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
O43603	Q9BT56	2	binding	up-regulates activity	0.339	Coevolution of the spexin/galanin/kisspeptin family: Spexin activates galanin receptor type II and III.	SIGNOR-268574
Q13177	Q70Z35	1	phosphorylation	down-regulates activity	0.359	P21-activated Kinases (PAKs) Mediate the Phosphorylation of PREX2 Protein to Initiate Feedback Inhibition of Rac1 GTPase. PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ.	SIGNOR-277182
P78352	O14490	2	relocalization	up-regulates activity	0.932	Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b).	SIGNOR-264196
P19086	O43613	2	binding	up-regulates activity	0.25	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257128
Q92911	P01222	0	transcriptional regulation	up-regulates quantity by expression	0.38	Iâ€“ uptake is stimulated by TSH, the master hormone for thyroid gland regulation. TSH stimulation results, at least in part, from the cAMP-mediated increase in NIS biosynthesis. TSH not only stimulates NIS transcription and biosynthesis but is also required for modulating the NIS phosphorylation pattern, maintaining its half-life, and retaining NIS at the thyrocyte plasma membrane	SIGNOR-251995
P35244	Q9NUX5	2	binding	down-regulates activity	0.263	The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA	SIGNOR-263326
Q9P2Y5	Q9UGI0	0	deubiquitination	up-regulates activity	0.2	Here we report that UVRAG is ubiquitinated by SMURF1 at lysine residues 517 and 559, which decreases the association of UVRAG with RUBCN and promotes autophagosome maturation. However, the deubiquitinase ZRANB1 specifically cleaves SMURF1-induced K29 and K33-linked polyubiquitin chains from UVRAG, thereby increasing the binding of UVRAG to RUBCN and inhibiting autophagy flux.	SIGNOR-273651
P78504	P46531	2	binding	up-regulates activity	0.642	We identify functional fragments of human notch-1 (n-1) and jagged-1 (j-1) which interact in a calcium-dependent manner.	SIGNOR-219253
P60484	P19784	0	phosphorylation	down-regulates activity	0.704	We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366).	SIGNOR-251025
Q86YJ5	P01920	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-271539
P53350	Q9NYQ6	1	phosphorylation	down-regulates activity	0.2	In contrast to the non autonomous polarity defects caused by transgenic expression of Celsr1 LLtoAA, Plk1 inhibition did not cause a significant alteration in Celsr1 interphase polarity (XREF_FIG).\|Plk1 phosphorylates the Celsr1 cytoplasmic domain in\nvitro .	SIGNOR-279094
P53778	P15336	1	phosphorylation	up-regulates	0.542	Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target	SIGNOR-65589
P00533	O15455	1	phosphorylation	up-regulates activity	0.426	Although both the ErbB1 and the ErbB2 isoforms of EGFR can bind to activated TLR3, functionally, only ErbB1 can trigger TLR3 signaling.\|There is a high degree of specificity of the targets of the two PTKs, EGFR and Src	SIGNOR-278932
O75460	O75460	2	phosphorylation	up-regulates activity	0.2	IRE1 transduces the unfolded protein response by splicing XBP1 through its C-terminal cytoplasmic kinase-RNase region. IRE1 autophosphorylation is coupled to RNase activity through formation of a back-to-back dimer, although the conservation of the underlying molecular mechanism is not clear from existing structures.	SIGNOR-275417
Q9UBS5	P27361	0	phosphorylation	down-regulates quantity by destabilization	0.276	We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1.	SIGNOR-277854
P46531	Q4G148	0	glycosylation	up-regulates	0.383	Activity on notch egf repeats was proven by in vitro xylosylation of a mouse notch1 fragment recombinantly produced in sf9 insect cells, a bacterially expressed egf repeat from mouse notch2 modified in vitro by rumi and gxylt2 and in vivo by co-expression of the enzyme with the notch1 fragment.	SIGNOR-177691
P39880	Q96FE7	1	transcriptional regulation	down-regulates quantity by repression	0.368	We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition.	SIGNOR-260072
Q8N752	P35222	1	phosphorylation	down-regulates	0.508	We show that a complex of axin and casein kinase i (cki) induces beta-catenin phosphorylation at a single site: serine 45 (s45).	SIGNOR-87430
Q5JSP0	P60953	1	guanine nucleotide exchange factor	up-regulates activity	0.648	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-260553
P07550	P50148	2	binding	up-regulates activity	0.336	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-257081
Q13315	O95863	1	phosphorylation	up-regulates activity	0.482	ATM-mediated Snail Serine 100 phosphorylation regulates cellular radiosensitivity.	SIGNOR-279587
P35398	Q16620	1	transcriptional regulation	up-regulates quantity by expression	0.266	Some genes which are directly regulated by RORA such as NLGN1 and NTRK2 have been shown to be associated with increased susceptibility to ASD (Correia et al. 2010; Ylisaukko-oja et al. 2005).	SIGNOR-265137
Q9UKP6	P63092	2	binding	up-regulates activity	0.25	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-256779
Q86WV6	Q9BRZ2	0	ubiquitination	up-regulates activity	0.2	In contrast, we found that TRIM56 preferentially promoted K63 linked ubiquitination of the same lysine residue of STING that was important for the dimer formation and TBK1 activation.\|Specifically, TRIM56 induces STING dimerization during dsDNA triggered signaling to potentiate antiviral responses while RNF5 may induce degradation of mitochondrial STING to suppress RLR induced antiviral responses.The findings that TRIM56 failed to interact with dsDNA and that there was no colocalization between TRIM56 and dsDNA within cells suggest that TRIM56 is unlikely to be a dsDNA sensor, and instead facilitates the STING function by ubiquitination.	SIGNOR-278621
Q13535	O15360	1	phosphorylation	up-regulates	0.598	The s1449a mutant failed to completely correct a variety of fa-associated phenotypes. The dna damage response is coordinated by phosphorylation events initiated by apical kinases atm (ataxia telangectasia mutated) and atr (atm and rad3-related), and atr is essential for proper fa pathway function. Serine 1449 is in a consensus atm/atr site	SIGNOR-182953
P06493	Q8NEB9	1	phosphorylation	down-regulates	0.42	We show that vps34 is phosphorylated on thr159 by cdk1, thr159 phosphorylation negatively regulates the ptdins3 kinase activity of vps34 and autophagy	SIGNOR-165768
Q13191	P43405	1	ubiquitination	down-regulates quantity	0.696	In summary, the studies presented here provide evidence that Cbl-b negatively regulates Syk through ubiquitination.\|The results presented suggest that Cbl-b ubiquitinates active phosphorylated Syk and thus functions to dampen B cell antigen receptor signaling after signaling is initiated and thus plays a role in the normal down modulation of B cell antigen receptor signaling.	SIGNOR-278754
