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
P35813	Q13153	1	dephosphorylation	down-regulates activity	0.337	Purified PP2Cα protein efficiently dephosphorylated PAK1 in vitro (Fig. 1, D and E). We previously assessed the time course of phospho-PAK1 dephosphorylation assessed using specific antibodies against either Ser(P)198/203 or Thr(P)422 sites in the PAK1 activation loop.	SIGNOR-248492
O00139	Q9H6R7	2	binding	up-regulates activity	0.2	PLK1 Phosphorylates MMAP to Promote Its Interaction with KIF2A and MRE11.	SIGNOR-273732
P63000	Q68EM7	0	guanine nucleotide exchange factor	up-regulates activity	0.566	ARHGAP17 is a Rho GTPase-activating protein of Rac1	SIGNOR-272166
P31270	P01236	1	transcriptional regulation	up-regulates quantity by expression	0.351	HoxA-11 enhanced upregulation of PRL only in differentiated cells.	SIGNOR-261630
Q7L5N1	P31749	0	phosphorylation	up-regulates	0.282	Mechanistic studies show that akt causes csn6 phosphorylation at ser 60, which, in turn, reduces ubiquitin-mediated protein degradation of csn6.	SIGNOR-252532
P06493	Q96EB6	1	phosphorylation	up-regulates	0.528	We identified cyclinb/cdk1 as a cell cycle-dependent kinase that forms a complex with and phosphorylates sirt1. Mutation of two residues phosphorylated by cyclin b/cdk1 (threonine 530 and serine 540) disturbs normal cell cycle progression and fails to rescue proliferation defects in sirt1-deficient cells	SIGNOR-182863
Q00987	P00519	0	phosphorylation	down-regulates activity	0.716	C-abl binds and phosphorylates mdm2 in vivo and in vitro;phosphorylation of mdm2 by c-abl impairs the inhibition of p53 by mdm2.	SIGNOR-90512
P15260	P49841	0	phosphorylation	up-regulates quantity by stabilization	0.2	Our data suggest that glycogen synthase kinase 3 beta (GSK3beta) phosphorylates IFNGR1 thereby enhancing receptor protein stability by limiting ubiquitin proteasomal degradation.	SIGNOR-279720
P51532	Q96EP1	0	polyubiquitination	down-regulates quantity by destabilization	0.333	Here we report that CHFR interacts with BRG1, SNF5, and BAF60a of the SWI/SNF-like BAF complex and ubiquitinates them to target for degradation through a proteasome-mediated pathway, and that SRG3/mBAF155 stabilizes these components by blocking their interaction with CHFR. These results suggest that CHFR enhances the degradation of the components of the SWI/SNF-like BAF complex by inducing their poly-ubiquitination.	SIGNOR-271457
Q68G74	Q5JUK2	0	transcriptional regulation	up-regulates quantity by expression	0.486	Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters.	SIGNOR-266076
P42127	P32245	2	binding	down-regulates activity	0.5	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268708
O00257	Q9UGL1	2	binding	up-regulates activity	0.399	Our results clearly showed that the PcG protein hPc2 interacted with the N-terminus of JARID1B both in vivo and in vitro. It is interesting that the C-terminus of hPc2 was essential for the interaction and transcriptional co-repression.	SIGNOR-226447
P07949	P27361	1	phosphorylation	up-regulates	0.433	We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1).	SIGNOR-140298
Q16584	Q16584	2	phosphorylation	up-regulates	0.2	These residues within the activation loop are critical for mlk-3 autophosphorylation and activation. In addition, when the thr277 and ser281 residues were mutated to negatively charged glutamic acid to mimic phosphorylated serine/threonine residues, the resulting mutants were fully functional, implying that these two residues may serve as the autophosphorylation sites.	SIGNOR-83407
P07711	Q9UNZ2	2	binding	down-regulates activity	0.2	The SEP domain of p47 acts as a reversible competitive inhibitor of cathepsin L.	SIGNOR-265043
O43711	P14921	2	binding	down-regulates activity	0.364	We show that the cortical thymic maturation arrest in T-lineage ALLs that overexpress TLX1 or TLX3 is due to binding of TLX1/TLX3 to ETS1, leading to repression of T cell receptor (TCR) α enhanceosome activity and blocked TCR-Jα rearrangement.	SIGNOR-259098
Q7Z6B7	P63000	1	gtpase-activating protein	down-regulates activity	0.56	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-260515
P98170	P31749	0	phosphorylation	up-regulates quantity by stabilization	0.618	Akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin.	SIGNOR-119488
Q13207	P15172	2	binding	down-regulates activity	0.31	We have found that TBX2 is highly up regulated in both ERMS and ARMS subtypes of RMS and demonstrate that TBX2 is a repressor of myogenesis by binding to MyoD and myogenin and inhibiting their activity.	SIGNOR-251560
P25445	P04637	0	transcriptional regulation	up-regulates quantity by expression	0.605	In an attempt to understand how CD95 expression is regulated by p53, we identified a p53-responsive element within the first intron of the CD95 gene, as well as three putative elements within the promoter. The intronic element conferred transcriptional activation by p53 and cooperated with p53-responsive elements in the promoter of the CD95 gene. wt p53 bound to and transactivated the CD95 gene,	SIGNOR-62376
Q86YJ5	P01909	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-271538
Q9Y2K6	Q13535	0	phosphorylation	down-regulates activity	0.306	On the other hand, USP20 is phosphorylated by ATR, which disrupts the interaction between USP20 and HERC2, resulting in USP20 stabilization.\|USP20 phosphorylation by ATR is important for its stabilization and checkpoint activation.	SIGNOR-278393
Q9UN72	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-265667
Q9NQC7	Q9Y4K3	1	deubiquitination	down-regulates	0.789	The nf-kappab activation by cyld is mediated, at least in part, by the deubiquitination and inactivation of tnfr-associated factor 2 (traf2) and, to a lesser extent, traf6.	SIGNOR-117856
P08253	P10915	1	cleavage	down-regulates quantity by destabilization	0.339	Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix.	SIGNOR-256333
Q13224	P12931	0	phosphorylation	up-regulates activity	0.559	We have investigated the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B by exogenous Src Phosphorylation-site specific antibodies identified NR2B Tyr1472 as a phosphorylation site for intrinsic PSD tyrosine kinases	SIGNOR-247180
Q03113	Q06187	2	binding	up-regulates activity	0.317	Here we show that Ga12 binds directly to, and stimulates the activity of, Bruton’s tyrosine kinase (Btk) and a Ras GTPase-activating protein, Gap1m, in vitro and in vivo	SIGNOR-278082
