNOR-276638
P04083	P12931	0	phosphorylation	up-regulates	0.389	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].Finally in 2013 caron et al. showed the relevance of y21 phosphorylation for the anxa1 stability. In fact the authors demonstrated that the tyrosine 21 phosphorylation is crucial for anxa1 sumoylation induced by egf	SIGNOR-202796
Q00613	P27361	0	phosphorylation	down-regulates	0.631	Sequential phosphorylation of hsf1 by mitogen-activated protein kinase and glycogen synthase kinase 3 at ser-303 and ser-307 represses transcriptional activation by heat shock factor-1.	SIGNOR-44999
Q13131	O60825	1	phosphorylation	up-regulates activity	0.464	Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b.	SIGNOR-84061
P19484	P16298	0	dephosphorylation	up-regulates activity	0.377	Lysosomal Ca2+ release via mucolipin 1 (MCOLN1) activates calcineurin, which binds and de-phosphorylates TFEB, thus promoting its nuclear translocation.	SIGNOR-255306
Q9NPG1	O14640	2	binding	up-regulates activity	0.659	When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp.	SIGNOR-134288

Q7L590

O94761

2

binding

down-regulates

0.509

Mcm10 inhibits recq4 helicase activity.

SIGNOR-187701

O75581

Q9ULV1

2

binding

up-regulates activity

0.649

Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction.

SIGNOR-258964

P15172

P40424

2

binding

up-regulates activity

0.41

These domains are necessary for the stable binding of myod to the myogenin promoter through an interaction with an adjacent protein complex containing the homeodomain protein pbx, which appears to be constitutively bound at this site

SIGNOR-124834

Q9Y243

P55265

1

phosphorylation

down-regulates activity

0.2

AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively

SIGNOR-276191

P01024

2

cleavage

up-regulates activity

0.2

C3 autoactivates in a process known as “tick-over,” which is characterized by spontaneous hydrolysis of a reactive thiol-ester to generate C3(H2O). Although C3(H2O)Bb produces only relatively small amounts of C3b compared to the other C3 convertases, it nevertheless generates enough C3b to set the C3 convertase amplification loop in motion.

SIGNOR-263483

Q9HAW9

Q99626

0

transcriptional regulation

up-regulates quantity by expression

0.26

Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter.

SIGNOR-253969

Q96P20

Q6PJ69

0

ubiquitination

down-regulates activity

0.2

These results suggest that TRIM65 could inhibit the activation of the NLRP3 inflammasome in response to multiple agonists.|Thus, TRIM65 deficiency impairs NLRP3 ubiquitination and enhances NLRP3 inflammasome activation, but has no effects on AIM2 or IPAF inflammasome activation.

SIGNOR-278566

P13498

P14598

2

binding

up-regulates activity

0.79

Stimulus-induced phosphorylation of p47phox causes a conformational change, by which both PX and SH3 domains become accessible to their membranous targets, phosphoinositides and p22phox, respectively. Cooperation of these two interactions, each being indispensable, enables p47phox to form a stable complex with cytochrome b558 (composed of the two subunit gp91phox and p22phox), leading to activation of the phagocyte NADPH oxidase.

SIGNOR-276625

P78352

Q7Z6G8

2

binding

up-regulates activity

0.45

The reversible removal of AIDA-1 from the PSD core under excitatory conditions is similar to the redistribution of another abundant PSD protein, SynGAP. Both SynGAP-alpha1 and AIDA-1 are known to bind PSD-95.

SIGNOR-264228

P04626

P22681

0

ubiquitination

down-regulates quantity by destabilization

0.601

Ligand binding to EGFR also leads to rapid internalization and proteosomal/lysosomal degradation of the receptors. This process results in a dramatic downregulation of both total and cell surface receptors. EGF-induced degradation of EGFR is thought to be initiated by phosphorylation of tyrosine 1045 of the receptor followed by binding of Cbl adaptor proteins and ubiquitination of the receptor. Internalized EGFR is transported to early endosomes where receptor-ligand complexes are sorted for either degradation or recycling to the cell surface.

SIGNOR-30794

O15444

P51686

2

binding

up-regulates

0.805

Ccr9 is a specific receptor for the beta-chemokine teck/ccl25.