Q9UN75	P05556	2	binding	up-regulates activity	0.2	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion.	SIGNOR-265673
P05981	P08709	1	cleavage	up-regulates activity	0.347	Hepsin, a putative membrane-associated serine protease, activates human factor VII and initiates a pathway of blood coagulation on the cell surface leading to thrombin formation\|In contrast, an activation cleavage site factor VII mutant, R152E factor VII, was not cleaved by hepsin-transfected cells, suggesting that factor VII and S344A factor VII were activated on these cells by cleavage of the Arg152-Ile153 peptide bond. I	SIGNOR-263638
P17252	Q13393	1	phosphorylation	up-regulates	0.714	Serine 2, threonine 147, and serine 561 were identified as phosphorylation sites of pld1 by pkcalpha in the cells.	SIGNOR-69938
P09429	Q16566	0	phosphorylation	up-regulates activity	0.285	Collectively, our results demonstrate that CaMKIV promotes the nucleocytoplasmic shuttling of HMGB1 and suggest that the process may be mediated through CaMKIV-dependent serine phosphorylation of HMGB1.	SIGNOR-278510
Q96JH7	P55072	2	binding	up-regulates activity	0.551	Golgi biogenesis requires two distinct p97ATPase-mediated membrane fusion, the p97/p47 and p97/p37 pathways. \|We clarified that VCIP135, an essential factor in both p97 membrane fusion pathways, is phosphorylated on Threonine-760 and Serine-767 by Cdc2 at mitosis and that this phosphorylated VCIP135 does not bind to p97.	SIGNOR-265039
O95243	O15528	1	transcriptional regulation	up-regulates quantity by expression	0.377	Phosphorylation of MBD4 promotes 5-meC glycosylase activity Further evidence emerged to support the involvement of MBD4 in active demethylation. Protein-kinase C phosphorylation of MBD4 at two specific serine residues (165 and 262) following parathyroid hormone stimulation was shown to promote demethylation within the CYP27B1 gene promoter [12]	SIGNOR-275682
Q9NR19	P10619	1	transcriptional regulation	up-regulates quantity by expression	0.2	Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy\|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1\|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants	SIGNOR-276550
P46019	P15735	2	binding	down-regulates activity	0.916	Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit.	SIGNOR-267406
Q14164	Q14164	2	phosphorylation	up-regulates activity	0.2	As previously reported, IKKε underwent rapid activation by auto-phosphorylation on T501 upon IFNβ treatment of control A549 cells, which was impaired by TRIM6si (Figure 4D)	SIGNOR-276637
Q13976	O96001	1	phosphorylation	up-regulates	0.656	Recombinant human G-substrate was phosphorylated efficiently by cGMP-dependent protein kinase exclusively at Thr residues, and it was recognized by antibodies specific for rabbit phospho-G-substrate. The amino acid sequences surrounding the sites of phosphorylation in G-substrate are related to those around Thr-34 and Thr-35 of the dopamine- and cAMP-regulated phosphoprotein DARPP-32 and inhibitor-1, respectively, two potent inhibitors of protein phosphatase 1.	SIGNOR-263148
Q9H2P0	P35222	2	binding	up-regulates quantity by stabilization	0.249	Here, we show that ADNP is required for neural induction and differentiation by enhancing Wnt signaling. Mechanistically, ADNP functions to stabilize β-Catenin through binding to its armadillo domain which prevents its association with key components of the degradation complex: Axin and APC.	SIGNOR-266756
Q5VSY0	O75382	0	polyubiquitination	down-regulates quantity by destabilization	0.248	Here we identify the RING finger-containing protein TRIM3 as a specific E3 ubiquitin ligase for the PSD scaffold GKAP/SAPAP1. Present in PSD fractions from rat brain, TRIM3 stimulates ubiquitination and proteasome-dependent degradation of GKAP, and induces the loss of GKAP and associated scaffold Shank1 from postsynaptic sites.	SIGNOR-271959
P35367	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-257318
P17612	P35222	1	phosphorylation	up-regulates activity	0.478	Although pka did not affect the formation of a complex between glycogen synthase kinase 3beta (gsk-3beta), beta-catenin, and axin, phosphorylation of beta-catenin by pka inhibited ubiquitination of beta-catenin in intact cells and in vitro.	SIGNOR-140902
P25963	Q9UN86	0	relocalization	down-regulates activity	0.342	IkappaBalpha interacts with G3BP2 both in vivo and in vitrothrough the IkappaBalpha CRS. Overexpression of G3BP2 directly promotes retention of IkappaBalpha in the cytoplasm.	SIGNOR-260985
Q14643	Q6GPH6	2	binding	up-regulates	0.2	Recruitment of g protein also can activate phospholipase c (plc) that in turn increases inositol triphosphate (ip3) levels and induces ca2+ release from internal stores.	SIGNOR-172497
P21579	P60880	2	binding	up-regulates activity	0.95	Because synaptotagmins bind SNAP-25 and Ca2+, SNAP-25 has also been linked to the Ca2+ dependence of exocytosis (42). One model suggests that synaptotagmin blocks full SNARE fusion pore formation by binding to t-SNAREs.This interaction prevents fusion from occurring in the absence of calcium. When Ca2+ is present, synaptotagmin releases the t-SNAREs so they can fully zipper with the v-SNARE, leading to fusion	SIGNOR-263975
P24385	Q96PU4	0	ubiquitination	down-regulates quantity by destabilization	0.294	We found that NIRF directly ubiquitinated cyclins D1 and E1, as evidenced by the appearance of the tail (Fig. 4B). In summary, the above findings suggest that NIRF tightly cooperates with the core cell cycle machinery and induces G1 arrest, which is accompanied by ubiquitination of cyclins D1 and E1.	SIGNOR-271885
Q05397	P46937	1	phosphorylation	up-regulates activity	0.284	Then, FAK phosphorylates and activates YAP, leading to the activation and nuclear translocation of YAP/TAZ transcription factor, which is known to be involved in such cellular mechanoresponses [ xref , xref ].	SIGNOR-280099
O60260	Q96M98	1	polyubiquitination	down-regulates quantity by destabilization	0.2	In this study, we found that CHIP promotes Parkin-mediated Pael-R ubiquitination and subsequent degradation. In vitro ubiquitination assays suggested that only a combination of both Parkin and its cofactor CHIP function as a ubiquitin ligase, which is able to sufficiently ubiquitinate Pael-R in vivo (Figure 6).	SIGNOR-272889
P60953	P49841	2	binding	down-regulates	0.377	Phospho-gsk3b-specific antibodies also revolved that lkb1 regulates gsk3b phosphorylation at a known inhibitory site, serine-9. This localized phosphorylation is cdc42 and pkc-zeta-dependent.	SIGNOR-119885
Q9UBU9	P84103	2	binding	up-regulates	0.68	9g8 and srp20 also enhance the tap rna-binding activity	SIGNOR-178111
P14859	P26583	2	binding	up-regulates activity	0.307	HMG2 and Oct2 interact via their HMG domains and POU homeodomains, respectively. This interaction is not restricted to Oct2, as other members of the octamer transcription factor family like Oct1 and Oct6 also interact with HMG2. The interaction with HMG2 results in a marked increase in the sequence-specific DNA binding activity of the Oct proteins	SIGNOR-240151
