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
P43034	P30622	2	binding	up-regulates activity	0.793	Here we demonstrate colocalization and direct interaction between CLIP-170 and LIS1. In mammalian cells, LIS1 recruitment to kinetochores is dynein/dynactin dependent, and recruitment there of CLIP-170 is dependent on its site of binding to LIS1, located in the distal zinc finger motif.	SIGNOR-252166
Q9BTU6	Q9HAW4	1	phosphorylation	down-regulates	0.2	These results indicate that plx1 phosphorylates claspin on s934, which is relatively close to the plx1-docking site at t906. Human claspin also contains a serine at position 984 in a homologous sequence	SIGNOR-159937
P49840	Q96F46	1	phosphorylation	down-regulates quantity by destabilization	0.2	Glycogen synthase kinase 3 (GSK3) constitutively bound to and phosphorylated IL-17RA at T780, leading to ubiquitination and proteasome-mediated degradation of IL-17RA, thus inhibiting IL-17-mediated inflammation.	SIGNOR-277206
P07237	Q8IXL6	0	phosphorylation	up-regulates activity	0.387	The secretory pathway kinase Fam20C phosphorylates Ser357 of PDI and responds rapidly to various ER stressors. Phosphorylation of Ser357 induces an open conformation of PDI and turns it from a "foldase" into a "holdase", which is critical for preventing protein misfolding in the ER. Phosphorylated PDI also binds to the lumenal domain of IRE1α, a major UPR signal transducer, and attenuates excessive IRE1α activity.	SIGNOR-275574
Q9BY78	Q13501	1	ubiquitination	up-regulates activity	0.358	SQSTM1 Is a Substrate for RNF26 and the DUB USP15. Catalytically competent RNF26 (light red) recruits SQSTM1 (blue) and mediates ubiquitin ligation (red), which serves to attract UBDs of specific vesicle-associated adaptors.	SIGNOR-269830
Q96RU2	P01106	1	deubiquitination	up-regulates	0.703	Usp28, an ubiquitin-specific protease, binds to myc through an interaction with fbw7alpha, an f-box protein that is part of an scf-type ubiquitin ligase. Therefore, it stabilizes myc.	SIGNOR-155590
P0DMV8	O15217	1	relocalization	up-regulates activity	0.2	Model showing Ser189/Thr193 protein kinase dependent phosphorylation of GST A4‐4 has increased affinity for chaperone Hsp70 which activates mitochondrial competent import signals for GSTA4‐4. \|Protein kinase A mediated phosphorylation of serine residues of CYPs increases the affinity of proteins for binding to cytoplasmic chaperones such as heat shock proteins (Hsp), Hsp70/Hsp90, resulting in increased mitochondrial translocation	SIGNOR-264799
P40763	Q13188	0	phosphorylation	down-regulates activity	0.2	Hippo pathway component MST2 kinase phosphorylates STAT3 at T622, which is located in the SH2 domain of STAT3. This phosphorylation blocks the SH2 domain in one STAT3 molecule to bind with the phosphorylated Y705 site in another STAT3 molecule, which further counteracts IL6-induced STAT3 dimerization and activation.	SIGNOR-277599
O43896	P20340	1	relocalization	up-regulates quantity	0.409	Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation.	SIGNOR-266877
Q8N122	Q15418	0	phosphorylation	up-regulates	0.546	Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity	SIGNOR-180466
P01215	P50458	0	transcriptional regulation	up-regulates quantity by expression	0.266	In Cos cells, LH-2 activated the a-subunit promoter approximately twofold	SIGNOR-266055
Q92878	Q13315	2	binding	up-regulates	0.813	One of the earliest events is recruitment and activation of the atm at the damaged dna sites through the mre11rad50nbs1 (mrn) sensor complex. . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm kinase.	SIGNOR-175053
P59595	P15336	1	transcriptional regulation	up-regulates quantity by expression	0.2	The transcription factors c-Fos, FosB, CREB-1, and ATF2 were all activated by the addition of SARS-CoV N protein to the sample well	SIGNOR-260727
P49841	P48729	2	binding	up-regulates activity	0.579	In the absence of secreted wnt ligands, cytosolic beta-catenin is phosphorylated at ser45 by the priming kinase casein kinase 1 (ck1). Consequently, glycogen synthase kinase 3 (gsk3), in complex with axin and adenomatous polyposis coli (apc), phosphorylates beta-catenin at thr41, ser37, and ser33 apc cooperates with axin to promote the phosphorylation of b-catenin by gsk3 [which requires priming phosphorylation by casein kinase 1, alpha-isoform (ck1alpha)]	SIGNOR-184696
O95644	Q9Y625	1	transcriptional regulation	up-regulates quantity by expression	0.251	NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype.	SIGNOR-264022
Q9Y6K9	P49841	0	phosphorylation	down-regulates quantity	0.431	For analysis of phosphorylation of NEMO on Ser8 and Ser17 by GSK-3, we generated phospho-specific antibodies (anti-phospho-NEMO-Ser8 and anti-phospho-NEMO-Ser17) while anti-phospho-NEMO-Ser31 and anti-phospho-NEMO-Ser43 were commercially available. Indeed, GSK-3\u03b2 was able to phosphorylate all four serines of rhNEMO in a time-dependent manner in an in vitro kinase assay (Fig. 3a).\|In this study, we identified NEMO as a GSK-3\u03b2 substrate that is phosphorylated at several serine residues located within the N-terminal domain.\|The kinase forms a complex with wild-type NEMO while point mutations of NEMO at the specific serines abrogated GSK-3Œ≤ binding and subsequent phosphorylation of NEMO resulting in its destabilization	SIGNOR-279527
P53805	P49841	0	phosphorylation	up-regulates activity	0.484	Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively \|Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin.	SIGNOR-249359
Q13085	P38398	2	binding	down-regulates activity	0.548	ACCA binds BRCA1 when phosphorylated onSer1263, thus supporting a model in which controlof lipid synthesis would be mediated at least in part,viaphosphorylation of the Ser1263.	SIGNOR-267474
P20645	Q8IWJ2	0	relocalization	up-regulates activity	0.532	Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector	SIGNOR-253086
O43683	P53350	2	binding	up-regulates	0.864	The plk1-bub1 interaction requires the polo-box domain (pbd) of plk1 and is enhanced by cyclin-dependent kinase 1 (cdk1)-mediated phosphorylation of bub1 at t609	SIGNOR-147061
O00187	P11226	2	binding	up-regulates activity	0.74	The results (Fig. 3A) show that the anti-MBL antibody, in addition to binding MBL captures both MASP-1 and MASP-2\|Our results emphasize the similarity between complement activation through the MBL, or 'MBLectin' pathway of the innate immune system and the classical pathway of complement activation (Fig. 5).	SIGNOR-263415
P18031	P42226	1	dephosphorylation	down-regulates activity	0.327	Phosphorylated STAT6 may also serve as a cytoplasmic substrate for PTP1B since overexpression of PTP1B leads to STAT6 dephosphorylation and the suppression of STAT6 transcriptional activity, whereas PTP1B deficiency increases IL-4-induced STAT6 signaling in B-cells.	SIGNOR-277122
P20393	O60890	2	binding	up-regulates activity	0.2	Rev-erbα regulates OPHN-1-mediated RhoA/ERM signalling in platelets., The results of the co-immunoprecipitation revealed that Rev-erbα coimmunoprecipitated with OPHN-1 in both mouse and human platelets and this interaction significantly increased upon stimulation with agonist U46619.	SIGNOR-268428
P28702	P55055	2	binding	up-regulates	0.696	We provide genetic and molecular evidence that cholesterol homeostasis in scs does not require pparalpha and beta, but depends upon the tif2 coactivator and rxrbeta/lxrbeta heterodimers, in which rxrbeta af-2 is transcriptionally active.	SIGNOR-123094