SIGNOR-104902

O00429

Q14012

0

phosphorylation

up-regulates activity

0.333

For example, protein kinase A (PKA) phosphorylation of Drp1S600 has been reported to decrease Drp1 GTPase activity in vitro (23, 24), whereas phosphorylation of the same conserved serine residue by Ca2+-calmodulin–dependent protein kinase Iα (CaMKIα) in Drp1 isoform 3 has been reported to cause a significant increase in mitochondrial fission

SIGNOR-262552

Q16595

P12931

0

phosphorylation

down-regulates quantity by destabilization

0.2

We found that frataxin can be phosphorylated by Src. Phosphorylation occurs primarily on Y118 and promotes frataxin ubiquitination, a signal for degradation.

SIGNOR-275585

P45984

Q9UPT6

2

phosphorylation

up-regulates

0.663

Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro.

SIGNOR-134576

P30307

Q9H4B4

0

phosphorylation

up-regulates

0.731

Cdc25c phosphorylation on serine 191 by plk3 promotes its nuclear translocation

SIGNOR-122090

Q15382

Q9NZJ5

2

binding

down-regulates activity

0.2

Rheb GTPase directly binds and activates PERK in vitro

SIGNOR-260873

Q8TDJ6

Q15042

2

binding

up-regulates quantity

0.54

We isolated here a novel protein that was co-immunoprecipitated with Rab3 GEP and GAP by their respective antibodies from the crude synaptic vesicle fraction of rat brain. The protein, named rabconnectin-3, bound both Rab3 GEP and GAP. These results indicate that rabconnectin-3 serves as a scaffold molecule for both Rab3 GEP and GAP on synaptic vesicles.

SIGNOR-265582

O43306

P04899

2

binding

down-regulates activity

0.522

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

SIGNOR-278078

P38405

P25100

2

binding

up-regulates activity

0.278

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-256951

Q6P0Q8

P60484

1

phosphorylation

up-regulates

0.666

We further demonstrate that binding of pten to specific pdz domains diminishes its degradation rate and facilitates its phosphorylation by mast kinases. Our results suggest a regulatory role of pdz domain binding on pten function by controlling its stability and phosphorylation status.

SIGNOR-138051

P35241

Q13464

0

phosphorylation

up-regulates activity

0.68

A peak of the phosphopeptide, in which only T573 was phosphorylated, was not detected. Quantitative analyses revealed that _100% of T564, but at most _40% of T573, was phosphorylated when C-rad was incubated with Rho-Kc for 1 h. Then we concluded that the major and primary phosphorylation site of radixin by Rho-kinase was T564 and referred to the Rho-Kcphosphorylated C-rad as T564-phosphorylated C-rad. | In this study, we found that the T564 phosphorylation of radixin markedly suppressed its head-to-tail association. This suggests that the T564-phosphorylation of radixin (and probably also the phosphorylation of ezrin T567 and moesin T558) keeps them open and active.

SIGNOR-248994

Q96F44

Q99453

1

ubiquitination

down-regulates

0.485

The e3 ubiquitin ligasetrim11mediates the degradation of congenital central hypoventilation syndrome-associated polyalanine-expandedphox2b.

SIGNOR-195878

Q15418

P67809

1

phosphorylation

up-regulates

0.543

We therefore conclude that rsk1/rsk2 are novel activators of yb-1, able to phosphorylate the serine 102 residue.

SIGNOR-182497

Q9UQF2

P45983

2

binding

down-regulates

0.879

The jip proteins function by aggregating components of a map kinase module (including mlk, mkk7, and jnk) and facilitate signal transmission by the protein kinase cascade. Overexpression of jip1 deactivates the jnk pathway selectively by cytoplasmic retention of jnk and thereby inhibits gene expression mediated by jnk, which occurs in the nucleus

SIGNOR-124727

O14939

P00533

0

phosphorylation

up-regulates activity

0.516

Using transiently transfected human embryonic kidney fibroblasts (HEK293), we demonstrate here that PLD1 activity, and to a lesser extent PLD2 activity, is stimulated in response to epidermal growth factor (EGF). PLD2, but not PLD1, associates with the EGF receptor in a ligand-independent manner and becomes tyrosine-phosphorylated upon EGF receptor activation. Tyrosine 11 (Tyr-11) of PLD2 was identified as the specific phosphorylation site. Mutation of this residue to phenylalanine enhanced basal activity almost 2-fold

SIGNOR-251095

P46527

P49792

0

relocalization

down-regulates quantity

0.2

RanBP2 can increase the sumoylation of p27kip1. In our study, the target protein p27kip1 mainly acts as a tumor-suppressor gene in the nucleus, RanBP2 and SUMO1 act as oncogenes by promoting the nuclear-cytoplasmic translocation and debilitate the G1-arrest brought by p27kip1 accumulation in the nucleus.