Q14012	P29475	1	phosphorylation	down-regulates activity	0.331	It was found that purified recombinant nNOS was phosphorylated by CaM-K Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847 with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme. The activity of mutant S847D was decreased to a level 50-60% as much as the wild-type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847 and mutant S847D was partially due to suppression of CaM binding, but not to impairment of dimer formation which is thought to be essential for enzyme activation.	SIGNOR-250614
Q7L9L4	Q13043	0	phosphorylation	up-regulates	0.851	Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction.	SIGNOR-175841
P45983	Q8WTR2	0	dephosphorylation	down-regulates	0.421	Skrp1 was highly specific for c-jun n-terminal kinase (jnk) in vitro and effectively suppressed the jnk activation in response to tumor necrosis factor alpha or thapsigargin skrp1 does not bind directly to its target jnk, but co-precipitation of skrp1 with the mapk kinase mkk7, a jnk activator, was found in vitro and in vivo.	SIGNOR-117260
P45983	P14618	1	phosphorylation	up-regulates activity	0.371	Active JNK1 specifically activates PKM2 but not PKM1. Mechanistically, PARP14 inhibits the pro-apoptotic kinase JNK1, which results in the activation of PKM2 through phosphorylation of Thr365.	SIGNOR-276933
Q86XI6	P54840	2	binding	up-regulates	0.769	In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2)	SIGNOR-271732
P38398	Q13315	0	phosphorylation	up-regulates	0.819	Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Brca1 is phosphorylated at tyrosine residues in an atm-dependent, radiation-dependent manner.	SIGNOR-72075
P10244	Q9UBW7	2	binding	up-regulates activity	0.2	Here we have identified the zinc-finger proteins ZMYM2 and ZMYM4 as novel B-MYB binding proteins. B-MYB has been implicated in cell cycle progression at two steps, namely at the G1/S- and the G2/M-transition. ZMYM2 is required for the G1/S-transition in HepG2 cells.	SIGNOR-269801
P24158	P25116	1	cleavage	down-regulates activity	0.42	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases \| The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II\|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.\|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.\|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site.	SIGNOR-263577
P06493	Q15717	1	phosphorylation	down-regulates activity	0.407	Cdk1 inhibition promoted a cytoplasmic accumulation of HuR, while a predominately nuclear localization of HuR was observed under conditions of high Cdk1 activity.\|Kim et al. further showed that Cdk1-dependent Ser-202 phosphorylation of HuR was essential for 14-3-3\u03b8 binding to HuR.	SIGNOR-279014
O95390	P19883	2	binding	down-regulates activity	0.664	Follistatin (FST) is a member of the tissue growth factor β family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. \|FST315-ΔHBS-Fc induced improvements in muscle repair after injury/atrophy by modulating the early inflammatory phase allowing for increased macrophage density, and Pax7-positive cells leading to an accelerated restoration of myofibers and muscle function.	SIGNOR-251716
P06493	Q8IWB6	1	phosphorylation	down-regulates quantity by destabilization	0.333	Cdk1 phosphorylation of Tex14 is required for the Tex14-Plk1 interaction	SIGNOR-273524
O00631	P16615	2	binding	down-regulates activity	0.505	The structure suggests a mechanism for selective Ca2+ loading and activation of SERCA, and provides new insight into how SLN and PLB inhibition arises from stabilization of this E1 intermediate state without bound Ca2+.	SIGNOR-264779
P61586	P26038	1	phosphorylation	up-regulates activity	0.61	Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies.	SIGNOR-268431
P31391	P08754	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-256823
P62877	Q00653	1	ubiquitination	up-regulates	0.281	Mechanism of processing of the nf-kappa b2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of nedd8-modification on the scf(beta-trcp) ubiquitin ligase.	SIGNOR-120342
P06493	Q9Y5B0	0	dephosphorylation	down-regulates activity	0.333	Thus, Fcp1 coordinates Cdk1 and Gwl inactivation to derepress PP2A-B55, generating a dephosphorylation switch that drives mitosis progression.\|We can not exclude that, in addition to S90 and S453, other Cdk1 phosphorylation sites in Gwl are dephosphorylated by Fcp1; nevertheless, assaying S67-Ensa kinase activity of V5-GwlS90A and V5-GwlS453A mutant proteins, isolated from transfected and prometaphase arrested HeLa cells, revealed that both mutants had significantly reduced S67-Ensa kinase activity compared to V5-GwlWT (XREF_FIG).\|We show here that activation of PP2A-B55, a major mitosis exit phosphatase, required the phosphatase Fcp1 downstream Cdk1 inactivation in human cells.	SIGNOR-277141
Q9NWF9	Q9NR97	1	polyubiquitination	down-regulates quantity by destabilization	0.257	E3 ligase RNF216 (ring finger protein 216) targets TLR8 for ubiquitination and degradation.	SIGNOR-272257
P31749	Q15118	2	phosphorylation	up-regulates activity	0.601	Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex.	SIGNOR-277272
Q969V1	P63096	2	binding	up-regulates activity	0.435	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-257067
Q8WU20	P06213	0	phosphorylation	up-regulates activity	0.371	We found that insulin receptor can directly phosphorylate FRS2.	SIGNOR-278945
P60709	P37802	2	binding	down-regulates activity	0.412	Taken together, our data propose a novel, oncogene-tumor suppressor interplay, where oncogenic PFTK1 confers HCC cell motility through inactivating the actin-binding motile suppressing function of TAGLN2 via phosphorylation.	SIGNOR-265104
Q86VP1	Q13114	2	binding	down-regulates activity	0.466	ABIN1 interacted with the A20 regulatory molecule TAX1BP1 and was essential for the recruitment of TAX1BP1 and A20 to the noncanonical IkappaB kinases TBK1 and IKKi in response to poly(I:C) transfection. ABIN1 and TAX1BP1 together disrupted the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKKi to attenuate lysine 63-linked polyubiquitination of TBK1/IKKi.	SIGNOR-275737
P10276	Q8IXJ9	2	binding	up-regulates activity	0.444	Therefore, ASXL1, a vertebrate PcG/TrxG protein, may mediate RA-regulated cell growth by modulating RAR activity.Finally, the ASXL1-induced accumulation of acetylated H3 may enhance the RAR-mediated transcriptional activity. In this study, we demonstrate that mammalian ASXL1 interacts with the AF-2 AD core of RAR (and RXR) through a novel, promiscuous NR box (LVMQLL) and enhances transcriptional activity of the receptors in certain cells.	SIGNOR-255910