P09429	O00206	2	binding	up-regulates activity	0.802	Here we show that Toll-like receptor 4 (TLR4), a pivotal receptor for activation of innate immunity and cytokine release, is required for HMGB1-dependent activation of macrophage TNF release.	SIGNOR-252057
P49792	P46527	1	relocalization	down-regulates quantity	0.2	RanBP2 can increase the sumoylation of p27kip1. In our study, the target protein p27kip1 mainly acts as a tumor-suppressor gene in the nucleus, RanBP2 and SUMO1 act as oncogenes by promoting the nuclear-cytoplasmic translocation and debilitate the G1-arrest brought by p27kip1 accumulation in the nucleus.	SIGNOR-259115
P31751	P55211	1	phosphorylation	down-regulates	0.528	Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity	SIGNOR-61561
P01116	Q8N653	0	ubiquitination	down-regulates activity	0.25	By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine-170. LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane.	SIGNOR-269068
Q00535	P07814	1	phosphorylation	down-regulates	0.2	Ser(886) phosphorylation is required for the interaction of nsap1, which blocks eprs binding to target mrnas. The same phosphorylation event induces subsequent binding of ribosomal protein l13a and gapdh and restores mrna binding. Ifn-_ activates cdk5 to phosphorylate ser(886) in the linker domain of glutamyl-prolyl trna synthetase (eprs), the initial event in assembly of the gait complex. Cdk5/p35 also induces, albeit indirectly via a distinct kinase, phosphorylation of ser(999), the second essential event in gait pathway activation	SIGNOR-187383
P62633	Q99873	0	methylation	down-regulates	0.368	Cnbp interacts with protein arginine methyltransferase prmt1 / r25 or r27 appear to be the major methylation sites in cnbp /arginine methylation of cnbp impedes rna binding	SIGNOR-204958
Q13555	Q9UQL6	1	phosphorylation	down-regulates	0.428	Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation.	SIGNOR-85102
P53567	P35247	1	transcriptional regulation	up-regulates quantity by expression	0.2	Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells\| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D.	SIGNOR-254058
P41743	P12931	0	phosphorylation	up-regulates	0.533	Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase c's via a src kinase pathway. tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain.	SIGNOR-111920
P49327	Q9P035	0	chemical activation	up-regulates activity	0.2	Very long-chain fatty acids are produced through a four-step cycle. However, the 3-hydroxyacyl-CoA dehydratase catalyzing the third step in mammals has remained unidentified. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases,	SIGNOR-267762
Q8IVT5	P10398	2	binding	up-regulates activity	0.567	In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically.	SIGNOR-273876
Q92882	Q15418	0	phosphorylation	down-regulates activity	0.352	SH3P2 was phosphorylated on Ser(202) by ribosomal S6 kinase (RSK) in an ERK pathway-dependent manner, and such phosphorylation inhibited the ability of SH3P2 to suppress cell motility.	SIGNOR-273838
Q86V24	Q15848	2	binding	up-regulates	0.773	Expression of adipor1/r2 or suppression of adipor1/r2 expression by small-interfering rna supports our conclusion that they serve as receptors for globular and full-length adiponectin,	SIGNOR-101809
Q15797	Q9UNE7	0	ubiquitination	down-regulates	0.328	These results suggest that chip can interact with the smad1/smad4 proteins and block bmp signal transduction through the ubiquitin-mediated degradation of smad proteins.	SIGNOR-120731
Q9Y4K3	O43318	1	ubiquitination	up-regulates activity	0.893	Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6.	SIGNOR-236071
P09958	P04275	1	cleavage	up-regulates activity	0.481	Like PACE,PACE4 was able to process pro-vWF to its mature form, and efficient cleavage required both the P4 arginine and the P2 lysine	SIGNOR-260368
Q92696	P20339	1	lipidation	up-regulates activity	0.625	Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional	SIGNOR-265572
P06493	Q9NQR1	1	phosphorylation	up-regulates quantity by stabilization	0.2	We found that PR-Set7 is phosphorylated at Ser 29 (S29) specifically by the cyclin-dependent kinase 1 (cdk1)/cyclinB complex, primarily from prophase through early anaphase, subsequent to global accumulation of H4K20me1. While S29 phosphorylation did not affect PR-Set7 methyltransferase activity, this event resulted in the removal of PR-Set7 from mitotic chromosomes. S29 phosphorylation also functions to stabilize PR-Set7 by directly inhibiting its interaction with the anaphase-promoting complex (APC), an E3 ubiquitin ligase.	SIGNOR-259832
P35240	P62140	0	dephosphorylation	up-regulates	0.378	When serine 518 is dephosphorylated by the myosin phosphatase mypt-1-pp1?, The tumor suppressor function of merlin is activated, inhibiting the ras signaling pathway and leading to growth arrest	SIGNOR-159836
P38936	Q00987	2	binding	down-regulates quantity by destabilization	0.643	MDM2 facilitates p21 degradation independent of ubiquitination and the E3 ligase function of MDM2. Instead, MDM2 promotes p21 degradation by facilitating binding of p21 with the proteasomal C8 subunit. The physical interaction between p21 and MDM2 was demonstrated both in vitro and in vivo with the binding region in amino acids 180-298 of the MDM2 protein.	SIGNOR-272954
P07384	P10636	1	cleavage	down-regulates activity	0.333	Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains	SIGNOR-251584
Q92769	P33076	1	deacetylation	down-regulates quantity by repression	0.413	We report that CIITA and histone deacetylase 2 (HDAC2) interact in smooth muscle cells and macrophages as assayed by co-immunoprecipitations. HDAC2 deacetylates CIITA whereas both the HDAC inhibitor trichostatin A (TSA) and over-expression of HDAC2 interfering RNA increase CIITA acetylation. HDAC2 down-regulates CIITA recruitment to target promoters as evidenced by chromatin immunoprecipitation assays, and suppresses MHC II activation and collagen repression mediated by CIITA in luciferase reporter assays.	SIGNOR-254231
P83916	P84243	2	binding	up-regulates activity	0.2	A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing.	SIGNOR-264491