SIGNOR-259115

P06748

P53350

0

phosphorylation

up-regulates

0.425

Phosphorylated at ser-4 by plk1 and plk2. Phosphorylation at ser-4 by plk2 in s phase is required for centriole duplication and is sufficient to trigger centriole replication. Phosphorylation at ser-4 by plk1 takes place during mitosis.

SIGNOR-125666

O75553

Q93034

0

polyubiquitination

down-regulates quantity by destabilization

0.327

SOCS7 promotes Dab1 polyubiquitylation and degradation. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SOCS7, a CRL5 substrate adaptor protein, is also required for neocortical layering. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1.

SIGNOR-272140

P07947

Q04760

1

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

Q9Y2I7

P31749

0

phosphorylation

up-regulates

0.491

Here we report that serine318 on the fyve domain-containing ptdins3p 5-kinase (pikfyve) is a novel substrate for pkb, and show that phosphorylation stimulates the ptdins3p 5-kinase activity of the enzyme.

SIGNOR-252474

Q14185

Q8WXX7

2

binding

up-regulates activity

0.2

Mutations in the Autism susceptibility candidate 2 gene (AUTS2), whose protein is believed to act in neuronal cell nuclei, have been associated with multiple psychiatric illnesses, including autism spectrum disorders, intellectual disability, and schizophrenia. Here we show that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development. AUTS2 activates Rac1 to induce lamellipodia but downregulates Cdc42 to suppress filopodia. Our loss-of-function and rescue experiments show that a cytoplasmic AUTS2-Rac1 pathway is involved in cortical neuronal migration and neuritogenesis in the developing brain. These results suggest that FL-AUTS2 can activate Rac1 via interaction with P-Rex1 and the Elmo2/Dock180 complex to regulate actin dynamics in N1E-115 cells.

SIGNOR-266820

P49137

Q00987

1

phosphorylation

up-regulates quantity by stabilization

0.364

Hdm2 phosphorylation by mapkap kinase 2 enhances hdm2 activity and promote the degradation of p53.

SIGNOR-133560

Q99523

P02647

2

binding

up-regulates quantity

0.331

Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/Aβ complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aβ in the brain and in aggravated plaque burden. Sortilin interacts with all human APOE isoforms.

SIGNOR-273722

Q92963

Q12967

2

binding

up-regulates activity

0.534

Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors.

SIGNOR-220859

P17813

O95393

2

binding

up-regulates activity

0.362

Soluble endoglin specifically binds bone morphogenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppresses tumor growth. We found that mouse and human endoglin ECD-Fc bound directly, specifically, and with high affinity to bone morphogenetic proteins 9 and 10 (BMP9 and BMP10) in surface plasmon resonance (Biacore) and cell-based assays.

SIGNOR-276657

P22694

P10644

2

binding

down-regulates activity

0.863

Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets

SIGNOR-258755

Q96EP1

Q93009

0

deubiquitination

up-regulates quantity by stabilization

0.432

In this study, we identified USP7 (also known as HAUSP), which is a member of a family of proteins that cleave polyubiquitin chains and/or ubiquitin precursors, as an interacting protein with Chfr by immunoaffinity purification and mass spectrometry, and their interaction greatly increases the stability of Chfr. In fact, USP7 can remove ubiquitin moiety from the autoubiquitinated Chfr both in vivo and in vitro, which results in the accumulation of Chfr in the cell. USP7 mediates deubiquitination of Chfr.

SIGNOR-271462

P41586

P18509

2

binding

up-regulates

0.877

Type i pacap receptors bind pacap-27 and -38. the potencies of the two forms of pacap are similar for adenylate cyclase stimulation, whereas pacap-38 is more potent than pacap-27 in phospholipase c activation.