P21127	P50613	0	phosphorylation	up-regulates activity	0.335	We conclude that CDK7 phsphorylates Cdk11, dependent on the conserved Thr219 residue in the CDK11 T loop, and it is therefore likely to be a genuine Cdk11 activating kinase	SIGNOR-245871
P11831	P49137	0	phosphorylation	up-regulates	0.584	Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2	SIGNOR-166640
Q9Y5I2	Q9Y5G8	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-265717
Q07021	P02746	2	binding	down-regulates activity	0.341	Previous studies have shown that gC1qR inhibits aggregated IgG-mediated complement activation by binding to the gC1q site on C1q, thereby preventing IgG from binding to the gh’s (28), suggesting that the binding sites for gC1qR and IgG on C1q may be identical or at least overlapping.	SIGNOR-263403
Q9NZJ5	P11021	2	binding	down-regulates activity	0.726	In the stressed ER, protein chaperone GRP78 binds to unfolded proteins and dissociates from the luminal domain of PERK, leading to oligomerization and activation of PERK by autophosphorylation.	SIGNOR-260164
P31749	O43464	1	phosphorylation	down-regulates	0.322	Akt attenuation of the serine protease activity of htra2/omi through phosphorylation of serine 212	SIGNOR-252500
Q16539	P54829	2	binding	up-regulates	0.489	First [] step prevents upstream activating kinases from promiscuously binding and activating p38a. Second, by blocking access to the mapk insert pocket, through the stepcat interaction, step can prevent the binding of allosteric signaling molecules that induce autoactivation of p38a.	SIGNOR-194829
Q96EB6	Q13043	0	phosphorylation	down-regulates activity	0.344	We found that MST1 increases p53 acetylation and transactivation by inhibiting the deacetylation of Sirtuin 1 (Sirt1) and its interaction with p53 and that Sirt1 can be phosphorylated by MST1 leading to the inhibition of Sirt1 activity.	SIGNOR-279574
Q01718	Q8TCY5	2	binding	up-regulates activity	0.76	We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling.We have previously identified MRAP as an accessory protein for MC2R, required for receptor trafficking to the cell surface and the formation of a functional MC2R. Here we have identified MRAP2 as a homologue of MRAP. Like MRAP, MRAP2 is able to support MC2R cell-surface expression, producing a functional ACTH-responsive receptor.	SIGNOR-252360
Q9NQ66	P50148	2	binding	up-regulates	0.768	The beta- but not the gamma- and delta-type isozymes of inositol phospholipid-specific phospholipase c (plc) are activated by g protein alpha q and beta gamma subunits.	SIGNOR-37149
Q92914	Q9Y5Y9	2	binding	down-regulates activity	0.2	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253442
P23443	Q6ZVD8	0	dephosphorylation	down-regulates activity	0.49	We show that PHLPP preferentially dephosphorylates the hydrophobic motif T389 site in S6K1 in vitro	SIGNOR-248247
P36873	P05198	1	dephosphorylation	up-regulates activity	0.412	Dephosphorylation of eIF2Î± is central to ISR signal termination to restore protein synthesis and normal cell functioning. It is mediated by protein phosphatase 1 (PP1) complex that recruits a PP1 catalytic subunit (PP1c) and one of the two regulatory subunits. In mammals, phosphatase activity is regulated by either PPP1R15A (also known as growth arrest and DNA damageâ€inducible protein, GADD34), which is induced as part of the ISR. the GADD34â€“PP1 complex acts as an important negative feedback loop to restore protein synthesis once the ER stress has been resolved, and as such aids in cell survival	SIGNOR-254119
P35348	Q14344	2	binding	up-regulates activity	0.623	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-257279
Q8WW43	P49768	2	binding	up-regulates	0.911	Biochemical and genetic studies have recently identified nicastrin, aph-1, and pen-2 as essential cofactors that physically interact with ps1 and are necessary for the gamma-secretase activity.	SIGNOR-97107
P29372	P51668	2	binding	up-regulates activity	0.2	Here we report that MID1 catalyzes the in vitro ubiquitination of the catalytic subunit of PP2A (PP2Ac) in the absence of alpha4. In the presence of alpha4, the level of PP2Ac ubiquitination is reduced.The high molecular weight smear pattern was not as obvious, suggesting that domains within the C-terminal half of MID1 may contribute to the polyubiquitination of PP2Ac. We observed that PP2Ac was ubiquitinated in the presence of UbcH5a-c and UbcH6, similar to results obtained with MID1-catalyzed ubiquitination of alpha4 (Figure 2E)	SIGNOR-271927
O15530	Q05513	1	phosphorylation	up-regulates	0.577	Our findings suggest that insulin, via pip(3), provokes increases in pkc-zeta enzyme activity through (a) pdk-1-dependent t410 loop phosphorylation, (b) t560 autophosphorylationcytoskeletal reorganization;tnni1(induces);desmin(induces);tpm1(induces);myo1c(induces);tnnt1(induces);	SIGNOR-85501
Q00535	Q8IWR1	1	phosphorylation	up-regulates activity	0.2	Here, we identify TRIM59 as a substrate of CDK5. EGFR-activated CDK5 directly binds to and phosphorylates TRIM59, a ubiquitin ligase at serine 308, which recruits PIN1 for cis-trans isomerization of TRIM59, leading to TRIM59 binding to importin α5 and nuclear translocation.	SIGNOR-272929
Q13615	P42345	1	null	down-regulates activity	0.354	The PtdIns3-phosphatase MTMR3 interacts with mTORC1 and suppresses its activity.	SIGNOR-245105
P01024	Q96PZ7	2	binding	down-regulates quantity	0.2	CUB and sushi multiple domains 1 (CSMD1) is a relatively poorly studied large transmembrane protein of 390 kDa composed of 14 N-terminal CUB domains interspersed with complement control protein (CCP) domains followed by 15 consecutive CCP domains. The active domains of CSMD1 were then identified in CCP17-21, which were shown to interact with C4b and C3b and present these complement proteins for degradation by factor	SIGNOR-265148
Q13332	Q96NI6	2	binding	up-regulates activity	0.368	SALM5 trans-synaptically interacts with LAR-RPTPs in a splicing-dependent manner to regulate synapse development. we identified LAR-RPTPs as novel ligands of SALM5 that mediates SALM5-dependent presynaptic differentiation in a splicing-dependent manner. Our data indicate that SALM5 interacts with all three known LAR-RPTPs—LAR, PTPδ, and PTPσ (Fig. 1).	SIGNOR-264088
O43765	P46379	2	binding	up-regulates activity	0.467	USP13 and gp78 control ubiquitination of Ubl4A.These data suggest that USP13 and gp78 play antagonizing roles in regulation of Ubl4A ubiquitination: While gp78 assembles ubiquitin chains on Ubl4A, USP13 antagonizes this activity to limit Ubl4A ubiquitination.Ubiquitination of Ubl4A preferentially occurs on Lys48. We identify the Bag6 cofactor Ubl4A as a shared substrate of gp78 and USP13. USP13 depletion is associated with hyper-ubiquitination of Ubl4A and altered interaction between the Bag6 complex and its co-chaperone SGTA. Because the interaction of Ubl4A with SGTA is mediated by positively-charged residues in Ubl4A including Lys48 (Chartron et al., 2012; Xu et al., 2012), which happens to be the major ubiquitination site, the simplest model to explain reduced Bag6-SGTA interaction in USP13 knockdown cells is that ubiquitin conjugates on Ubl4A sterically hinder SGTA binding.	SIGNOR-272859
Q15796	O96013	0	phosphorylation	down-regulates quantity by destabilization	0.339	In addition, PAK4 phosphorylates Smad2 on Ser465, leading to the degradation of Smad2 through ubiquitin-proteasome-dependent pathway under hepatocyte growth factor (HGF) stimulation.	SIGNOR-279084