Q9Y4C1	Q07912	0	phosphorylation	down-regulates activity	0.37	We report that ACK1 phosphorylates the ER co-activator, KDM3A, a H3K9 demethylase, at an evolutionary conserved tyrosine 1114 site in a heregulin-dependent manner, even in the presence of tamoxifen.	SIGNOR-276842
Q09472	O60885	2	binding	up-regulates activity	0.426	In this study, we explored the role of Brd4 and its interaction with the p300 acetyltransferase in the regulation of Nox4 and the in vivo efficacy of a BET inhibitor to reverse established age-associated lung fibrosis. \|Together, these studies suggest that Brd4 enhances p300-mediated histone acetylation.	SIGNOR-262064
O14746	Q9NPE3	2	binding	up-regulates activity	0.62	Dyskerin was recently found to be associated with active human telomerase (34), and mutations in dyskerin or NOP10 or deletion of the H/ACA motif of hTERC result in diminished telomerase activity	SIGNOR-263331
Q7Z5H3	P61586	1	gtpase-activating protein	down-regulates activity	0.564	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-260476
P67775	P19484	1	dephosphorylation	up-regulates activity	0.2	MS analysis revealed that PP2A dephosphorylates TFEB at several residues, including Ser-109, Ser-114, Ser-122, and Ser-211, thus facilitating TFEB activation.	SIGNOR-277881
Q00653	Q969H0	2	binding	down-regulates quantity by destabilization	0.396	Fbxw7α is a member of the F-box family of proteins, which function as the substrate-targeting subunits of SCF (Skp1/Cul1/F-box protein) ubiquitin ligase complexes. Using differential purifications and mass spectrometry, we identified p100, an inhibitor of NF-κB signalling, as an interactor of Fbxw7α. p100 is constitutively targeted in the nucleus for proteasomal degradation by Fbxw7α	SIGNOR-272907
P08912	O95837	2	binding	up-regulates activity	0.385	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257291
P42771	P24941	2	binding	down-regulates	0.48	However, induction of p16(ink4a) also causes marked inhibition of cdk2 activity.	SIGNOR-64431
Q9UPP1	P68400	0	phosphorylation	up-regulates activity	0.2	The CK2 kinase is responsible for PHF8 phosphorylation at Ser854. PHF8 is phosphorylated by CK2, which regulates binding of PHF8 to TopBP1. The Ser854 residue of PHF8 is required for its interaction with TopBP1.	SIGNOR-273628
Q08209	Q13469	1	dephosphorylation	up-regulates activity	0.629	NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248690
Q96GD4	Q9UPY8	1	phosphorylation	up-regulates	0.472	Phosphorylation of eb3 at s176 by aurora b ensures successful cytokinesis completion by promoting midbody mt stability and midbody stabilization.	SIGNOR-202130
Q00534	P42773	2	binding	down-regulates	0.88	The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb.	SIGNOR-44601
Q13887	Q9HAU4	0	ubiquitination	down-regulates quantity by destabilization	0.37	Consistent with these observations, another study documented that Smurf2 specifically destabilizes KLF5, that the degradation of KLF5 by Smurf2 is disrupted by the proteasome inhibitor MG132, and that Smurf2 ubiquitinates KLF5 .	SIGNOR-278781
Q13224	P51608	0	transcriptional regulation	down-regulates quantity by repression	0.35	The interaction of MeCP2 with the 2BI3 and 2BI5 sites was strikingly reduced in neurons maintained in the presence of TTX (Fig. 2C). This result is consistent with the classical view of MeCP2 as a general transcriptional repressor, in that the reduced association leads to increased expression of NR2B.	SIGNOR-264685
P28482	Q15831	1	phosphorylation	down-regulates activity	0.402	Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK.	SIGNOR-209876
P68431	O15550	0	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-260017
Q9H0E2	P51617	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
P17612	P08151	1	phosphorylation	down-regulates	0.551	We report that activation of PKA retains Gli1 in the cytoplasm. Conversely, inhibition of PKA activity promotes nuclear accumulation of Gli1.We provide direct evidence to support that the cAMP/PKA signaling axis regulates Gli1 protein localization primarily through a site at Thr374. .These data suggest that Thr374 is an important PKA site responsible for PKA phosphorylation and for the transcriptional activity of Gli1.	SIGNOR-253539
P31749	Q13950	1	phosphorylation	down-regulates activity	0.446	Here we show that Akt kinase directly phosphorylates Runx2 to regulate invasive properties of breast cancer cells.	SIGNOR-280176
Q15437	Q969U6	0	ubiquitination	down-regulates quantity by destabilization	0.2	SCFFBXW5 interacts with SEC23B and targets it for ubiquitylation and proteasome-mediated degradation.	SIGNOR-265286
Q9NRF2	O60674	2	binding	up-regulates activity	0.692	The SH2B adaptor protein 1 (SH2B1) is a key regulator of leptin, as it enhances leptin signalling by both stimulating Janus kinase 2 (JAK2) activity and assembling a JAK2/IRS1/2 signalling complex	SIGNOR-253078
P63092	Q99500	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 ‚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-256790
O43280	P06493	0	phosphorylation	up-regulates activity	0.268	Ewald et al. reported that at the G1/S transition, cyclin-dependent kinase 1 (CDK1) phosphorylates and activates the neutral trehalase (NTH1) to funnel trehalose into glycolysis (Ewald et al. xref ).	SIGNOR-280206
P12931	P40337	1	phosphorylation	down-regulates quantity by destabilization	0.29	We have found that elevated Src can trigger a drastic reduction in VHL stability even under normoxic conditions, through phosphorylation of VHL tyrosine residue 185, leading to ubiquitination and proteasome mediated degradation of VHL.	SIGNOR-279125
Q13541	Q16539	0	phosphorylation	down-regulates activity	0.433	4E-BP1 Is Phosphorylated in Vitro by Active p38 Kinase. In the present study we demonstrated that UVB induced 4E-BP1 phosphorylation at multiple sites, Thr-36, Thr-45, Ser-64, and Thr-69, leading to dissociation of 4E-BP1 from eIF-4E.	SIGNOR-250097
Q00535	Q96QB1	1	phosphorylation	up-regulates activity	0.2	The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin.	SIGNOR-276444
Q9UGL1	P55771	2	binding	up-regulates activity	0.483	Human PLU-1 Has transcriptional repression properties and interacts with the developmental transcription factors BF-1 and PAX9. In a reporter assay system, PLU-1 has potent transcriptional repression activity. BF-1 and PAX9 also represses transcription in the same assay, but co-expression of PLU-1 with BF-1 or PAX9 significantly enhances this repression	SIGNOR-223875