SIGNOR-43225

Q9UD71

P68400

0

phosphorylation

up-regulates activity

0.34

Study of [Plphosphate release during manual Edman degradation confirmed that the phosphorylated residues in rat DARPP-32 were Ser45 and Ser102. | Phosphorylation by casein kinase II did not affect the potency of DARPP-32 as an inhibitor of protein phosphatase-1, which depended only on phosphorylation of Thr34 by cAMP-dependent protein kinase. However, phosphorylation of DARPP-32 by casein kinase II facilitated phosphorylation of Thr34 by cAMP-dependent protein kinase

SIGNOR-250927

Q8IZD2

P10276

2

binding

up-regulates activity

0.334

MLL5 binds to retinoic acid receptor α (RARα) and induces transcriptional activation of RARα target genes by methylation of lysine residues of histone H3.

SIGNOR-260041

P00533

Q16539

0

phosphorylation

down-regulates

0.508

In conclusion, the use of pharmacological agents suggests that p38 mapk is the enzyme involved in egfr phosphorylation, as well as internalization, following exposure of cells to various stress-inducing conditions.

SIGNOR-149089

P35580

Q06413

0

transcriptional regulation

up-regulates quantity by expression

0.345

Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation

SIGNOR-238769

Q86YJ5

Q96LA5

1

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-271543

P10145

P25024

2

binding

up-regulates

0.78

Il-8 activates both the cxcr1 and the cxcr2 on microvascular endothelial cells, using different signal transduction cascades.

SIGNOR-107920

P36897

O95405

2

binding

up-regulates activity

0.631

Sara functions to recruit smad2 to the tgfbeta receptor by controlling the subcellular localization of smad2 and by interacting with the tgfbeta receptor complex

SIGNOR-62868

P07947

P30530

0

phosphorylation

up-regulates activity

0.2

Here, we show that EphA2, YES1, and ANXA2 form a signal axis, in which YES1 activated by EphA2 phosphorylates ANXA2 at Tyr24 site, leading to ANXA2 activation and increased ANXA2 nuclear distribution in gastric cancer (GC) cells.

SIGNOR-277555

O95297

Q06124

0

dephosphorylation

down-regulates

0.522

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

SIGNOR-75220

P84243

O75151

0

demethylation

up-regulates activity

0.2

PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark.

SIGNOR-264518

P51003

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-268330

Q9NRI5

P33176

2

binding

up-regulates activity

0.2

We identified Kinesin-1, a microtubule-dependent and plus-end directed motor, as a DISC1-interacting molecule. Our results show that DISC1 links Kinesin-1 to the NUDEL/LIS1/14-3-3ε complex, serves as the cargo receptor, and regulates the transport of the complex to axons, leading to axon elongation. DISC1 directly interacted with kinesin heavy chain of Kinesin-1. Kinesin-1 interacted with the NUDEL/LIS1/14-3-3ε complex through DISC1

SIGNOR-252161

E9PAV3

Q13418

0

phosphorylation

up-regulates

0.426

The inactivation of gsk3? In response to adhesion and ilk activation (6) would then result in a thr-159-hypophosphorylated ?-Nac that would become unavailable for proteasome degradation but would become a substrate for the ilk kinase activity on residue ser-43. The ser-43-phosphorylated ?-Nac would preferentially interact with c-jun (30), translocate to the nucleus, and potentiate transcription

SIGNOR-127631

Q99704

Q13882

0

phosphorylation

down-regulates activity

0.494

BRK downregulates Dok1 via proteasomal degradation.|BRK phosphorylates Dok1 at tyrosine 362.

SIGNOR-278301

Q9NZQ7

Q9Y4X5

0

polyubiquitination

down-regulates quantity by destabilization

0.2

We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal degradation following GSK3α-mediated phosphorylation of Ser279/Ser283. We identify ARIH1 as the E3 ubiquitin ligase responsible for targeting PD-L1 to degradation.

SIGNOR-277553

P12931

P56945

1

phosphorylation

up-regulates activity

0.803

Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs

SIGNOR-246393

P05204

P17252

0

phosphorylation

down-regulates

0.29

Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools.

SIGNOR-76320

P29474

P17252

0

phosphorylation

down-regulates activity

0.3

The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites

SIGNOR-251620

O75030

P49840

0

phosphorylation

up-regulates

0.294

Glycogen synthase kinase 3 (gsk3) was found to phosphorylate ser298 in vitro, thereby enhancing the binding of mitf to the tyrosinase promoter

SIGNOR-72878

Q9NX18

P21912

2

binding

up-regulates

0.617

Sdh5 is required for sdh activity and stability / the sdh1-sdh5 interaction is likely to be functionally important because the sdh5_ mutant lacks sdh activity

SIGNOR-187239

P49757

P46531

1

ubiquitination

down-regulates quantity by destabilization

0.798

Mammalian numb proteins promote notch1 receptor ubiquitination and degradation of the notch1 intracellular domain

SIGNOR-99762

P16220

Q92911

1

transcriptional regulation

up-regulates quantity by expression

0.267

CREB recognized and bound to the promoter of SLC5A5 to facilitate its transcription.