P50148	P24530	2	binding	up-regulates activity	0.577	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-257379
Q99741	P24941	0	phosphorylation	down-regulates activity	0.942	Hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)\|An HsCdc6A1A2A3 mutant, which mimics unphosphorylated HsCdc6, is exclusively nuclear, and its expression inhibits initiation of DNA replication. An HsCdc6E1E2E3 mutant, which mimics phosphorylated HsCdc6, is exclusively cytoplasmic and is not associated with the chromatin/nuclear matrix fraction.	SIGNOR-67544
P14317	P07948	0	phosphorylation	up-regulates activity	0.714	Lyn and Syk synergistically phosphorylate HS1, and that Tyr-378 and Tyr-397 of HS1 are the critical residues for its BCR-induced phosphorylation. tyrosine phosphorylation of HS1 is required for BCR-induced apoptosis and nuclear translocation of HS1 may be a prerequisite for B cell apoptosis. PMID: 9104825 PMCID: PMC2196252	SIGNOR-251401
Q07820	Q9BXH1	2	binding	down-regulates	0.752	Only bimbh3 and bbc3 had comparable strong affinities for all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.	SIGNOR-133817
P61586	Q52LW3	0	gtpase-activating protein	down-regulates activity	0.552	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-260484
Q03431	O75581	2	binding	up-regulates	0.337	Parathyroid hormone (pth) binding to its receptor pth1r induces association of the pthpth1r complex with lrp6and phosphorylation of pppsp sites by protein kinase_ a, which in turn triggers wnt.	SIGNOR-199533
O95202	Q9BXM7	0	phosphorylation	up-regulates activity	0.358	Here we demonstrate that PINK1 directly interacts with and phosphorylates LETM1 at Thr192 in vitro.\|Phosphorylated LETM1 or the phospho-mimetic LETM1-T192E increase calcium release in artificial liposomes and facilitates calcium transport in intact mitochondria.	SIGNOR-262540
P01130	P04114	2	binding	up-regulates	0.805	In the case of ldl, binding of apolipoprotein b (apob) to the ldl-r18-20 and proteoglycans17 21 initiates plasma clearance and lipoprotein degradation	SIGNOR-87035
O00327	Q14995	0	transcriptional regulation	down-regulates quantity by repression	0.467	A retinoic acid receptor-related orphan receptor (ROR) response element within the BMAL1 promoter is responsive to both ROR and REV-ERB (encoded by the genes NR1D1 and NR1D2); ROR activates the transcription of BMAL1, whereas REV-ERB suppresses its transcription.	SIGNOR-268006
Q92502	P60953	1	gtpase-activating protein	down-regulates activity	0.511	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-260520
P16662	P12931	0	phosphorylation	up-regulates	0.343	Overexpression of regular or active src, but not dominant-negative src, in 2b7-transfected cos-1 cells increased 2b7 activity and phospho-y438-2b7 by 50%	SIGNOR-184613
Q9Y6M0	O60216	1	cleavage	up-regulates	0.2	Rad21 is a component of the cohesin complex that holds sister chromatids together during mitosis and repairs double-strand dna breaks. Interestingly, rad21 is cleaved by a caspase-like esp1/separase at the onset of anaphase to trigger sister chromatid separation.	SIGNOR-115426
P78368	Q9Y5P4	1	phosphorylation	down-regulates	0.2	These results indicate that ckigamma2 hyperphosphorylates the serine-repeat motif of cert, thereby inactivating cert and down-regulating the synthesis of sphingomyelin.	SIGNOR-182160
P51617	Q9H0E2	2	binding	down-regulates activity	0.799	Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs)	SIGNOR-251980
Q99683	Q13627	0	phosphorylation	up-regulates activity	0.395	Moreover, Dyrk1A appears to directly phosphorylate the C-terminal domain of ASK1.\|The current finding that Dyrk1A enhances the activities of ASK1 and JNK1, it could act as a pro-apoptotic player.	SIGNOR-279366
Q15750	Q9Y4K3	2	binding	up-regulates activity	0.865	The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex.	SIGNOR-205455
P35637	Q92973	0	relocalization	up-regulates activity	0.642	The C-terminal nuclear localization sequence of FUsed in Sarcoma (FUS-NLS) is critical for its nuclear import mediated by transportin (Trn1).	SIGNOR-262101
P43403	P15498	2	phosphorylation	up-regulates activity	0.838	These results suggest that CBAP may serve as an adaptor or scaffold in the integrin \u03b21/CBAP/ZAP70-containing complex that, upon chemokine treatment, would allow Vav1 or ZAP70 (or both) to adopt an optimal conformation(s) for ZAP70 to phosphorylate Vav1.\|Together, these results suggested that CBAP is an important component in ZAP70 dependent activation of the Vav1 and Rac1 signaling axis.	SIGNOR-278390
P36897	P63151	2	binding	up-regulates	0.536	In this report, we show that another WD-40 repeat protein, the B_ subunit of protein phosphatase 2A, associates with the cytoplasmic domain of type I TGF-_ receptors. [...] We therefore conclude that B_ specifically and directly associates with the type I receptor cytoplasmic domain in vitro.	SIGNOR-227517
Q16539	Q8TDD2	1	phosphorylation	up-regulates activity	0.408	We therefore propose that Osterix binds to Sp1 sequences on target gene promoters and that its phosphorylation by p38 enhances recruitment of coactivators to form transcriptionally active complexes	SIGNOR-255791
Q13131	Q8ND76	1	phosphorylation	up-regulates activity	0.2	Our in vitro and cellular analyses supported the mass spectrometry data that implicated serine 326 (S326) as the phospho-acceptor site on CCNY by AMPK. \|Mechanistically the S326 phosphorylation by AMPK promotes the interaction of CCNY with CDK16, which in turn autophosphorylates S336, which serves as a marker for active CCNY-CDK16	SIGNOR-273011
P50148	O43613	2	binding	up-regulates activity	0.466	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-257220
Q8IXJ6	Q00535	0	phosphorylation	up-regulates activity	0.397	Cdk5 phosphorylation-induced SIRT2 nuclear translocation promotes the death of dopaminergic neurons in Parkinson's disease.\|Moreover, the cyclin-dependent kinase 5 (Cdk5)-mediated phosphorylation of SIRT2 at the Ser331 and Ser335 sites appears to be necessary for such nuclear translocation.	SIGNOR-279684
P17612	O60928	1	phosphorylation	up-regulates	0.2	Pka activation induced an increase of kir7.1 currents. This effect was absent in mutant kir7.1 channels lacking pka consensus site (287)s	SIGNOR-181859
P01111	Q92565	0	guanine nucleotide exchange factor	up-regulates	0.436	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-183738
Q9NS23	Q13315	0	phosphorylation	up-regulates	0.549	We show that, upon dna damage, rassf1a is phosphorylated by atm on ser131 and is involved in the activation of both mst2 and lats1, leading to the stabilization of p73.	SIGNOR-161934
P01100	Q13536	0	transcriptional regulation	up-regulates quantity by expression	0.2	CROC-4: a novel brain specific transcriptional activator of c-fos expressed from proliferation through to maturation of multiple neuronal cell types.	SIGNOR-261569