Q14896	Q5VU43	2	binding	up-regulates	0.31	This study ascribes a novel function to mmgl isoform 4: it meets all criteria for classification as an akap, and we show that is involved in the phosphorylation of cmybpc as well as ctni, hence mmgl is an important regulator of cardiac contractility.	SIGNOR-173766
P42345	Q9UHD2	0	phosphorylation	up-regulates activity	0.42	They later demonstrated that TANK-binding kinase 1 (TBK1) interacts with and phosphorylates mTOR on Ser 2159, to promote catalytic activity of mTOR [216].	SIGNOR-278237
P51151	Q7Z6M1	1	null	up-regulates activity	0.581	P40 is a very potent transport factor in that the pure, recombinant protein can stimulate, significantly, an in vitro transport assay that measures transport of mannose 6-phosphate receptors from endosomes to the trans-Golgi network. The functional importance of p40 is confirmed by the finding that anti-p40 antibodies inhibit in vitro transport. Finally, p40 shows synergy with Rab9 in terms of its ability to stimulate mannose 6-phosphate receptor transport. These data are consistent with a model in which p40 and Rab9 act together to drive the process of transport vesicle docking.	SIGNOR-253088
P53779	P31947	1	phosphorylation	down-regulates	0.2	Here we demonstrate that activated jnk promotes bax translocation to mitochondria through phosphorylation of 14-3-3, a cytoplasmic anchor of bax. Phosphorylation of 14-3-3 led to dissociation of bax from this protein.Jnk phosphorylates 14-3-3zeta_ at ser-184 and 14-3-3sigma_ at ser-191	SIGNOR-124005
P01137	P13385	2	binding	down-regulates activity	0.2	Ere, we provide evidence supporting a novel mechanism in which Cripto inhibits the tumor suppressor function of TGF-beta. Cripto bound TGF-beta and reduced the association of TGF-beta with its type I receptor, TbetaRI.	SIGNOR-150006
O15054	P68431	1	demethylation	down-regulates activity	0.2	Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX) and Jumonji D3 (JMJD3) as novel histone demethylases that catalyze the removal of di- and trimethyl groups on histone H3 lysine 27, thereby promoting target gene activation.	SIGNOR-260018
P46937	Q14164	0	phosphorylation	down-regulates quantity by destabilization	0.44	Virus-activated kinase IKKɛ phosphorylated YAP at Ser403 and thereby triggered degradation of YAP in lysosomes and, consequently, relief of YAP-mediated inhibition of the cellular antiviral response.	SIGNOR-277355
Q9Y6Q9	P06493	0	phosphorylation	down-regulates	0.368	We demonstrate that aib1 is phosphorylated on ser728 and ser867 by cdk1/cyclin b at the onset of mitosis and remains phosphorylated until exit from m phase.	SIGNOR-195233
Q9UKT4	P12931	0	phosphorylation	up-regulates	0.324	We found that emi1 stability was regulated by phosphorylation and mutation of tyrosine 142 reduced the stability. Our data suggested bcr-abl-induced emi1 phosphorylation might be mediated by src kinase.	SIGNOR-167529
Q15643	P06400	2	binding	down-regulates	0.324	The wild-type rb is able to interact with the rb-binding domain of trip230 / rb represses trip230-mediated activation of tr-regulated transcription.	SIGNOR-50266
Q96LC7	P52333	0	phosphorylation	up-regulates	0.2	These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Y597 and y667 are likely involved in intracellular signaling	SIGNOR-112479
P40763	O60469	2	binding	up-regulates activity	0.2	Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels.	SIGNOR-264277
P31749	P19367	2	binding	up-regulates	0.445	The glucose dependence of the antiapoptotic effects of growth factors and akt plus a strong correlation between akt-regulated mitochondrial hexokinase association and apoptotic susceptibility suggest a major role for hexokinases in these effects.	SIGNOR-252495
Q16555	Q5TCY1	0	phosphorylation	up-regulates activity	0.243	TTBK1 induces complex formation of pCRMP2 with pTau.\|These data suggest that TTBK1-induced T514 CRMP2 phosphorylation is dependent on both S522 phosphorylation by Cdk5 and T555 phosphorylation by RhoK.	SIGNOR-279313
P06241	P10636	1	phosphorylation	down-regulates	0.535	In this study we determined that human tau tyr18 was phosphorylated by the src family tyrosine kinase fyn.	SIGNOR-123099
O95477	Q8TBB1	0	ubiquitination	down-regulates quantity by destabilization	0.242	We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.	SIGNOR-272902
Q9Y2K6	O95714	0	ubiquitination	down-regulates quantity	0.372	HERC2 promotes USP20 degradation.\|Under unperturbed condition, HERC2 ubiquitinates USP20 and promotes ubiquitination mediated proteasomal degradation of USP20, regulating the status of K48 linked polyubiquitination of CLASPIN and ensuring appropriate protein levels of CLASPIN during the S-phase.	SIGNOR-278692
P08581	P18031	0	dephosphorylation	down-regulates activity	0.637	It has been reported that the protein tyrosine phosphatase PTP1B could inactivate MET by direct dephosphorylation of Tyr 1234 and 1235 in its activation loop, and that this dephosphorylation takes place in peri-nuclear region of the cell [ xref ].	SIGNOR-277001
P10721	Q9ULZ2	2	phosphorylation	up-regulates activity	0.507	STAP-1 was tyrosine-phosphorylated by activated c-kit. An in vitro binding assay suggested that the STAP-1 SH2 domain interacted with several tyrosine-phosphorylated proteins including c-kit and STAT5. These suggest that STAP-1 functions as an adaptor molecule downstream of c-kit in hematopoietic stem cells.	SIGNOR-261820
O95343	Q08117	2	binding	down-regulates activity	0.2	Biochemical and mutational analysis shows that the Six domain of both SIX3 and SIX6 strongly interact with the QD domain of TLE1 and AES. AES abrogates SIX3- and SIX6-induced phenotypes	SIGNOR-234586
O00398	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-257121
P36894	Q6KF10	2	binding	up-regulates	0.596	We found that transfection of small hairpin rna for bmprii and actriia in mc3t3 cells suppressed the signaling of gdf6, gdf7, and bmp10.	SIGNOR-139090
P06730	Q9HBH9	0	phosphorylation	up-regulates	0.56	Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and mnk-mediated eukaryotic translation initiation factor 4e phosphorylation.Therefore, eif4e is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eif4e (usually at ser209) increases its binding affinity for the cap of mrna and may also favor its entry into initiation complexes.	SIGNOR-157537
P48730	P43629	1	phosphorylation	up-regulates	0.2	In this study, we have mapped constitutive phosphorylation sites for casein kinases, protein kinase c, and an unidentified kinase on the kir cytoplasmic domain. Three of these phosphorylation sites are highly conserved in human inhibitory kir. Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover.	SIGNOR-158125
Q9Y6X9	P06493	0	phosphorylation	down-regulates quantity by destabilization	0.2	Mechanically, PTX and VCR activate cyclin-dependent kinase 1, which in turn induces MORC2 phosphorylation at threonine 717 (T717) and T733. Phosphorylated MORC2 enhances its interation with HSPA8 and LAMP2A, two essential components of the chaperone-mediated autophagy (CMA) mechinery, resulting in its autophagic degradation.	SIGNOR-277837
P32004	Q15418	0	phosphorylation	up-regulates activity	0.506	Western blot analysis demonstrated that the L1 kinase activity from PC12 cells that phosphorylated this site was co-eluted with the S6 kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity co-immunoprecipitate with L1 from brain, and metabolic labeling studies have demonstrated that Ser1152 is phosphorylated in vivo in the developing rat brain. \| These data demonstrate that the membrane-proximal 15 amino acids of the cytoplasmic domain of L1 are important for neurite outgrowth on L1, and the interactions it mediates may be regulated by phosphorylation of Ser1152.	SIGNOR-248948