P00519	Q92769	1	phosphorylation	up-regulates quantity by stabilization	0.285	C-Abl stabilizes HDAC2 levels by tyrosine phosphorylation repressing neuronal gene expression in Alzheimer's disease.	SIGNOR-260928
P28698	P17252	1	transcriptional regulation	up-regulates quantity by expression	0.384	The luciferase reporter assay results revealed that the presence of both MZF-1 and Elk-1 significantly contributed to the upregulation of PKCα gene transcription activity.	SIGNOR-256337
P53350	Q9NYZ3	1	phosphorylation	up-regulates	0.736	In this study, we show that g2 and s-phase-expressed 1 (gtse1) protein, a negative regulator of p53, is required for g2 checkpoint recovery and that plk1 phosphorylation of gtse1 at ser 435 promotes its nuclear localization, and thus shuttles p53 out of the nucleus to lead to its degradation during the recovery.	SIGNOR-166417
P60953	P10911	0	guanine nucleotide exchange factor	up-regulates activity	0.777	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-260558
P31260	Q06124	0	dephosphorylation	up-regulates	0.373	We also identified hoxa10 as a substrate for shp2 in undifferentiated myeloid cells, an effect that diminished during myelopoiesis. However, a constitutively active form of shp2 dephosphorylated hoxa10 throughout ex vivo myelopoiesis and sustained repression of hoxa10 target genes involved in phagocyte effector functions.	SIGNOR-182475
P25098	P17252	0	phosphorylation	up-regulates activity	0.2	Phosphorylation of GRK2 by protein kinase C abolishes its inhibition by calmodulin. In vitro, GRK2 was preferentially phosphorylated by PKC isoforms alpha, gamma, and delta. Two-dimensional peptide mapping of PKCalpha-phosphorylated GRK2 showed a single site of phosphorylation, which was identified as serine 29 by HPLC-MS. A S29A mutant of GRK2 was not phosphorylated by PKC in vitro and showed no phorbol ester-stimulated phosphorylation when transfected into human embryonic kidney (HEK)293 cells.	SIGNOR-249058
P0DTC2	P07711	0	cleavage	up-regulates activity	0.2	SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines.	SIGNOR-260737
Q05655	P49840	1	phosphorylation	down-regulates	0.342	Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway.	SIGNOR-115722
Q7Z2Y5	Q9UNE7	0	polyubiquitination	down-regulates quantity by destabilization	0.2	Our results indicate that Nrk is ubiquitinated by CHIP in a chaperone-dependent manner, resulting in its proteasomal degradation.	SIGNOR-274110
P27986	P42336	2	binding	up-regulates activity	0.936	Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival	SIGNOR-242637
O14763	P50591	2	binding	up-regulates	0.934	Tumour necrosis factor-related apoptosis inducing ligand (trail) receptor 2 (trail-r2) also known as tnfrsf10b (tumour necrosis factor receptor (tnfr) super family 10b) or killer/dr5, a member of the tnfr family, is a promising candidate tumour suppressor gene at 8p21-22.	SIGNOR-134524
Q9UL51	Q13237	0	phosphorylation	down-regulates activity	0.2	Here, we show for the first time that in the HCN2 channel cGMP can also exert an inhibitory effect on gating via cGMP-dependent protein kinase II (cGKII)-mediated phosphorylation.We identify the proximal C-terminus of HCN2 as binding region of cGKII and show that cGKII phosphorylates HCN2 at a specific serine residue (S641) in the C-terminal end of the CNBD. The cGKII shifts the voltage-dependence of HCN2 activation to 2-5 mV more negative voltages and, hence, counteracts the stimulatory effect of cGMP on gating.	SIGNOR-263185
O14640	Q9GZV5	2	binding	down-regulates	0.358	Taz binds to dvl proteins, thereby inhibiting dvl phosphorylation by casein kinase 1-delta and -epsilon kinases (ck1d/e), thus promoting beta-catenin degradation.	SIGNOR-195212
Q5JWF2	P41968	0	null	up-regulates activity	0.547	We hypothesize that XLŒ±s may be involved in this regulatory loop by coupling to melanocortin receptors 3 and 4 in the hypothalamus.	SIGNOR-253068
O00429	Q9UM11	0	ubiquitination	down-regulates quantity	0.349	Here we demonstrate that changes in mitochondrial dynamics as cells exit mitosis are driven in part through ubiquitylation of Drp1 catalyzed by the APC/Ccdh1 (anaphase-promoting complex/cyclosome and its coactivator (Cdh1) E3 ubiquiting ligase complex	SIGNOR-274127
P17252	O15350	1	phosphorylation	up-regulates activity	0.2	Here, we report that p73 is able to induce cell cycle arrest independently of its amino-terminal transactivation domain, whereas this domain is crucial for p73 proapoptotic functions. its activity is regulated throughout the cell cycle and modified by protein kinase C-dependent phosphorylation at serine residue 388.	SIGNOR-276235
Q9UPT9	P06493	0	phosphorylation	up-regulates activity	0.47	On the other hand, CDK1 enhances USP22 activity to stabilize CCNB1 during the G2/M phase.\|Phosphorylation of USP22 by CDK1 enhances its activity in deubiquitinating CCNB1.	SIGNOR-278241
P27361	P06401	1	phosphorylation	down-regulates	0.561	Specifically, down-regulation of mature prs occurs by a mechanism in which ligand binding activates pr phosphorylation by mapks at a unique serine residue, which then targets the receptors for degradation.	SIGNOR-74716
O00755	P03956	1	transcriptional regulation	up-regulates quantity by expression	0.261	Because MMP1 is also another direct target of the canonical Wnt pathway (22), Wnt7a overexpression upregulated MMP1/10 to degrade the extracellular matrix and to facilitate UBC cell invasion.	SIGNOR-278868
P52306	P15153	2	binding	up-regulates	0.5	Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob	SIGNOR-171421
Q15131	P15036	1	phosphorylation	down-regulates quantity by destabilization	0.528	Altogether, these results suggest that CDK10/cyclin M directly controls ETS2 degradation through the phosphorylation of these two serines.	SIGNOR-260914
Q5VTR2	Q13315	0	phosphorylation	up-regulates	0.522	E3 ubiquitin ligase, a heterodimeric complex of the ringfinger rfn20/rfn40 is phosphorylated by atm.	SIGNOR-174949
P12931	P42681	1	phosphorylation	up-regulates activity	0.348	We further demonstrate that Rlk can be phosphorylated and activated by Src kinases, leading to a decrease in its half-life. A specific tyrosine in the activation loop of Rlk, Y420, is required for phosphorylation and activation, as well as for decreased stability, but is not required for lipid RAFT association.	SIGNOR-247346