O43603

Q9BT56

2

binding

up-regulates activity

0.339

Coevolution of the spexin/galanin/kisspeptin family: Spexin activates galanin receptor type II and III.

SIGNOR-268574

Q13177

Q70Z35

1

phosphorylation

down-regulates activity

0.359

P21-activated Kinases (PAKs) Mediate the Phosphorylation of PREX2 Protein to Initiate Feedback Inhibition of Rac1 GTPase. PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ.

SIGNOR-277182

P78352

O14490

2

relocalization

up-regulates activity

0.932

Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b).

SIGNOR-264196

P19086

O43613

2

binding

up-regulates activity

0.25

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-257128

Q92911

P01222

0

transcriptional regulation

up-regulates quantity by expression

0.38

Iâ€“ uptake is stimulated by TSH, the master hormone for thyroid gland regulation. TSH stimulation results, at least in part, from the cAMP-mediated increase in NIS biosynthesis. TSH not only stimulates NIS transcription and biosynthesis but is also required for modulating the NIS phosphorylation pattern, maintaining its half-life, and retaining NIS at the thyrocyte plasma membrane

SIGNOR-251995

P35244

Q9NUX5

2

binding

down-regulates activity

0.263

The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA

SIGNOR-263326

Q9P2Y5

Q9UGI0

0

deubiquitination

up-regulates activity

0.2

Here we report that UVRAG is ubiquitinated by SMURF1 at lysine residues 517 and 559, which decreases the association of UVRAG with RUBCN and promotes autophagosome maturation. However, the deubiquitinase ZRANB1 specifically cleaves SMURF1-induced K29 and K33-linked polyubiquitin chains from UVRAG, thereby increasing the binding of UVRAG to RUBCN and inhibiting autophagy flux.

SIGNOR-273651

P78504

P46531

2

binding

up-regulates activity

0.642

We identify functional fragments of human notch-1 (n-1) and jagged-1 (j-1) which interact in a calcium-dependent manner.

SIGNOR-219253

P60484

P19784

0

phosphorylation

down-regulates activity

0.704

We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366).

SIGNOR-251025

Q86YJ5

P01920

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-271539

P53350

Q9NYQ6

1

phosphorylation

down-regulates activity

0.2

In contrast to the non autonomous polarity defects caused by transgenic expression of Celsr1 LLtoAA, Plk1 inhibition did not cause a significant alteration in Celsr1 interphase polarity (XREF_FIG).|Plk1 phosphorylates the Celsr1 cytoplasmic domain in\nvitro .

SIGNOR-279094

P53778

P15336

1

phosphorylation

up-regulates

0.542

Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target

SIGNOR-65589

P00533

O15455

1

phosphorylation

up-regulates activity

0.426

Although both the ErbB1 and the ErbB2 isoforms of EGFR can bind to activated TLR3, functionally, only ErbB1 can trigger TLR3 signaling.|There is a high degree of specificity of the targets of the two PTKs, EGFR and Src

SIGNOR-278932

O75460

2

phosphorylation

up-regulates activity

0.2

IRE1 transduces the unfolded protein response by splicing XBP1 through its C-terminal cytoplasmic kinase-RNase region. IRE1 autophosphorylation is coupled to RNase activity through formation of a back-to-back dimer, although the conservation of the underlying molecular mechanism is not clear from existing structures.

SIGNOR-275417

Q9UBS5

P27361

0

phosphorylation

down-regulates quantity by destabilization

0.276

We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1.

SIGNOR-277854

P46531

Q4G148

0

glycosylation

up-regulates

0.383

Activity on notch egf repeats was proven by in vitro xylosylation of a mouse notch1 fragment recombinantly produced in sf9 insect cells, a bacterially expressed egf repeat from mouse notch2 modified in vitro by rumi and gxylt2 and in vivo by co-expression of the enzyme with the notch1 fragment.

SIGNOR-177691

P39880

Q96FE7

1

transcriptional regulation

down-regulates quantity by repression

0.368

We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition.

SIGNOR-260072

Q8N752

P35222

1

phosphorylation

down-regulates

0.508

We show that a complex of axin and casein kinase i (cki) induces beta-catenin phosphorylation at a single site: serine 45 (s45).

SIGNOR-87430

Q5JSP0

P60953

1

guanine nucleotide exchange factor

up-regulates activity

0.648

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-260553

P07550

P50148

2

binding

up-regulates activity

0.336

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-257081

Q13315

O95863

1

phosphorylation

up-regulates activity

0.482

ATM-mediated Snail Serine 100 phosphorylation regulates cellular radiosensitivity.

SIGNOR-279587

P35398

Q16620

1

transcriptional regulation

up-regulates quantity by expression

0.266

Some genes which are directly regulated by RORA such as NLGN1 and NTRK2 have been shown to be associated with increased susceptibility to ASD (Correia et al. 2010; Ylisaukko-oja et al. 2005).

SIGNOR-265137

Q9UKP6

P63092

2

binding

up-regulates activity

0.25

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0.

SIGNOR-256779

Q86WV6

Q9BRZ2

0

ubiquitination

up-regulates activity

0.2

In contrast, we found that TRIM56 preferentially promoted K63 linked ubiquitination of the same lysine residue of STING that was important for the dimer formation and TBK1 activation.|Specifically, TRIM56 induces STING dimerization during dsDNA triggered signaling to potentiate antiviral responses while RNF5 may induce degradation of mitochondrial STING to suppress RLR induced antiviral responses.The findings that TRIM56 failed to interact with dsDNA and that there was no colocalization between TRIM56 and dsDNA within cells suggest that TRIM56 is unlikely to be a dsDNA sensor, and instead facilitates the STING function by ubiquitination.

SIGNOR-278621

Q13535

O15360

1

phosphorylation

up-regulates

0.598

The s1449a mutant failed to completely correct a variety of fa-associated phenotypes. The dna damage response is coordinated by phosphorylation events initiated by apical kinases atm (ataxia telangectasia mutated) and atr (atm and rad3-related), and atr is essential for proper fa pathway function. Serine 1449 is in a consensus atm/atr site

SIGNOR-182953

P06493

Q8NEB9

1

phosphorylation

down-regulates

0.42

We show that vps34 is phosphorylated on thr159 by cdk1, thr159 phosphorylation negatively regulates the ptdins3 kinase activity of vps34 and autophagy

SIGNOR-165768

Q13191

P43405

1

ubiquitination

down-regulates quantity

0.696

In summary, the studies presented here provide evidence that Cbl-b negatively regulates Syk through ubiquitination.|The results presented suggest that Cbl-b ubiquitinates active phosphorylated Syk and thus functions to dampen B cell antigen receptor signaling after signaling is initiated and thus plays a role in the normal down modulation of B cell antigen receptor signaling.

SIGNOR-278754

Q9UN75

P05556

2

binding

up-regulates activity

0.2

The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion.