P61328	Q14524	2	binding	down-regulates activity	0.579	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253416
P20936	P29323	2	binding	up-regulates	0.576	We have localized an in vitro rasgap-binding site to conserved tyrosine residues y604 and y610 in the juxtamembrane region of ephb2, and demonstrated that substitution of these amino acids abolishes ephrin-b1-induced signalling events in ephb2-expressing ng108-15 cells.	SIGNOR-50100
O95631	P43146	2	binding	up-regulates activity	0.91	DCC (Deleted in Colorectal Cancer) is a single-pass transmembrane protein that belongs to the immunoglobulin superfamily. It was originally identified as a prognostic tumor marker and then subsequently found to be a receptor for netrin-1. DCC plays a key role in axon guidance and also in a number of other important cellular processes.	SIGNOR-268162
Q14004	P23588	1	phosphorylation	up-regulates activity	0.251	CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation.	SIGNOR-273115
Q9UQM7	O95997	1	phosphorylation	down-regulates quantity by destabilization	0.309	CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase	SIGNOR-276381
Q8IW41	O60229	1	phosphorylation	up-regulates activity	0.385	The brain-specific nucleotide exchange factor kalirin-7 (Kal7) was identified as an MK5 interaction partner and substrate protein. The MK5 substrate Kal7, a Rho GEF and known activator of Rac GTPases, further contributes to PAK activation and actin filament reorganization. Thus, the coordinated phosphorylation of Borg proteins and Kal7 by ERK3 and MK5 constitute a novel signaling cascade involving feed-forward circuits, multiple GTPases, and cytoskeletal elements. The fragment SR3-6, but not the mutated fragment SR3-6-S487A, is phosphorylated by MK5.	SIGNOR-263093
P12034	P11362	2	binding	up-regulates	0.7	Fgf-5 can bind and induce autophosphorylation of human fgf receptors (fgfr) 1 and 2.	SIGNOR-38704
Q9Y4B6	Q99878	1	phosphorylation	up-regulates activity	0.2	Here we report that VprBP possesses an intrinsic protein kinase activity and is capable of phosphorylating histone H2A on threonine 120 (H2AT120p) in a nucleosomal context. Functional studies reveal that H2AT120p by VprBP is sufficient to repress chromatin transcription.	SIGNOR-279884
Q15417	Q06187	0	phosphorylation	up-regulates quantity	0.2	Co-expression of calponin-3 with various kinases in S2 Schneider cells promoted a phosphorylation of calponin-3 by Syk, but also by the Tec family kinase Btk.	SIGNOR-280196
A6NJZ7	Q9UQ26	2	binding	down-regulates activity	0.265	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-264367
O95837	P24530	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-257428
P08754	P28335	2	binding	up-regulates activity	0.28	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-256877
P37198	P53778	0	phosphorylation	down-regulates quantity by destabilization	0.2	We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38γ MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1).	SIGNOR-277416
P36896	P27037	0	phosphorylation	up-regulates	0.687	In this complex, the actrii??/Iib kinase phosphorylates alk4 within a glycine- and serine-rich region called the gs domain, and this phosphorylation event activates the alk4 kinase	SIGNOR-99995
Q53G59	O14640	2	binding	down-regulates quantity by destabilization	0.621	KLHL12 recruits Dsh to Cullin-3 for protein degradation. In vitro ubiquitination of Dsh3 by KLHL12–Cullin-3–Roc1. The E3 ligase complex was obtained by transfection of HEK293T cells . We show that the BTB-containing protein KLHL12 negatively regulates Dsh function by recruiting a pool of Dsh to the Cullin-3 ligase scaffold, thereby promoting its ubiquitination and degradation.	SIGNOR-271558
P42771	O14920	0	phosphorylation	down-regulates	0.396	Ikkbeta specifically binds to p16 and phosphorylates ser8 of p16 phosphorylation at ser8 of p16 brings about a significant loss of its cyclin-dependent kinase (cdk) 4-inhibitory activity	SIGNOR-163801
P03372	P12931	0	phosphorylation	up-regulates	0.778	Although the molecular mechanisms underlying ligand-independent activation of era are not completely understood, phosphorylation of a serine residue in af1 has been implicated in the response to epidermal growth factor. Era is also a target for tyrosine phosphorylation, anda single tyrosine residue located immediately adjacent to af2 has been identified as a substrate for src-family tyrosine kinases.	SIGNOR-55857
Q02156	P09211	1	phosphorylation	up-regulates activity	0.2	Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently	SIGNOR-276021
Q92949	Q96DT5	1	transcriptional regulation	up-regulates quantity by expression	0.361	FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).	SIGNOR-266931
P07332	P40763	1	phosphorylation	up-regulates activity	0.402	Fes also induced Tyr 705 phosphorylation and DNA binding activity of STAT3, in agreement with the idea that Fes can regulate transcriptional activation through Fes dependent phosphorylation of transcription factors.On the basis of these findings, we propose that Fes activation of critical transcriptional regulators such as PU.1 is part of the mechanism by which this kinase induces macrophage differentiation of myeloid progenitors.\|We conclude that Fes may regulate granulocytic differentiation at least in part through activation of C/EBP-alpha and STAT3.In 32D cells, Fes activated STAT3 and C/EBP-alpha, two important regulators of granulocytic differentiation [14,15].	SIGNOR-278937
P12931	P46527	1	phosphorylation	down-regulates	0.496	Src regulates p27 stability through phosphorylation of p27 at tyrosine 74 and tyrosine 88. Our data indicate that phosphorylation by src impairs the cdk2 inhibitory action of p27	SIGNOR-152839
Q9NRY4	P63000	1	gtpase-activating protein	down-regulates activity	0.724	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-260493
O14757	Q9HB96	1	phosphorylation	up-regulates	0.716	Chk1 directly phosphorylates the fance subunit of the fa core complex on two conserved sites (threonine 346 and serine 374). chk1-mediated phosphorylation of fance is required for the fanconi anemia/brca pathway.	SIGNOR-153023
Q9GZM8	P43034	2	binding	up-regulates activity	0.843	We demonstrate that LIS1 directly interacts with the cytoplasmic dynein heavy chain (CDHC) and NUDEL. LIS1 is required for the proper distribution of NUDEL and cellular components regulated by CDHC function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex	SIGNOR-252157
P08754	P30874	2	binding	up-regulates activity	0.45	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-256827
P38936	Q92945	0	post transcriptional regulation	down-regulates quantity by destabilization	0.252	Importantly, KSRP knockdown in C2C12 GM cells (Figure 2D) stabilized endogenous my- ogenin and p21 transcripts (Figure 2E). Furthermore, stable knockdown of KSRP, using shRNA, induced the accumulation of p21 mRNA in C2C12 GM while it did not affect the expression of late myogenic markers (MHC and muscle-creatine kinase [MCK])	SIGNOR-235859
Q9UI32	P04637	0	transcriptional regulation	up-regulates quantity by expression	0.631	Glutaminase 2 (GLS2) can be directly transactivated by p53 and can therefore mediate p53-dependent regulation of cellular energy metabolism. G	SIGNOR-268041