P35813

Q13153

1

dephosphorylation

down-regulates activity

0.337

Purified PP2Cα protein efficiently dephosphorylated PAK1 in vitro (Fig. 1, D and E). We previously assessed the time course of phospho-PAK1 dephosphorylation assessed using specific antibodies against either Ser(P)198/203 or Thr(P)422 sites in the PAK1 activation loop.

SIGNOR-248492

O00139

Q9H6R7

2

binding

up-regulates activity

0.2

PLK1 Phosphorylates MMAP to Promote Its Interaction with KIF2A and MRE11.

SIGNOR-273732

P63000

Q68EM7

0

guanine nucleotide exchange factor

up-regulates activity

0.566

ARHGAP17 is a Rho GTPase-activating protein of Rac1

SIGNOR-272166

P31270

P01236

1

transcriptional regulation

up-regulates quantity by expression

0.351

HoxA-11 enhanced upregulation of PRL only in differentiated cells.

SIGNOR-261630

Q7L5N1

P31749

0

phosphorylation

up-regulates

0.282

Mechanistic studies show that akt causes csn6 phosphorylation at ser 60, which, in turn, reduces ubiquitin-mediated protein degradation of csn6.

SIGNOR-252532

P06493

Q96EB6

1

phosphorylation

up-regulates

0.528

We identified cyclinb/cdk1 as a cell cycle-dependent kinase that forms a complex with and phosphorylates sirt1. Mutation of two residues phosphorylated by cyclin b/cdk1 (threonine 530 and serine 540) disturbs normal cell cycle progression and fails to rescue proliferation defects in sirt1-deficient cells

SIGNOR-182863

Q00987

P00519

0

phosphorylation

down-regulates activity

0.716

C-abl binds and phosphorylates mdm2 in vivo and in vitro;phosphorylation of mdm2 by c-abl impairs the inhibition of p53 by mdm2.

SIGNOR-90512

P15260

P49841

0

phosphorylation

up-regulates quantity by stabilization

0.2

Our data suggest that glycogen synthase kinase 3 beta (GSK3beta) phosphorylates IFNGR1 thereby enhancing receptor protein stability by limiting ubiquitin proteasomal degradation.

SIGNOR-279720

P51532

Q96EP1

0

polyubiquitination

down-regulates quantity by destabilization

0.333

Here we report that CHFR interacts with BRG1, SNF5, and BAF60a of the SWI/SNF-like BAF complex and ubiquitinates them to target for degradation through a proteasome-mediated pathway, and that SRG3/mBAF155 stabilizes these components by blocking their interaction with CHFR. These results suggest that CHFR enhances the degradation of the components of the SWI/SNF-like BAF complex by inducing their poly-ubiquitination.

SIGNOR-271457

Q68G74

Q5JUK2

0

transcriptional regulation

up-regulates quantity by expression

0.486

Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters.

SIGNOR-266076

P42127

P32245

2

binding

down-regulates activity

0.5

The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins

SIGNOR-268708

O00257

Q9UGL1

2

binding

up-regulates activity

0.399

Our results clearly showed that the PcG protein hPc2 interacted with the N-terminus of JARID1B both in vivo and in vitro. It is interesting that the C-terminus of hPc2 was essential for the interaction and transcriptional co-repression.