SIGNOR-265673

P05981

P08709

1

cleavage

up-regulates activity

0.347

Hepsin, a putative membrane-associated serine protease, activates human factor VII and initiates a pathway of blood coagulation on the cell surface leading to thrombin formation|In contrast, an activation cleavage site factor VII mutant, R152E factor VII, was not cleaved by hepsin-transfected cells, suggesting that factor VII and S344A factor VII were activated on these cells by cleavage of the Arg152-Ile153 peptide bond. I

SIGNOR-263638

P17252

Q13393

1

phosphorylation

up-regulates

0.714

Serine 2, threonine 147, and serine 561 were identified as phosphorylation sites of pld1 by pkcalpha in the cells.

SIGNOR-69938

P09429

Q16566

0

phosphorylation

up-regulates activity

0.285

Collectively, our results demonstrate that CaMKIV promotes the nucleocytoplasmic shuttling of HMGB1 and suggest that the process may be mediated through CaMKIV-dependent serine phosphorylation of HMGB1.

SIGNOR-278510

Q96JH7

P55072

2

binding

up-regulates activity

0.551

Golgi biogenesis requires two distinct p97ATPase-mediated membrane fusion, the p97/p47 and p97/p37 pathways. |We clarified that VCIP135, an essential factor in both p97 membrane fusion pathways, is phosphorylated on Threonine-760 and Serine-767 by Cdc2 at mitosis and that this phosphorylated VCIP135 does not bind to p97.

SIGNOR-265039

O95243

O15528

1

transcriptional regulation

up-regulates quantity by expression

0.377

Phosphorylation of MBD4 promotes 5-meC glycosylase activity Further evidence emerged to support the involvement of MBD4 in active demethylation. Protein-kinase C phosphorylation of MBD4 at two specific serine residues (165 and 262) following parathyroid hormone stimulation was shown to promote demethylation within the CYP27B1 gene promoter [12]

SIGNOR-275682

Q9NR19

P10619

1

transcriptional regulation

up-regulates quantity by expression

0.2

Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants

SIGNOR-276550

P46019

P15735

2

binding

down-regulates activity

0.916

Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit.

SIGNOR-267406

Q14164

2

phosphorylation

up-regulates activity

0.2

As previously reported, IKKε underwent rapid activation by auto-phosphorylation on T501 upon IFNβ treatment of control A549 cells, which was impaired by TRIM6si (Figure 4D)

SIGNOR-276637

Q13976

O96001

1

phosphorylation

up-regulates

0.656

Recombinant human G-substrate was phosphorylated efficiently by cGMP-dependent protein kinase exclusively at Thr residues, and it was recognized by antibodies specific for rabbit phospho-G-substrate. The amino acid sequences surrounding the sites of phosphorylation in G-substrate are related to those around Thr-34 and Thr-35 of the dopamine- and cAMP-regulated phosphoprotein DARPP-32 and inhibitor-1, respectively, two potent inhibitors of protein phosphatase 1.

SIGNOR-263148

Q9H2P0

P35222

2

binding

up-regulates quantity by stabilization

0.249

Here, we show that ADNP is required for neural induction and differentiation by enhancing Wnt signaling. Mechanistically, ADNP functions to stabilize β-Catenin through binding to its armadillo domain which prevents its association with key components of the degradation complex: Axin and APC.

SIGNOR-266756

Q5VSY0

O75382

0

polyubiquitination

down-regulates quantity by destabilization

0.248

Here we identify the RING finger-containing protein TRIM3 as a specific E3 ubiquitin ligase for the PSD scaffold GKAP/SAPAP1. Present in PSD fractions from rat brain, TRIM3 stimulates ubiquitination and proteasome-dependent degradation of GKAP, and induces the loss of GKAP and associated scaffold Shank1 from postsynaptic sites.

SIGNOR-271959

P35367

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-257318

P17612

P35222

1

phosphorylation

up-regulates activity

0.478

Although pka did not affect the formation of a complex between glycogen synthase kinase 3beta (gsk-3beta), beta-catenin, and axin, phosphorylation of beta-catenin by pka inhibited ubiquitination of beta-catenin in intact cells and in vitro.

SIGNOR-140902

P25963

Q9UN86

0

relocalization

down-regulates activity

0.342

IkappaBalpha interacts with G3BP2 both in vivo and in vitrothrough the IkappaBalpha CRS. Overexpression of G3BP2 directly promotes retention of IkappaBalpha in the cytoplasm.

SIGNOR-260985

Q14643

Q6GPH6

2

binding

up-regulates

0.2

Recruitment of g protein also can activate phospholipase c (plc) that in turn increases inositol triphosphate (ip3) levels and induces ca2+ release from internal stores.

SIGNOR-172497

P21579

P60880

2

binding

up-regulates activity

0.95

Because synaptotagmins bind SNAP-25 and Ca2+, SNAP-25 has also been linked to the Ca2+ dependence of exocytosis (42). One model suggests that synaptotagmin blocks full SNARE fusion pore formation by binding to t-SNAREs.This interaction prevents fusion from occurring in the absence of calcium. When Ca2+ is present, synaptotagmin releases the t-SNAREs so they can fully zipper with the v-SNARE, leading to fusion

SIGNOR-263975

P24385

Q96PU4

0

ubiquitination

down-regulates quantity by destabilization

0.294

We found that NIRF directly ubiquitinated cyclins D1 and E1, as evidenced by the appearance of the tail (Fig. 4B). In summary, the above findings suggest that NIRF tightly cooperates with the core cell cycle machinery and induces G1 arrest, which is accompanied by ubiquitination of cyclins D1 and E1.

SIGNOR-271885

Q05397

P46937

1

phosphorylation

up-regulates activity

0.284

Then, FAK phosphorylates and activates YAP, leading to the activation and nuclear translocation of YAP/TAZ transcription factor, which is known to be involved in such cellular mechanoresponses [ xref , xref ].

SIGNOR-280099

O60260

Q96M98

1

polyubiquitination

down-regulates quantity by destabilization

0.2

In this study, we found that CHIP promotes Parkin-mediated Pael-R ubiquitination and subsequent degradation. In vitro ubiquitination assays suggested that only a combination of both Parkin and its cofactor CHIP function as a ubiquitin ligase, which is able to sufficiently ubiquitinate Pael-R in vivo (Figure 6).

SIGNOR-272889

P60953

P49841

2

binding

down-regulates

0.377

Phospho-gsk3b-specific antibodies also revolved that lkb1 regulates gsk3b phosphorylation at a known inhibitory site, serine-9. This localized phosphorylation is cdc42 and pkc-zeta-dependent.