P43034

P30622

2

binding

up-regulates activity

0.793

Here we demonstrate colocalization and direct interaction between CLIP-170 and LIS1. In mammalian cells, LIS1 recruitment to kinetochores is dynein/dynactin dependent, and recruitment there of CLIP-170 is dependent on its site of binding to LIS1, located in the distal zinc finger motif.

SIGNOR-252166

Q9BTU6

Q9HAW4

1

phosphorylation

down-regulates

0.2

These results indicate that plx1 phosphorylates claspin on s934, which is relatively close to the plx1-docking site at t906. Human claspin also contains a serine at position 984 in a homologous sequence

SIGNOR-159937

P49840

Q96F46

1

phosphorylation

down-regulates quantity by destabilization

0.2

Glycogen synthase kinase 3 (GSK3) constitutively bound to and phosphorylated IL-17RA at T780, leading to ubiquitination and proteasome-mediated degradation of IL-17RA, thus inhibiting IL-17-mediated inflammation.

SIGNOR-277206

P07237

Q8IXL6

0

phosphorylation

up-regulates activity

0.387

The secretory pathway kinase Fam20C phosphorylates Ser357 of PDI and responds rapidly to various ER stressors. Phosphorylation of Ser357 induces an open conformation of PDI and turns it from a "foldase" into a "holdase", which is critical for preventing protein misfolding in the ER. Phosphorylated PDI also binds to the lumenal domain of IRE1α, a major UPR signal transducer, and attenuates excessive IRE1α activity.

SIGNOR-275574

Q9BY78

Q13501

1

ubiquitination

up-regulates activity

0.358

SQSTM1 Is a Substrate for RNF26 and the DUB USP15. Catalytically competent RNF26 (light red) recruits SQSTM1 (blue) and mediates ubiquitin ligation (red), which serves to attract UBDs of specific vesicle-associated adaptors.

SIGNOR-269830

Q96RU2

P01106

1

deubiquitination

up-regulates

0.703

Usp28, an ubiquitin-specific protease, binds to myc through an interaction with fbw7alpha, an f-box protein that is part of an scf-type ubiquitin ligase. Therefore, it stabilizes myc.

SIGNOR-155590

P0DMV8

O15217

1

relocalization

up-regulates activity

0.2

Model showing Ser189/Thr193 protein kinase dependent phosphorylation of GST A4‐4 has increased affinity for chaperone Hsp70 which activates mitochondrial competent import signals for GSTA4‐4. |Protein kinase A mediated phosphorylation of serine residues of CYPs increases the affinity of proteins for binding to cytoplasmic chaperones such as heat shock proteins (Hsp), Hsp70/Hsp90, resulting in increased mitochondrial translocation

SIGNOR-264799

P40763

Q13188

0

phosphorylation

down-regulates activity

0.2

Hippo pathway component MST2 kinase phosphorylates STAT3 at T622, which is located in the SH2 domain of STAT3. This phosphorylation blocks the SH2 domain in one STAT3 molecule to bind with the phosphorylated Y705 site in another STAT3 molecule, which further counteracts IL6-induced STAT3 dimerization and activation.

SIGNOR-277599

O43896

P20340

1

relocalization

up-regulates quantity

0.409

Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation.

SIGNOR-266877

Q8N122

Q15418

0

phosphorylation

up-regulates

0.546

Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity

SIGNOR-180466

P01215

P50458

0

transcriptional regulation

up-regulates quantity by expression

0.266

In Cos cells, LH-2 activated the a-subunit promoter approximately twofold

SIGNOR-266055

Q92878

Q13315

2

binding

up-regulates

0.813

One of the earliest events is recruitment and activation of the atm at the damaged dna sites through the mre11rad50nbs1 (mrn) sensor complex. . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm kinase.

SIGNOR-175053

P59595

P15336

1

transcriptional regulation

up-regulates quantity by expression

0.2

The transcription factors c-Fos, FosB, CREB-1, and ATF2 were all activated by the addition of SARS-CoV N protein to the sample well

SIGNOR-260727

P49841

P48729

2

binding

up-regulates activity

0.579

In the absence of secreted wnt ligands, cytosolic beta-catenin is phosphorylated at ser45 by the priming kinase casein kinase 1 (ck1). Consequently, glycogen synthase kinase 3 (gsk3), in complex with axin and adenomatous polyposis coli (apc), phosphorylates beta-catenin at thr41, ser37, and ser33 apc cooperates with axin to promote the phosphorylation of b-catenin by gsk3 [which requires priming phosphorylation by casein kinase 1, alpha-isoform (ck1alpha)]

SIGNOR-184696

O95644

Q9Y625

1

transcriptional regulation

up-regulates quantity by expression

0.251

NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype.

SIGNOR-264022

Q9Y6K9

P49841

0

phosphorylation

down-regulates quantity

0.431

For analysis of phosphorylation of NEMO on Ser8 and Ser17 by GSK-3, we generated phospho-specific antibodies (anti-phospho-NEMO-Ser8 and anti-phospho-NEMO-Ser17) while anti-phospho-NEMO-Ser31 and anti-phospho-NEMO-Ser43 were commercially available. Indeed, GSK-3\u03b2 was able to phosphorylate all four serines of rhNEMO in a time-dependent manner in an in vitro kinase assay (Fig. 3a).|In this study, we identified NEMO as a GSK-3\u03b2 substrate that is phosphorylated at several serine residues located within the N-terminal domain.|The kinase forms a complex with wild-type NEMO while point mutations of NEMO at the specific serines abrogated GSK-3Œ≤ binding and subsequent phosphorylation of NEMO resulting in its destabilization

SIGNOR-279527

P53805

P49841

0

phosphorylation

up-regulates activity

0.484

Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin.

SIGNOR-249359

Q13085

P38398

2

binding

down-regulates activity

0.548

ACCA binds BRCA1 when phosphorylated onSer1263, thus supporting a model in which controlof lipid synthesis would be mediated at least in part,viaphosphorylation of the Ser1263.

SIGNOR-267474

P20645

Q8IWJ2

0

relocalization

up-regulates activity

0.532

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

SIGNOR-253086

O43683

P53350

2

binding

up-regulates

0.864

The plk1-bub1 interaction requires the polo-box domain (pbd) of plk1 and is enhanced by cyclin-dependent kinase 1 (cdk1)-mediated phosphorylation of bub1 at t609

SIGNOR-147061

O00187

P11226

2

binding

up-regulates activity

0.74

The results (Fig. 3A) show that the anti-MBL antibody, in addition to binding MBL captures both MASP-1 and MASP-2|Our results emphasize the similarity between complement activation through the MBL, or 'MBLectin' pathway of the innate immune system and the classical pathway of complement activation (Fig. 5).

SIGNOR-263415

P18031

P42226

1

dephosphorylation

down-regulates activity

0.327

Phosphorylated STAT6 may also serve as a cytoplasmic substrate for PTP1B since overexpression of PTP1B leads to STAT6 dephosphorylation and the suppression of STAT6 transcriptional activity, whereas PTP1B deficiency increases IL-4-induced STAT6 signaling in B-cells.

SIGNOR-277122

P20393

O60890

2

binding

up-regulates activity

0.2

Rev-erbα regulates OPHN-1-mediated RhoA/ERM signalling in platelets., The results of the co-immunoprecipitation revealed that Rev-erbα coimmunoprecipitated with OPHN-1 in both mouse and human platelets and this interaction significantly increased upon stimulation with agonist U46619.

SIGNOR-268428

P28702

P55055

2

binding

up-regulates

0.696

We provide genetic and molecular evidence that cholesterol homeostasis in scs does not require pparalpha and beta, but depends upon the tif2 coactivator and rxrbeta/lxrbeta heterodimers, in which rxrbeta af-2 is transcriptionally active.