SIGNOR-226447

P07949

P27361

1

phosphorylation

up-regulates

0.433

We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1).

SIGNOR-140298

Q16584

2

phosphorylation

up-regulates

0.2

These residues within the activation loop are critical for mlk-3 autophosphorylation and activation. In addition, when the thr277 and ser281 residues were mutated to negatively charged glutamic acid to mimic phosphorylated serine/threonine residues, the resulting mutants were fully functional, implying that these two residues may serve as the autophosphorylation sites.

SIGNOR-83407

P07711

Q9UNZ2

2

binding

down-regulates activity

0.2

The SEP domain of p47 acts as a reversible competitive inhibitor of cathepsin L.

SIGNOR-265043

O43711

P14921

2

binding

down-regulates activity

0.364

We show that the cortical thymic maturation arrest in T-lineage ALLs that overexpress TLX1 or TLX3 is due to binding of TLX1/TLX3 to ETS1, leading to repression of T cell receptor (TCR) α enhanceosome activity and blocked TCR-Jα rearrangement.

SIGNOR-259098

Q7Z6B7

P63000

1

gtpase-activating protein

down-regulates activity

0.56

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-260515

P98170

P31749

0

phosphorylation

up-regulates quantity by stabilization

0.618

Akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin.

SIGNOR-119488

Q13207

P15172

2

binding

down-regulates activity

0.31

We have found that TBX2 is highly up regulated in both ERMS and ARMS subtypes of RMS and demonstrate that TBX2 is a repressor of myogenesis by binding to MyoD and myogenin and inhibiting their activity.

SIGNOR-251560

P25445

P04637

0

transcriptional regulation

up-regulates quantity by expression

0.605

In an attempt to understand how CD95 expression is regulated by p53, we identified a p53-responsive element within the first intron of the CD95 gene, as well as three putative elements within the promoter. The intronic element conferred transcriptional activation by p53 and cooperated with p53-responsive elements in the promoter of the CD95 gene. wt p53 bound to and transactivated the CD95 gene,

SIGNOR-62376

Q86YJ5

P01909

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-271538

Q9Y2K6

Q13535

0

phosphorylation

down-regulates activity

0.306

On the other hand, USP20 is phosphorylated by ATR, which disrupts the interaction between USP20 and HERC2, resulting in USP20 stabilization.|USP20 phosphorylation by ATR is important for its stabilization and checkpoint activation.

SIGNOR-278393

Q9UN72

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-265667

Q9NQC7

Q9Y4K3

1

deubiquitination

down-regulates

0.789

The nf-kappab activation by cyld is mediated, at least in part, by the deubiquitination and inactivation of tnfr-associated factor 2 (traf2) and, to a lesser extent, traf6.

SIGNOR-117856

P08253

P10915

1

cleavage

down-regulates quantity by destabilization

0.339

Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix.

SIGNOR-256333

Q13224

P12931

0

phosphorylation

up-regulates activity

0.559

We have investigated the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B by exogenous Src Phosphorylation-site specific antibodies identified NR2B Tyr1472 as a phosphorylation site for intrinsic PSD tyrosine kinases

SIGNOR-247180

Q03113

Q06187

2

binding

up-regulates activity

0.317

Here we show that Ga12 binds directly to, and stimulates the activity of, Bruton’s tyrosine kinase (Btk) and a Ras GTPase-activating protein, Gap1m, in vitro and in vivo

SIGNOR-278082

P09429

O00206

2

binding

up-regulates activity

0.802

Here we show that Toll-like receptor 4 (TLR4), a pivotal receptor for activation of innate immunity and cytokine release, is required for HMGB1-dependent activation of macrophage TNF release.

SIGNOR-252057

P49792

P46527

1

relocalization

down-regulates quantity

0.2

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

SIGNOR-259115

P31751

P55211

1

phosphorylation

down-regulates

0.528

Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity

SIGNOR-61561

P01116

Q8N653

0

ubiquitination

down-regulates activity

0.25

By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine-170. LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane.

SIGNOR-269068

Q00535

P07814

1

phosphorylation

down-regulates

0.2

Ser(886) phosphorylation is required for the interaction of nsap1, which blocks eprs binding to target mrnas. The same phosphorylation event induces subsequent binding of ribosomal protein l13a and gapdh and restores mrna binding. Ifn-_ activates cdk5 to phosphorylate ser(886) in the linker domain of glutamyl-prolyl trna synthetase (eprs), the initial event in assembly of the gait complex. Cdk5/p35 also induces, albeit indirectly via a distinct kinase, phosphorylation of ser(999), the second essential event in gait pathway activation

SIGNOR-187383

P62633

Q99873

0

methylation

down-regulates

0.368

Cnbp interacts with protein arginine methyltransferase prmt1 / r25 or r27 appear to be the major methylation sites in cnbp /arginine methylation of cnbp impedes rna binding

SIGNOR-204958

Q13555

Q9UQL6

1

phosphorylation

down-regulates

0.428

Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation.

SIGNOR-85102

P53567

P35247

1

transcriptional regulation

up-regulates quantity by expression

0.2

Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D.

SIGNOR-254058

P41743

P12931

0

phosphorylation

up-regulates

0.533

Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase c's via a src kinase pathway. tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain.

SIGNOR-111920

P49327

Q9P035

0

chemical activation

up-regulates activity

0.2

Very long-chain fatty acids are produced through a four-step cycle. However, the 3-hydroxyacyl-CoA dehydratase catalyzing the third step in mammals has remained unidentified. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases,

SIGNOR-267762

Q8IVT5

P10398

2

binding

up-regulates activity

0.567

In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically.

SIGNOR-273876

Q92882

Q15418

0

phosphorylation

down-regulates activity

0.352

SH3P2 was phosphorylated on Ser(202) by ribosomal S6 kinase (RSK) in an ERK pathway-dependent manner, and such phosphorylation inhibited the ability of SH3P2 to suppress cell motility.