SIGNOR-267137

Q92889

Q8IY92

2

binding

up-regulates

0.755

Slx4 is a tumor suppressor that stimulates the activity of the nuclease xpf-ercc1 in dna crosslink repair.

SIGNOR-204890

Q13043

P04406

1

phosphorylation

up-regulates activity

0.279

Interestingly, GAPDH is phosphorylated by Mst1 to a comparable extent as its known substrate MBP, suggesting that GAPDH is a good substrate of Mst1 at least in vitro.|Moreover, interaction of Mst1 with GAPDH caused a robust phosphorylation of GAPDH and markedly increased the Mst1 activity in cells.

SIGNOR-279295

P17252

P15382

1

phosphorylation

down-regulates activity

0.307

Inhibition of the current was not seen in channels in which Ser103 was replaced by Ala, although other properties of the current were unchanged. These results indicate that inhibition of the potassium current results from direct phosphorylation of the channel subunit protein at Ser103.

SIGNOR-248852

P20366

P21452

2

binding

up-regulates

0.874

The mammalian tachykinins include substance p, neurokinin a and neurokinin b, which exert their effects by binding to specific receptors. These tachykinin receptors are divided into three types, designated nk1, nk2 and nk3, respectively. The interaction of tachykinin with its receptor activates gq, which in turn activates phospholipase c to break down phosphatidyl inositol bisphosphate into inositol trisphosphate (ip3) and diacylglycerol (dag).

SIGNOR-44773

P09086

P07947

0

phosphorylation

up-regulates activity

0.2

These data suggest that Yes1 is the TKI-sensitive kinase that can directly phosphorylate OCT2.

SIGNOR-279664

P01344

P08069

2

binding

up-regulates activity

0.821

These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients.

SIGNOR-251495

P35222

Q9Y3M2

2

binding

down-regulates

0.693

Here we report a conserved nuclear protein, named chibby, which was identified in a screen for proteins that directly interact with the c-terminal region of beta-catenin. In mammalian cultured cells we demonstrate that chibby inhibits beta-catenin-mediated transcriptional activation by competing with lef-1 to bind to beta-catenin.

SIGNOR-100835

P12931

P23469

0

dephosphorylation

up-regulates activity

0.402

PTPepsilonM activated c-Src kinase probably by directly dephosphorylating phospho-Tyr527, a negative regulatory site of c-Src.

SIGNOR-238074

P60953

Q6XZF7

0

guanine nucleotide exchange factor

up-regulates activity

0.572

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-260547

O43318

P53805

1

phosphorylation

up-regulates activity

0.2

Here we showed that TAK1 directly phosphorylated RCAN1 at two novel sites (serine 94 and -136), resulting in activation of calcineurin-NFAT signaling.|Indeed, low doses of RCAN1 facilitated calcineurin-nuclear factor of activated T cells signaling in the presence of TGF-\u03b2-activated kinase 1+TAB1 ( ), suggesting that TGF-\u03b2-activated kinase 1 augments calcineurin-nuclear factor of activated T cells signaling through RCAN1.

SIGNOR-279535

P49840

P17612

0

phosphorylation

down-regulates

0.372

Phosphorylation of ser21 and inactivation of glycogen synthase kinase 3 by protein kinase a.

SIGNOR-83221

Q9ULJ6

P46531

2

binding

up-regulates activity

0.452

The N-terminal domain (NTD) is critical for Zmiz1 to function as a Notch collaborator. Zmiz1 and Notch1 cooperatively recruit each other to chromatin through the TPR domain. The N-terminal domain (NTD) of Zmiz1 is important for enhancing Notch reporter activity and contains tetratricopeptide repeats (TPR) that mediate protein-protein interactions

SIGNOR-263936

O75385

Q6ZNE5

1

phosphorylation

up-regulates activity

0.651

ULK1 phosphorylates ATG14 at serine 29.

SIGNOR-278433

Q13950

P31749

0

phosphorylation

down-regulates activity

0.446

Here we show that Akt kinase directly phosphorylates Runx2 to regulate invasive properties of breast cancer cells.