SIGNOR-123094

P21127

P50613

0

phosphorylation

up-regulates activity

0.335

We conclude that CDK7 phsphorylates Cdk11, dependent on the conserved Thr219 residue in the CDK11 T loop, and it is therefore likely to be a genuine Cdk11 activating kinase

SIGNOR-245871

P11831

P49137

0

phosphorylation

up-regulates

0.584

Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2

SIGNOR-166640

Q9Y5I2

Q9Y5G8

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-265717

Q07021

P02746

2

binding

down-regulates activity

0.341

Previous studies have shown that gC1qR inhibits aggregated IgG-mediated complement activation by binding to the gC1q site on C1q, thereby preventing IgG from binding to the gh’s (28), suggesting that the binding sites for gC1qR and IgG on C1q may be identical or at least overlapping.

SIGNOR-263403

Q9NZJ5

P11021

2

binding

down-regulates activity

0.726

In the stressed ER, protein chaperone GRP78 binds to unfolded proteins and dissociates from the luminal domain of PERK, leading to oligomerization and activation of PERK by autophosphorylation.

SIGNOR-260164

P31749

O43464

1

phosphorylation

down-regulates

0.322

Akt attenuation of the serine protease activity of htra2/omi through phosphorylation of serine 212

SIGNOR-252500

Q16539

P54829

2

binding

up-regulates

0.489

First [] step prevents upstream activating kinases from promiscuously binding and activating p38a. Second, by blocking access to the mapk insert pocket, through the stepcat interaction, step can prevent the binding of allosteric signaling molecules that induce autoactivation of p38a.

SIGNOR-194829

Q96EB6

Q13043

0

phosphorylation

down-regulates activity

0.344

We found that MST1 increases p53 acetylation and transactivation by inhibiting the deacetylation of Sirtuin 1 (Sirt1) and its interaction with p53 and that Sirt1 can be phosphorylated by MST1 leading to the inhibition of Sirt1 activity.

SIGNOR-279574

Q01718

Q8TCY5

2

binding

up-regulates activity

0.76

We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling.We have previously identified MRAP as an accessory protein for MC2R, required for receptor trafficking to the cell surface and the formation of a functional MC2R. Here we have identified MRAP2 as a homologue of MRAP. Like MRAP, MRAP2 is able to support MC2R cell-surface expression, producing a functional ACTH-responsive receptor.

SIGNOR-252360

Q9NQ66

P50148

2

binding

up-regulates

0.768

The beta- but not the gamma- and delta-type isozymes of inositol phospholipid-specific phospholipase c (plc) are activated by g protein alpha q and beta gamma subunits.

SIGNOR-37149

Q92914

Q9Y5Y9

2

binding

down-regulates activity

0.2

Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.

SIGNOR-253442

P23443

Q6ZVD8

0

dephosphorylation

down-regulates activity

0.49

We show that PHLPP preferentially dephosphorylates the hydrophobic motif T389 site in S6K1 in vitro

SIGNOR-248247

P36873

P05198

1

dephosphorylation

up-regulates activity

0.412

Dephosphorylation of eIF2Î± is central to ISR signal termination to restore protein synthesis and normal cell functioning. It is mediated by protein phosphatase 1 (PP1) complex that recruits a PP1 catalytic subunit (PP1c) and one of the two regulatory subunits. In mammals, phosphatase activity is regulated by either PPP1R15A (also known as growth arrest and DNA damageâ€inducible protein, GADD34), which is induced as part of the ISR. the GADD34â€“PP1 complex acts as an important negative feedback loop to restore protein synthesis once the ER stress has been resolved, and as such aids in cell survival

SIGNOR-254119

P35348

Q14344

2

binding

up-regulates activity

0.623

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-257279

Q8WW43

P49768

2

binding

up-regulates

0.911

Biochemical and genetic studies have recently identified nicastrin, aph-1, and pen-2 as essential cofactors that physically interact with ps1 and are necessary for the gamma-secretase activity.

SIGNOR-97107

P29372

P51668

2

binding

up-regulates activity

0.2

Here we report that MID1 catalyzes the in vitro ubiquitination of the catalytic subunit of PP2A (PP2Ac) in the absence of alpha4. In the presence of alpha4, the level of PP2Ac ubiquitination is reduced.The high molecular weight smear pattern was not as obvious, suggesting that domains within the C-terminal half of MID1 may contribute to the polyubiquitination of PP2Ac. We observed that PP2Ac was ubiquitinated in the presence of UbcH5a-c and UbcH6, similar to results obtained with MID1-catalyzed ubiquitination of alpha4 (Figure 2E)

SIGNOR-271927

O15530

Q05513

1

phosphorylation

up-regulates

0.577

Our findings suggest that insulin, via pip(3), provokes increases in pkc-zeta enzyme activity through (a) pdk-1-dependent t410 loop phosphorylation, (b) t560 autophosphorylationcytoskeletal reorganization;tnni1(induces);desmin(induces);tpm1(induces);myo1c(induces);tnnt1(induces);

SIGNOR-85501

Q00535

Q8IWR1

1

phosphorylation

up-regulates activity

0.2

Here, we identify TRIM59 as a substrate of CDK5. EGFR-activated CDK5 directly binds to and phosphorylates TRIM59, a ubiquitin ligase at serine 308, which recruits PIN1 for cis-trans isomerization of TRIM59, leading to TRIM59 binding to importin α5 and nuclear translocation.

SIGNOR-272929

Q13615

P42345

1

null

down-regulates activity

0.354

The PtdIns3-phosphatase MTMR3 interacts with mTORC1 and suppresses its activity.

SIGNOR-245105

P01024

Q96PZ7

2

binding

down-regulates quantity

0.2

CUB and sushi multiple domains 1 (CSMD1) is a relatively poorly studied large transmembrane protein of 390 kDa composed of 14 N-terminal CUB domains interspersed with complement control protein (CCP) domains followed by 15 consecutive CCP domains. The active domains of CSMD1 were then identified in CCP17-21, which were shown to interact with C4b and C3b and present these complement proteins for degradation by factor

SIGNOR-265148

Q13332

Q96NI6

2

binding

up-regulates activity

0.368

SALM5 trans-synaptically interacts with LAR-RPTPs in a splicing-dependent manner to regulate synapse development. we identified LAR-RPTPs as novel ligands of SALM5 that mediates SALM5-dependent presynaptic differentiation in a splicing-dependent manner. Our data indicate that SALM5 interacts with all three known LAR-RPTPs—LAR, PTPδ, and PTPσ (Fig. 1).

SIGNOR-264088

O43765

P46379

2

binding

up-regulates activity

0.467

USP13 and gp78 control ubiquitination of Ubl4A.These data suggest that USP13 and gp78 play antagonizing roles in regulation of Ubl4A ubiquitination: While gp78 assembles ubiquitin chains on Ubl4A, USP13 antagonizes this activity to limit Ubl4A ubiquitination.Ubiquitination of Ubl4A preferentially occurs on Lys48. We identify the Bag6 cofactor Ubl4A as a shared substrate of gp78 and USP13. USP13 depletion is associated with hyper-ubiquitination of Ubl4A and altered interaction between the Bag6 complex and its co-chaperone SGTA. Because the interaction of Ubl4A with SGTA is mediated by positively-charged residues in Ubl4A including Lys48 (Chartron et al., 2012; Xu et al., 2012), which happens to be the major ubiquitination site, the simplest model to explain reduced Bag6-SGTA interaction in USP13 knockdown cells is that ubiquitin conjugates on Ubl4A sterically hinder SGTA binding.