SIGNOR-273838

Q86V24

Q15848

2

binding

up-regulates

0.773

Expression of adipor1/r2 or suppression of adipor1/r2 expression by small-interfering rna supports our conclusion that they serve as receptors for globular and full-length adiponectin,

SIGNOR-101809

Q15797

Q9UNE7

0

ubiquitination

down-regulates

0.328

These results suggest that chip can interact with the smad1/smad4 proteins and block bmp signal transduction through the ubiquitin-mediated degradation of smad proteins.

SIGNOR-120731

Q9Y4K3

O43318

1

ubiquitination

up-regulates activity

0.893

Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6.

SIGNOR-236071

P09958

P04275

1

cleavage

up-regulates activity

0.481

Like PACE,PACE4 was able to process pro-vWF to its mature form, and efficient cleavage required both the P4 arginine and the P2 lysine

SIGNOR-260368

Q92696

P20339

1

lipidation

up-regulates activity

0.625

Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional

SIGNOR-265572

P06493

Q9NQR1

1

phosphorylation

up-regulates quantity by stabilization

0.2

We found that PR-Set7 is phosphorylated at Ser 29 (S29) specifically by the cyclin-dependent kinase 1 (cdk1)/cyclinB complex, primarily from prophase through early anaphase, subsequent to global accumulation of H4K20me1. While S29 phosphorylation did not affect PR-Set7 methyltransferase activity, this event resulted in the removal of PR-Set7 from mitotic chromosomes. S29 phosphorylation also functions to stabilize PR-Set7 by directly inhibiting its interaction with the anaphase-promoting complex (APC), an E3 ubiquitin ligase.

SIGNOR-259832

P35240

P62140

0

dephosphorylation

up-regulates

0.378

When serine 518 is dephosphorylated by the myosin phosphatase mypt-1-pp1?, The tumor suppressor function of merlin is activated, inhibiting the ras signaling pathway and leading to growth arrest

SIGNOR-159836

P38936

Q00987

2

binding

down-regulates quantity by destabilization

0.643

MDM2 facilitates p21 degradation independent of ubiquitination and the E3 ligase function of MDM2. Instead, MDM2 promotes p21 degradation by facilitating binding of p21 with the proteasomal C8 subunit. The physical interaction between p21 and MDM2 was demonstrated both in vitro and in vivo with the binding region in amino acids 180-298 of the MDM2 protein.

SIGNOR-272954

P07384

P10636

1

cleavage

down-regulates activity

0.333

Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains

SIGNOR-251584

Q92769

P33076

1

deacetylation

down-regulates quantity by repression

0.413

We report that CIITA and histone deacetylase 2 (HDAC2) interact in smooth muscle cells and macrophages as assayed by co-immunoprecipitations. HDAC2 deacetylates CIITA whereas both the HDAC inhibitor trichostatin A (TSA) and over-expression of HDAC2 interfering RNA increase CIITA acetylation. HDAC2 down-regulates CIITA recruitment to target promoters as evidenced by chromatin immunoprecipitation assays, and suppresses MHC II activation and collagen repression mediated by CIITA in luciferase reporter assays.

SIGNOR-254231

P83916

P84243

2

binding

up-regulates activity

0.2

A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing.

SIGNOR-264491

Q9Y4C1

Q07912

0

phosphorylation

down-regulates activity

0.37

We report that ACK1 phosphorylates the ER co-activator, KDM3A, a H3K9 demethylase, at an evolutionary conserved tyrosine 1114 site in a heregulin-dependent manner, even in the presence of tamoxifen.

SIGNOR-276842

Q09472

O60885

2

binding

up-regulates activity

0.426

In this study, we explored the role of Brd4 and its interaction with the p300 acetyltransferase in the regulation of Nox4 and the in vivo efficacy of a BET inhibitor to reverse established age-associated lung fibrosis. |Together, these studies suggest that Brd4 enhances p300-mediated histone acetylation.

SIGNOR-262064

O14746

Q9NPE3

2

binding

up-regulates activity

0.62

Dyskerin was recently found to be associated with active human telomerase (34), and mutations in dyskerin or NOP10 or deletion of the H/ACA motif of hTERC result in diminished telomerase activity

SIGNOR-263331

Q7Z5H3

P61586

1

gtpase-activating protein

down-regulates activity

0.564

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-260476

P67775

P19484

1

dephosphorylation

up-regulates activity

0.2

MS analysis revealed that PP2A dephosphorylates TFEB at several residues, including Ser-109, Ser-114, Ser-122, and Ser-211, thus facilitating TFEB activation.

SIGNOR-277881

Q00653

Q969H0

2

binding

down-regulates quantity by destabilization

0.396

Fbxw7α is a member of the F-box family of proteins, which function as the substrate-targeting subunits of SCF (Skp1/Cul1/F-box protein) ubiquitin ligase complexes. Using differential purifications and mass spectrometry, we identified p100, an inhibitor of NF-κB signalling, as an interactor of Fbxw7α. p100 is constitutively targeted in the nucleus for proteasomal degradation by Fbxw7α

SIGNOR-272907

P08912

O95837

2

binding

up-regulates activity

0.385

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

SIGNOR-257291

P42771

P24941

2

binding

down-regulates

0.48

However, induction of p16(ink4a) also causes marked inhibition of cdk2 activity.

SIGNOR-64431

Q9UPP1

P68400

0

phosphorylation

up-regulates activity

0.2

The CK2 kinase is responsible for PHF8 phosphorylation at Ser854. PHF8 is phosphorylated by CK2, which regulates binding of PHF8 to TopBP1. The Ser854 residue of PHF8 is required for its interaction with TopBP1.