SIGNOR-119885

Q9UBU9

P84103

2

binding

up-regulates

0.68

9g8 and srp20 also enhance the tap rna-binding activity

SIGNOR-178111

P14859

P26583

2

binding

up-regulates activity

0.307

HMG2 and Oct2 interact via their HMG domains and POU homeodomains, respectively. This interaction is not restricted to Oct2, as other members of the octamer transcription factor family like Oct1 and Oct6 also interact with HMG2. The interaction with HMG2 results in a marked increase in the sequence-specific DNA binding activity of the Oct proteins

SIGNOR-240151

Q14012

P29475

1

phosphorylation

down-regulates activity

0.331

It was found that purified recombinant nNOS was phosphorylated by CaM-K Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847 with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme. The activity of mutant S847D was decreased to a level 50-60% as much as the wild-type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847 and mutant S847D was partially due to suppression of CaM binding, but not to impairment of dimer formation which is thought to be essential for enzyme activation.

SIGNOR-250614

Q7L9L4

Q13043

0

phosphorylation

up-regulates

0.851

Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction.

SIGNOR-175841

P45983

Q8WTR2

0

dephosphorylation

down-regulates

0.421

Skrp1 was highly specific for c-jun n-terminal kinase (jnk) in vitro and effectively suppressed the jnk activation in response to tumor necrosis factor alpha or thapsigargin skrp1 does not bind directly to its target jnk, but co-precipitation of skrp1 with the mapk kinase mkk7, a jnk activator, was found in vitro and in vivo.

SIGNOR-117260

P45983

P14618

1

phosphorylation

up-regulates activity

0.371

Active JNK1 specifically activates PKM2 but not PKM1. Mechanistically, PARP14 inhibits the pro-apoptotic kinase JNK1, which results in the activation of PKM2 through phosphorylation of Thr365.

SIGNOR-276933

Q86XI6

P54840

2

binding

up-regulates

0.769

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

SIGNOR-271732

P38398

Q13315

0

phosphorylation

up-regulates

0.819

Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Brca1 is phosphorylated at tyrosine residues in an atm-dependent, radiation-dependent manner.

SIGNOR-72075

P10244

Q9UBW7

2

binding

up-regulates activity

0.2

Here we have identified the zinc-finger proteins ZMYM2 and ZMYM4 as novel B-MYB binding proteins. B-MYB has been implicated in cell cycle progression at two steps, namely at the G1/S- and the G2/M-transition. ZMYM2 is required for the G1/S-transition in HepG2 cells.

SIGNOR-269801

P24158

P25116

1

cleavage

down-regulates activity

0.42

PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site.

SIGNOR-263577

P06493

Q15717

1

phosphorylation

down-regulates activity

0.407

Cdk1 inhibition promoted a cytoplasmic accumulation of HuR, while a predominately nuclear localization of HuR was observed under conditions of high Cdk1 activity.|Kim et al. further showed that Cdk1-dependent Ser-202 phosphorylation of HuR was essential for 14-3-3\u03b8 binding to HuR.

SIGNOR-279014

O95390

P19883

2

binding

down-regulates activity

0.664

Follistatin (FST) is a member of the tissue growth factor β family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. |FST315-ΔHBS-Fc induced improvements in muscle repair after injury/atrophy by modulating the early inflammatory phase allowing for increased macrophage density, and Pax7-positive cells leading to an accelerated restoration of myofibers and muscle function.

SIGNOR-251716

P06493

Q8IWB6

1

phosphorylation

down-regulates quantity by destabilization

0.333

Cdk1 phosphorylation of Tex14 is required for the Tex14-Plk1 interaction

SIGNOR-273524

O00631

P16615

2

binding

down-regulates activity

0.505

The structure suggests a mechanism for selective Ca2+ loading and activation of SERCA, and provides new insight into how SLN and PLB inhibition arises from stabilization of this E1 intermediate state without bound Ca2+.

SIGNOR-264779

P61586

P26038

1

phosphorylation

up-regulates activity

0.61

Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies.

SIGNOR-268431

P31391

P08754

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-256823

P62877

Q00653

1

ubiquitination

up-regulates

0.281

Mechanism of processing of the nf-kappa b2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of nedd8-modification on the scf(beta-trcp) ubiquitin ligase.

SIGNOR-120342

P06493

Q9Y5B0

0

dephosphorylation

down-regulates activity

0.333

Thus, Fcp1 coordinates Cdk1 and Gwl inactivation to derepress PP2A-B55, generating a dephosphorylation switch that drives mitosis progression.|We can not exclude that, in addition to S90 and S453, other Cdk1 phosphorylation sites in Gwl are dephosphorylated by Fcp1; nevertheless, assaying S67-Ensa kinase activity of V5-GwlS90A and V5-GwlS453A mutant proteins, isolated from transfected and prometaphase arrested HeLa cells, revealed that both mutants had significantly reduced S67-Ensa kinase activity compared to V5-GwlWT (XREF_FIG).|We show here that activation of PP2A-B55, a major mitosis exit phosphatase, required the phosphatase Fcp1 downstream Cdk1 inactivation in human cells.

SIGNOR-277141

Q9NWF9

Q9NR97

1

polyubiquitination

down-regulates quantity by destabilization

0.257

E3 ligase RNF216 (ring finger protein 216) targets TLR8 for ubiquitination and degradation.

SIGNOR-272257

P31749

Q15118

2

phosphorylation

up-regulates activity

0.601

Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex.

SIGNOR-277272

Q969V1

P63096

2

binding

up-regulates activity

0.435

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-257067

Q8WU20

P06213

0

phosphorylation

up-regulates activity

0.371

We found that insulin receptor can directly phosphorylate FRS2.

SIGNOR-278945

P60709

P37802

2

binding

down-regulates activity

0.412

Taken together, our data propose a novel, oncogene-tumor suppressor interplay, where oncogenic PFTK1 confers HCC cell motility through inactivating the actin-binding motile suppressing function of TAGLN2 via phosphorylation.

SIGNOR-265104

Q86VP1

Q13114

2

binding

down-regulates activity

0.466

ABIN1 interacted with the A20 regulatory molecule TAX1BP1 and was essential for the recruitment of TAX1BP1 and A20 to the noncanonical IkappaB kinases TBK1 and IKKi in response to poly(I:C) transfection. ABIN1 and TAX1BP1 together disrupted the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKKi to attenuate lysine 63-linked polyubiquitination of TBK1/IKKi.

SIGNOR-275737

P10276

Q8IXJ9

2

binding

up-regulates activity

0.444

Therefore, ASXL1, a vertebrate PcG/TrxG protein, may mediate RA-regulated cell growth by modulating RAR activity.Finally, the ASXL1-induced accumulation of acetylated H3 may enhance the RAR-mediated transcriptional activity. In this study, we demonstrate that mammalian ASXL1 interacts with the AF-2 AD core of RAR (and RXR) through a novel, promiscuous NR box (LVMQLL) and enhances transcriptional activity of the receptors in certain cells.

SIGNOR-255910

P50148

P24530

2

binding

up-regulates activity

0.577

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-257379

Q99741

P24941

0

phosphorylation

down-regulates activity

0.942

Hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)|An HsCdc6A1A2A3 mutant, which mimics unphosphorylated HsCdc6, is exclusively nuclear, and its expression inhibits initiation of DNA replication. An HsCdc6E1E2E3 mutant, which mimics phosphorylated HsCdc6, is exclusively cytoplasmic and is not associated with the chromatin/nuclear matrix fraction.