SIGNOR-272859

Q15796

O96013

0

phosphorylation

down-regulates quantity by destabilization

0.339

In addition, PAK4 phosphorylates Smad2 on Ser465, leading to the degradation of Smad2 through ubiquitin-proteasome-dependent pathway under hepatocyte growth factor (HGF) stimulation.

SIGNOR-279084

Q14896

Q5VU43

2

binding

up-regulates

0.31

This study ascribes a novel function to mmgl isoform 4: it meets all criteria for classification as an akap, and we show that is involved in the phosphorylation of cmybpc as well as ctni, hence mmgl is an important regulator of cardiac contractility.

SIGNOR-173766

P42345

Q9UHD2

0

phosphorylation

up-regulates activity

0.42

They later demonstrated that TANK-binding kinase 1 (TBK1) interacts with and phosphorylates mTOR on Ser 2159, to promote catalytic activity of mTOR [216].

SIGNOR-278237

P51151

Q7Z6M1

1

null

up-regulates activity

0.581

P40 is a very potent transport factor in that the pure, recombinant protein can stimulate, significantly, an in vitro transport assay that measures transport of mannose 6-phosphate receptors from endosomes to the trans-Golgi network. The functional importance of p40 is confirmed by the finding that anti-p40 antibodies inhibit in vitro transport. Finally, p40 shows synergy with Rab9 in terms of its ability to stimulate mannose 6-phosphate receptor transport. These data are consistent with a model in which p40 and Rab9 act together to drive the process of transport vesicle docking.

SIGNOR-253088

P53779

P31947

1

phosphorylation

down-regulates

0.2

Here we demonstrate that activated jnk promotes bax translocation to mitochondria through phosphorylation of 14-3-3, a cytoplasmic anchor of bax. Phosphorylation of 14-3-3 led to dissociation of bax from this protein.Jnk phosphorylates 14-3-3zeta_ at ser-184 and 14-3-3sigma_ at ser-191

SIGNOR-124005

P01137

P13385

2

binding

down-regulates activity

0.2

Ere, we provide evidence supporting a novel mechanism in which Cripto inhibits the tumor suppressor function of TGF-beta. Cripto bound TGF-beta and reduced the association of TGF-beta with its type I receptor, TbetaRI.

SIGNOR-150006

O15054

P68431

1

demethylation

down-regulates activity

0.2

Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX) and Jumonji D3 (JMJD3) as novel histone demethylases that catalyze the removal of di- and trimethyl groups on histone H3 lysine 27, thereby promoting target gene activation.

SIGNOR-260018

P46937

Q14164

0

phosphorylation

down-regulates quantity by destabilization

0.44

Virus-activated kinase IKKɛ phosphorylated YAP at Ser403 and thereby triggered degradation of YAP in lysosomes and, consequently, relief of YAP-mediated inhibition of the cellular antiviral response.

SIGNOR-277355

Q9Y6Q9

P06493

0

phosphorylation

down-regulates

0.368

We demonstrate that aib1 is phosphorylated on ser728 and ser867 by cdk1/cyclin b at the onset of mitosis and remains phosphorylated until exit from m phase.

SIGNOR-195233

Q9UKT4

P12931

0

phosphorylation

up-regulates

0.324

We found that emi1 stability was regulated by phosphorylation and mutation of tyrosine 142 reduced the stability. Our data suggested bcr-abl-induced emi1 phosphorylation might be mediated by src kinase.

SIGNOR-167529

Q15643

P06400

2

binding

down-regulates

0.324

The wild-type rb is able to interact with the rb-binding domain of trip230 / rb represses trip230-mediated activation of tr-regulated transcription.

SIGNOR-50266

Q96LC7

P52333

0

phosphorylation

up-regulates

0.2

These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Y597 and y667 are likely involved in intracellular signaling

SIGNOR-112479

P40763

O60469

2

binding

up-regulates activity

0.2

Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels.

SIGNOR-264277

P31749

P19367

2

binding

up-regulates

0.445

The glucose dependence of the antiapoptotic effects of growth factors and akt plus a strong correlation between akt-regulated mitochondrial hexokinase association and apoptotic susceptibility suggest a major role for hexokinases in these effects.

SIGNOR-252495

Q16555

Q5TCY1

0

phosphorylation

up-regulates activity

0.243

TTBK1 induces complex formation of pCRMP2 with pTau.|These data suggest that TTBK1-induced T514 CRMP2 phosphorylation is dependent on both S522 phosphorylation by Cdk5 and T555 phosphorylation by RhoK.

SIGNOR-279313

P06241

P10636

1

phosphorylation

down-regulates

0.535

In this study we determined that human tau tyr18 was phosphorylated by the src family tyrosine kinase fyn.

SIGNOR-123099

O95477

Q8TBB1

0

ubiquitination

down-regulates quantity by destabilization

0.242

We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.

SIGNOR-272902

Q9Y2K6

O95714

0

ubiquitination

down-regulates quantity

0.372

HERC2 promotes USP20 degradation.|Under unperturbed condition, HERC2 ubiquitinates USP20 and promotes ubiquitination mediated proteasomal degradation of USP20, regulating the status of K48 linked polyubiquitination of CLASPIN and ensuring appropriate protein levels of CLASPIN during the S-phase.

SIGNOR-278692

P08581

P18031

0

dephosphorylation

down-regulates activity

0.637

It has been reported that the protein tyrosine phosphatase PTP1B could inactivate MET by direct dephosphorylation of Tyr 1234 and 1235 in its activation loop, and that this dephosphorylation takes place in peri-nuclear region of the cell [ xref ].

SIGNOR-277001

P10721

Q9ULZ2

2

phosphorylation

up-regulates activity

0.507

STAP-1 was tyrosine-phosphorylated by activated c-kit. An in vitro binding assay suggested that the STAP-1 SH2 domain interacted with several tyrosine-phosphorylated proteins including c-kit and STAT5. These suggest that STAP-1 functions as an adaptor molecule downstream of c-kit in hematopoietic stem cells.

SIGNOR-261820

O95343

Q08117

2

binding

down-regulates activity

0.2

Biochemical and mutational analysis shows that the Six domain of both SIX3 and SIX6 strongly interact with the QD domain of TLE1 and AES. AES abrogates SIX3- and SIX6-induced phenotypes

SIGNOR-234586

O00398

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-257121

P36894

Q6KF10

2

binding

up-regulates

0.596

We found that transfection of small hairpin rna for bmprii and actriia in mc3t3 cells suppressed the signaling of gdf6, gdf7, and bmp10.

SIGNOR-139090

P06730

Q9HBH9

0

phosphorylation

up-regulates

0.56

Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and mnk-mediated eukaryotic translation initiation factor 4e phosphorylation.Therefore, eif4e is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eif4e (usually at ser209) increases its binding affinity for the cap of mrna and may also favor its entry into initiation complexes.

SIGNOR-157537

P48730

P43629

1

phosphorylation

up-regulates

0.2

In this study, we have mapped constitutive phosphorylation sites for casein kinases, protein kinase c, and an unidentified kinase on the kir cytoplasmic domain. Three of these phosphorylation sites are highly conserved in human inhibitory kir. Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover.

SIGNOR-158125

Q9Y6X9

P06493

0

phosphorylation

down-regulates quantity by destabilization

0.2

Mechanically, PTX and VCR activate cyclin-dependent kinase 1, which in turn induces MORC2 phosphorylation at threonine 717 (T717) and T733. Phosphorylated MORC2 enhances its interation with HSPA8 and LAMP2A, two essential components of the chaperone-mediated autophagy (CMA) mechinery, resulting in its autophagic degradation.