SIGNOR-280176

P48775

P43694

0

transcriptional regulation

down-regulates quantity by repression

0.252

GATA4 inhibits expression of the tryptophan oxygenase gene by binding to the TATA box in fetal hepatocytes.

SIGNOR-268994

Q9UMX1

P51955

0

phosphorylation

up-regulates activity

0.2

Intriguingly, Nek2A is found to stabilize SuFu at least partly depending on its kinase activity, thereby triggering phosphorylation of the SuFu protein.|Nek2A phosphorylates and stabilizes SuFu: A new strategy of Gli2/Hedgehog signaling regulatory mechanism.

SIGNOR-279235

Q9BRS8

P31749

0

phosphorylation

up-regulates activity

0.353

Akt dependent phosphorylation of LARP6. We provide the first description that LARP6 is phosphorylated at multiple sites and that phosphorylation of S451 is critical to activate the protein in type I collagen biosynthesis.

SIGNOR-277213

P16220

P51812

0

phosphorylation

up-regulates activity

0.726

MAPK activates CREB kinase, which in turn phosphorylates and activates CREB. Purification, sequencing, and biochemical characterization of CREB kinase revealed that it is identical to a member of the pp90(RSK) family, RSK2. RSK2 was shown to mediate growth factor induction of CREB serine-133 phosphorylation both in vitro and in vivo. These findings identify a cellular function for RSK2 and define a mechanism whereby growth factor signals mediated by RAS and MAPK are transmitted to the nucleus to activate gene expression

SIGNOR-248951

P14784

P29353

2

binding

up-regulates

0.558

The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival

SIGNOR-204975

P19784

P41236

1

phosphorylation

up-regulates activity

0.307

Recombinant wild-type I-2 and the Ala-120/121 mutant were phosphorylated synergistically by GSK-3 and casein kinase II. The Thr-72 and Ser-86 mutants, however, did not undergo this synergistic phosphorylation. Our studies indicate that Thr-72 is the only GSK-3 site and that Ser-86 is the casein kinase II site required for the potentiation of GSK-3 action.

SIGNOR-251021

Q9Y6Y8

Q15436

2

binding

up-regulates activity

0.572

The results showed that the N-terminal region of p125 is important for the interaction with Sec23p. We confirmed the interaction between the two proteins by a yeast two-hybrid assay. Overexpression of p125, like that of mammalian Sec23p, caused disorganization of the endoplasmic reticulum-Golgi intermediate compartment and Golgi apparatus, suggesting its role in the early secretory pathway.

SIGNOR-265307

Q9NTG7

P36888

0

phosphorylation

down-regulates activity

0.2

We also hypothesize that, besides activating ACAT1 through Y407 phosphorylation (Fan et al., 2016), FLT3 might simultaneously phosphorylate and regulate SIRT3. Our mutational studies on all of the seven tyrosine sites of SIRT3 revealed that purified rFLT3 directly phosphorylated purified rSIRT3 in an in vitro kinase assay, leading to decreased SIRT3 deacetylase activity that was assessed by ability to deacetylate K413 of mIDH2 (Figure 4H, first three samples in left, middle, and right panels), whereas replacement of Y226 completely abolished inhibition of SIRT3 by FLT3 (Figure 4H, right).

SIGNOR-267631

Q9UQ13

P62136

2

binding

up-regulates activity

0.596

Using a proteomics approach, we have identified a complex comprised of Shoc2/Sur-8 and the catalytic subunit of protein phosphatase 1 (PP1c) as a highly specific M-Ras effector. M-Ras targets Shoc2-PP1c to stimulate Raf activity by dephosphorylating the S259 inhibitory site

SIGNOR-251647

P67809

P28482

0

phosphorylation

up-regulates activity

0.47

ERK2 may also directly phosphorylate YB-1 and therefore promotes its ability to transactivate target genes.

SIGNOR-279227

P05106

P31749

0

phosphorylation

down-regulates activity

0.613

A survey of several protein kinases revealed that Thr-753 was avidly phosphorylated by PDK1 and Akt/PKB in vitro. These observations suggest that activation of PDK1 and/or Akt/PKB in platelets may modulate the binding activity and/or specificity of beta(3) for signaling molecules.

SIGNOR-252552

Q14980

Q13885

2

binding

up-regulates

0.2

Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.