SIGNOR-67544

P14317

P07948

0

phosphorylation

up-regulates activity

0.714

Lyn and Syk synergistically phosphorylate HS1, and that Tyr-378 and Tyr-397 of HS1 are the critical residues for its BCR-induced phosphorylation. tyrosine phosphorylation of HS1 is required for BCR-induced apoptosis and nuclear translocation of HS1 may be a prerequisite for B cell apoptosis. PMID: 9104825 PMCID: PMC2196252

SIGNOR-251401

Q07820

Q9BXH1

2

binding

down-regulates

0.752

Only bimbh3 and bbc3 had comparable strong affinities for all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.

SIGNOR-133817

P61586

Q52LW3

0

gtpase-activating protein

down-regulates activity

0.552

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-260484

Q03431

O75581

2

binding

up-regulates

0.337

Parathyroid hormone (pth) binding to its receptor pth1r induces association of the pthpth1r complex with lrp6and phosphorylation of pppsp sites by protein kinase_ a, which in turn triggers wnt.

SIGNOR-199533

O95202

Q9BXM7

0

phosphorylation

up-regulates activity

0.358

Here we demonstrate that PINK1 directly interacts with and phosphorylates LETM1 at Thr192 in vitro.|Phosphorylated LETM1 or the phospho-mimetic LETM1-T192E increase calcium release in artificial liposomes and facilitates calcium transport in intact mitochondria.

SIGNOR-262540

P01130

P04114

2

binding

up-regulates

0.805

In the case of ldl, binding of apolipoprotein b (apob) to the ldl-r18-20 and proteoglycans17 21 initiates plasma clearance and lipoprotein degradation

SIGNOR-87035

O00327

Q14995

0

transcriptional regulation

down-regulates quantity by repression

0.467

A retinoic acid receptor-related orphan receptor (ROR) response element within the BMAL1 promoter is responsive to both ROR and REV-ERB (encoded by the genes NR1D1 and NR1D2); ROR activates the transcription of BMAL1, whereas REV-ERB suppresses its transcription.

SIGNOR-268006

Q92502

P60953

1

gtpase-activating protein

down-regulates activity

0.511

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-260520

P16662

P12931

0

phosphorylation

up-regulates

0.343

Overexpression of regular or active src, but not dominant-negative src, in 2b7-transfected cos-1 cells increased 2b7 activity and phospho-y438-2b7 by 50%

SIGNOR-184613

Q9Y6M0

O60216

1

cleavage

up-regulates

0.2

Rad21 is a component of the cohesin complex that holds sister chromatids together during mitosis and repairs double-strand dna breaks. Interestingly, rad21 is cleaved by a caspase-like esp1/separase at the onset of anaphase to trigger sister chromatid separation.

SIGNOR-115426

P78368

Q9Y5P4

1

phosphorylation

down-regulates

0.2

These results indicate that ckigamma2 hyperphosphorylates the serine-repeat motif of cert, thereby inactivating cert and down-regulating the synthesis of sphingomyelin.

SIGNOR-182160

P51617

Q9H0E2

2

binding

down-regulates activity

0.799

Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs)

SIGNOR-251980

Q99683

Q13627

0

phosphorylation

up-regulates activity

0.395

Moreover, Dyrk1A appears to directly phosphorylate the C-terminal domain of ASK1.|The current finding that Dyrk1A enhances the activities of ASK1 and JNK1, it could act as a pro-apoptotic player.

SIGNOR-279366

Q15750

Q9Y4K3

2

binding

up-regulates activity

0.865

The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex.

SIGNOR-205455

P35637

Q92973

0

relocalization

up-regulates activity

0.642

The C-terminal nuclear localization sequence of FUsed in Sarcoma (FUS-NLS) is critical for its nuclear import mediated by transportin (Trn1).

SIGNOR-262101

P43403

P15498

2

phosphorylation

up-regulates activity

0.838

These results suggest that CBAP may serve as an adaptor or scaffold in the integrin \u03b21/CBAP/ZAP70-containing complex that, upon chemokine treatment, would allow Vav1 or ZAP70 (or both) to adopt an optimal conformation(s) for ZAP70 to phosphorylate Vav1.|Together, these results suggested that CBAP is an important component in ZAP70 dependent activation of the Vav1 and Rac1 signaling axis.

SIGNOR-278390

P36897

P63151

2

binding

up-regulates

0.536

In this report, we show that another WD-40 repeat protein, the B_ subunit of protein phosphatase 2A, associates with the cytoplasmic domain of type I TGF-_ receptors. [...] We therefore conclude that B_ specifically and directly associates with the type I receptor cytoplasmic domain in vitro.

SIGNOR-227517

Q16539

Q8TDD2

1

phosphorylation

up-regulates activity

0.408

We therefore propose that Osterix binds to Sp1 sequences on target gene promoters and that its phosphorylation by p38 enhances recruitment of coactivators to form transcriptionally active complexes

SIGNOR-255791

Q13131

Q8ND76

1

phosphorylation

up-regulates activity

0.2

Our in vitro and cellular analyses supported the mass spectrometry data that implicated serine 326 (S326) as the phospho-acceptor site on CCNY by AMPK. |Mechanistically the S326 phosphorylation by AMPK promotes the interaction of CCNY with CDK16, which in turn autophosphorylates S336, which serves as a marker for active CCNY-CDK16

SIGNOR-273011

P50148

O43613

2

binding

up-regulates activity

0.466

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-257220

Q8IXJ6

Q00535

0

phosphorylation

up-regulates activity

0.397

Cdk5 phosphorylation-induced SIRT2 nuclear translocation promotes the death of dopaminergic neurons in Parkinson's disease.|Moreover, the cyclin-dependent kinase 5 (Cdk5)-mediated phosphorylation of SIRT2 at the Ser331 and Ser335 sites appears to be necessary for such nuclear translocation.

SIGNOR-279684

P17612

O60928

1

phosphorylation

up-regulates

0.2

Pka activation induced an increase of kir7.1 currents. This effect was absent in mutant kir7.1 channels lacking pka consensus site (287)s

SIGNOR-181859

P01111

Q92565

0

guanine nucleotide exchange factor

up-regulates

0.436

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

SIGNOR-183738

Q9NS23

Q13315

0

phosphorylation

up-regulates

0.549

We show that, upon dna damage, rassf1a is phosphorylated by atm on ser131 and is involved in the activation of both mst2 and lats1, leading to the stabilization of p73.

SIGNOR-161934

P01100

Q13536

0

transcriptional regulation

up-regulates quantity by expression

0.2

CROC-4: a novel brain specific transcriptional activator of c-fos expressed from proliferation through to maturation of multiple neuronal cell types.

SIGNOR-261569