SIGNOR-277837

P32004

Q15418

0

phosphorylation

up-regulates activity

0.506

Western blot analysis demonstrated that the L1 kinase activity from PC12 cells that phosphorylated this site was co-eluted with the S6 kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity co-immunoprecipitate with L1 from brain, and metabolic labeling studies have demonstrated that Ser1152 is phosphorylated in vivo in the developing rat brain. | These data demonstrate that the membrane-proximal 15 amino acids of the cytoplasmic domain of L1 are important for neurite outgrowth on L1, and the interactions it mediates may be regulated by phosphorylation of Ser1152.

SIGNOR-248948

P61328

Q14524

2

binding

down-regulates activity

0.579

Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.

SIGNOR-253416

P20936

P29323

2

binding

up-regulates

0.576

We have localized an in vitro rasgap-binding site to conserved tyrosine residues y604 and y610 in the juxtamembrane region of ephb2, and demonstrated that substitution of these amino acids abolishes ephrin-b1-induced signalling events in ephb2-expressing ng108-15 cells.

SIGNOR-50100

O95631

P43146

2

binding

up-regulates activity

0.91

DCC (Deleted in Colorectal Cancer) is a single-pass transmembrane protein that belongs to the immunoglobulin superfamily. It was originally identified as a prognostic tumor marker and then subsequently found to be a receptor for netrin-1. DCC plays a key role in axon guidance and also in a number of other important cellular processes.

SIGNOR-268162

Q14004

P23588

1

phosphorylation

up-regulates activity

0.251

CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation.

SIGNOR-273115

Q9UQM7

O95997

1

phosphorylation

down-regulates quantity by destabilization

0.309

CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase

SIGNOR-276381

Q8IW41

O60229

1

phosphorylation

up-regulates activity

0.385

The brain-specific nucleotide exchange factor kalirin-7 (Kal7) was identified as an MK5 interaction partner and substrate protein. The MK5 substrate Kal7, a Rho GEF and known activator of Rac GTPases, further contributes to PAK activation and actin filament reorganization. Thus, the coordinated phosphorylation of Borg proteins and Kal7 by ERK3 and MK5 constitute a novel signaling cascade involving feed-forward circuits, multiple GTPases, and cytoskeletal elements. The fragment SR3-6, but not the mutated fragment SR3-6-S487A, is phosphorylated by MK5.

SIGNOR-263093

P12034

P11362

2

binding

up-regulates

0.7

Fgf-5 can bind and induce autophosphorylation of human fgf receptors (fgfr) 1 and 2.

SIGNOR-38704

Q9Y4B6

Q99878

1

phosphorylation

up-regulates activity

0.2

Here we report that VprBP possesses an intrinsic protein kinase activity and is capable of phosphorylating histone H2A on threonine 120 (H2AT120p) in a nucleosomal context. Functional studies reveal that H2AT120p by VprBP is sufficient to repress chromatin transcription.

SIGNOR-279884

Q15417

Q06187

0

phosphorylation

up-regulates quantity

0.2

Co-expression of calponin-3 with various kinases in S2 Schneider cells promoted a phosphorylation of calponin-3 by Syk, but also by the Tec family kinase Btk.

SIGNOR-280196

A6NJZ7

Q9UQ26

2

binding

down-regulates activity

0.265

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-264367

O95837

P24530

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-257428

P08754

P28335

2

binding

up-regulates activity

0.28

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-256877

P37198

P53778

0

phosphorylation

down-regulates quantity by destabilization

0.2

We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38γ MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1).

SIGNOR-277416

P36896

P27037

0

phosphorylation

up-regulates

0.687

In this complex, the actrii??/Iib kinase phosphorylates alk4 within a glycine- and serine-rich region called the gs domain, and this phosphorylation event activates the alk4 kinase

SIGNOR-99995

Q53G59

O14640

2

binding

down-regulates quantity by destabilization

0.621

KLHL12 recruits Dsh to Cullin-3 for protein degradation. In vitro ubiquitination of Dsh3 by KLHL12–Cullin-3–Roc1. The E3 ligase complex was obtained by transfection of HEK293T cells . We show that the BTB-containing protein KLHL12 negatively regulates Dsh function by recruiting a pool of Dsh to the Cullin-3 ligase scaffold, thereby promoting its ubiquitination and degradation.

SIGNOR-271558

P42771

O14920

0

phosphorylation

down-regulates

0.396

Ikkbeta specifically binds to p16 and phosphorylates ser8 of p16 phosphorylation at ser8 of p16 brings about a significant loss of its cyclin-dependent kinase (cdk) 4-inhibitory activity

SIGNOR-163801

P03372

P12931

0

phosphorylation

up-regulates

0.778

Although the molecular mechanisms underlying ligand-independent activation of era are not completely understood, phosphorylation of a serine residue in af1 has been implicated in the response to epidermal growth factor. Era is also a target for tyrosine phosphorylation, anda single tyrosine residue located immediately adjacent to af2 has been identified as a substrate for src-family tyrosine kinases.

SIGNOR-55857

Q02156

P09211

1

phosphorylation

up-regulates activity

0.2

Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently

SIGNOR-276021

Q92949

Q96DT5

1

transcriptional regulation

up-regulates quantity by expression

0.361

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

SIGNOR-266931

P07332

P40763

1

phosphorylation

up-regulates activity

0.402

Fes also induced Tyr 705 phosphorylation and DNA binding activity of STAT3, in agreement with the idea that Fes can regulate transcriptional activation through Fes dependent phosphorylation of transcription factors.On the basis of these findings, we propose that Fes activation of critical transcriptional regulators such as PU.1 is part of the mechanism by which this kinase induces macrophage differentiation of myeloid progenitors.|We conclude that Fes may regulate granulocytic differentiation at least in part through activation of C/EBP-alpha and STAT3.In 32D cells, Fes activated STAT3 and C/EBP-alpha, two important regulators of granulocytic differentiation [14,15].

SIGNOR-278937

P12931

P46527

1

phosphorylation

down-regulates

0.496

Src regulates p27 stability through phosphorylation of p27 at tyrosine 74 and tyrosine 88. Our data indicate that phosphorylation by src impairs the cdk2 inhibitory action of p27

SIGNOR-152839

Q9NRY4

P63000

1

gtpase-activating protein

down-regulates activity

0.724

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-260493

O14757

Q9HB96

1

phosphorylation

up-regulates

0.716

Chk1 directly phosphorylates the fance subunit of the fa core complex on two conserved sites (threonine 346 and serine 374). chk1-mediated phosphorylation of fance is required for the fanconi anemia/brca pathway.

SIGNOR-153023

Q9GZM8

P43034

2

binding

up-regulates activity

0.843

We demonstrate that LIS1 directly interacts with the cytoplasmic dynein heavy chain (CDHC) and NUDEL. LIS1 is required for the proper distribution of NUDEL and cellular components regulated by CDHC function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex

SIGNOR-252157

P08754

P30874

2

binding

up-regulates activity

0.45

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-256827

P38936

Q92945

0

post transcriptional regulation

down-regulates quantity by destabilization

0.252

Importantly, KSRP knockdown in C2C12 GM cells (Figure 2D) stabilized endogenous my- ogenin and p21 transcripts (Figure 2E). Furthermore, stable knockdown of KSRP, using shRNA, induced the accumulation of p21 mRNA in C2C12 GM while it did not affect the expression of late myogenic markers (MHC and muscle-creatine kinase [MCK])

SIGNOR-235859

Q9UI32

P04637

0

transcriptional regulation

up-regulates quantity by expression

0.631

Glutaminase 2 (GLS2) can be directly transactivated by p53 and can therefore mediate p53-dependent regulation of cellular energy metabolism. G

SIGNOR-268041