SIGNOR-116936

Q96PU5

P35240

1

ubiquitination

up-regulates activity

0.261

Merlin ubiquitination is mediated by the E3 ubiquitin ligase, NEDD4L, which requires a scaffold protein, AMOTL1, to approach Merlin. Several NF2-patient-derived Merlin mutations disrupt its binding to AMOTL1 and its regulation by the AMOTL1-NEDD4L apparatus. Lysine (K) 396 is the major ubiquitin conjugation residue. Disruption of Merlin ubiquitination by the K396R mutation or NEDD4L depletion diminishes its binding to Lats1 and inhibits Lats1 activation. These effects are also accompanied by loss of Merlin's anti-mitogenic and tumor suppressive properties. Thus, we propose that dephosphorylation and ubiquitination compose an intramolecular relay to activate Merlin functions in activating the Hippo pathway during growth control.

SIGNOR-263662

P17252

P48050

1

phosphorylation

down-regulates activity

0.2

These results therefore indicate that Kir2.3 is directly modulated by PKC phosphorylation of its channel protein and threonine 53 is the PKC phosphorylation site in Kir2.3.

SIGNOR-275965

P84022

Q9UNE7

0

ubiquitination

down-regulates quantity by destabilization

0.57

These results suggest that Smad3 could be easily ubiquitinated and degraded by CHIP when Hsp90 activity was inhibited.To demonstrate the role of Hsp70 and Hsp90 on the regulation of Smad3 by CHIP, we over-expressed Hsp70 and Hsp90 in mammalian cells.

SIGNOR-278785

P17655

P28482

0

phosphorylation

up-regulates

0.628

Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo.

SIGNOR-123079

P29803

Q16654

0

phosphorylation

down-regulates

0.547

Pyruvate dehydrogenase (pdh) activity (pdha) controls the entry of carbohydrate into the tricarboxylic cycle and is regulated by pdh kinase (pdk), which phosphorylates and inactivates the enzyme, and pdh phosphatase, which dephosphorylates the enzyme to the active form

SIGNOR-121936

P15924

P17612

0

phosphorylation

down-regulates activity

0.328

HeLa cells treated with forskolin indicated that stimulation of protein kinase A in transfected cells could decrease the interaction of DP.AN.SerC23 with keratin IF networks. phosphorylation of Ser-C23 could destabilize interactions that occur either directly through this 20 residue sequence or that are dependent on its correct conformation

SIGNOR-250353

P63096

P35414

2

binding

up-regulates activity

0.437

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-256681

Q05655

P10588

1

phosphorylation

down-regulates

0.2

Ser-83 on recombinant nr2f6is a pkc substrate site;mutation of ser-83 (but not ser-89) to alanine strongly reduced pkc-mediated nr2f6 phosphorylation, confirming ser-83 as the major pkc phosphorylation site in nr2f6;the dna-binding capacity of nr2f6 is antagonized by a (p)ser-83 switch on nr2f6.

SIGNOR-180017

P05771

Q8NER1

2

phosphorylation

up-regulates activity

0.2

PKCβII causes the downregulation of TRPV1 by phosphorylating the channel. The increased threonine phosphorylation was substantially reduced by mutating Thr705, showing that Thr705 is indeed a major PKCβII phosphorylation site.

SIGNOR-276638

P04083

P12931

0

phosphorylation

up-regulates

0.389

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].Finally in 2013 caron et al. showed the relevance of y21 phosphorylation for the anxa1 stability. In fact the authors demonstrated that the tyrosine 21 phosphorylation is crucial for anxa1 sumoylation induced by egf

SIGNOR-202796

Q00613

P27361

0

phosphorylation

down-regulates

0.631

Sequential phosphorylation of hsf1 by mitogen-activated protein kinase and glycogen synthase kinase 3 at ser-303 and ser-307 represses transcriptional activation by heat shock factor-1.

SIGNOR-44999

Q13131

O60825

1

phosphorylation

up-regulates activity

0.464

Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b.

SIGNOR-84061

P19484

P16298

0

dephosphorylation

up-regulates activity

0.377

Lysosomal Ca2+ release via mucolipin 1 (MCOLN1) activates calcineurin, which binds and de-phosphorylates TFEB, thus promoting its nuclear translocation.

SIGNOR-255306

Q9NPG1

O14640

2

binding

up-regulates activity

0.659

When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp.

SIGNOR-134288