SIGNOR-273628

Q08209

Q13469

1

dephosphorylation

up-regulates activity

0.629

NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity

SIGNOR-248690

Q96GD4

Q9UPY8

1

phosphorylation

up-regulates

0.472

Phosphorylation of eb3 at s176 by aurora b ensures successful cytokinesis completion by promoting midbody mt stability and midbody stabilization.

SIGNOR-202130

Q00534

P42773

2

binding

down-regulates

0.88

The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb.

SIGNOR-44601

Q13887

Q9HAU4

0

ubiquitination

down-regulates quantity by destabilization

0.37

Consistent with these observations, another study documented that Smurf2 specifically destabilizes KLF5, that the degradation of KLF5 by Smurf2 is disrupted by the proteasome inhibitor MG132, and that Smurf2 ubiquitinates KLF5 .

SIGNOR-278781

Q13224

P51608

0

transcriptional regulation

down-regulates quantity by repression

0.35

The interaction of MeCP2 with the 2BI3 and 2BI5 sites was strikingly reduced in neurons maintained in the presence of TTX (Fig. 2C). This result is consistent with the classical view of MeCP2 as a general transcriptional repressor, in that the reduced association leads to increased expression of NR2B.

SIGNOR-264685

P28482

Q15831

1

phosphorylation

down-regulates activity

0.402

Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK.

SIGNOR-209876

P68431

O15550

0

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-260017

Q9H0E2

P51617

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

P17612

P08151

1

phosphorylation

down-regulates

0.551

We report that activation of PKA retains Gli1 in the cytoplasm. Conversely, inhibition of PKA activity promotes nuclear accumulation of Gli1.We provide direct evidence to support that the cAMP/PKA signaling axis regulates Gli1 protein localization primarily through a site at Thr374. .These data suggest that Thr374 is an important PKA site responsible for PKA phosphorylation and for the transcriptional activity of Gli1.

SIGNOR-253539

P31749

Q13950

1

phosphorylation

down-regulates activity

0.446

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

SIGNOR-280176

Q15437

Q969U6

0

ubiquitination

down-regulates quantity by destabilization

0.2

SCFFBXW5 interacts with SEC23B and targets it for ubiquitylation and proteasome-mediated degradation.

SIGNOR-265286

Q9NRF2

O60674

2

binding

up-regulates activity

0.692

The SH2B adaptor protein 1 (SH2B1) is a key regulator of leptin, as it enhances leptin signalling by both stimulating Janus kinase 2 (JAK2) activity and assembling a JAK2/IRS1/2 signalling complex

SIGNOR-253078

P63092

Q99500

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 ‚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-256790

O43280

P06493

0

phosphorylation

up-regulates activity

0.268

Ewald et al. reported that at the G1/S transition, cyclin-dependent kinase 1 (CDK1) phosphorylates and activates the neutral trehalase (NTH1) to funnel trehalose into glycolysis (Ewald et al. xref ).

SIGNOR-280206

P12931

P40337

1

phosphorylation

down-regulates quantity by destabilization

0.29

We have found that elevated Src can trigger a drastic reduction in VHL stability even under normoxic conditions, through phosphorylation of VHL tyrosine residue 185, leading to ubiquitination and proteasome mediated degradation of VHL.

SIGNOR-279125

Q13541

Q16539

0

phosphorylation

down-regulates activity

0.433

4E-BP1 Is Phosphorylated in Vitro by Active p38 Kinase. In the present study we demonstrated that UVB induced 4E-BP1 phosphorylation at multiple sites, Thr-36, Thr-45, Ser-64, and Thr-69, leading to dissociation of 4E-BP1 from eIF-4E.

SIGNOR-250097

Q00535

Q96QB1

1

phosphorylation

up-regulates activity

0.2

The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin.

SIGNOR-276444

Q9UGL1

P55771

2

binding

up-regulates activity

0.483

Human PLU-1 Has transcriptional repression properties and interacts with the developmental transcription factors BF-1 and PAX9. In a reporter assay system, PLU-1 has potent transcriptional repression activity. BF-1 and PAX9 also represses transcription in the same assay, but co-expression of PLU-1 with BF-1 or PAX9 significantly enhances this repression

SIGNOR-223875

P00519

Q92769

1

phosphorylation

up-regulates quantity by stabilization

0.285

C-Abl stabilizes HDAC2 levels by tyrosine phosphorylation repressing neuronal gene expression in Alzheimer's disease.

SIGNOR-260928

P28698

P17252

1

transcriptional regulation

up-regulates quantity by expression

0.384

The luciferase reporter assay results revealed that the presence of both MZF-1 and Elk-1 significantly contributed to the upregulation of PKCα gene transcription activity.

SIGNOR-256337

P53350

Q9NYZ3

1

phosphorylation

up-regulates

0.736

In this study, we show that g2 and s-phase-expressed 1 (gtse1) protein, a negative regulator of p53, is required for g2 checkpoint recovery and that plk1 phosphorylation of gtse1 at ser 435 promotes its nuclear localization, and thus shuttles p53 out of the nucleus to lead to its degradation during the recovery.

SIGNOR-166417

P60953

P10911

0

guanine nucleotide exchange factor

up-regulates activity

0.777

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-260558

P31260

Q06124

0

dephosphorylation

up-regulates

0.373

We also identified hoxa10 as a substrate for shp2 in undifferentiated myeloid cells, an effect that diminished during myelopoiesis. However, a constitutively active form of shp2 dephosphorylated hoxa10 throughout ex vivo myelopoiesis and sustained repression of hoxa10 target genes involved in phagocyte effector functions.

SIGNOR-182475

P25098

P17252

0

phosphorylation

up-regulates activity

0.2

Phosphorylation of GRK2 by protein kinase C abolishes its inhibition by calmodulin. In vitro, GRK2 was preferentially phosphorylated by PKC isoforms alpha, gamma, and delta. Two-dimensional peptide mapping of PKCalpha-phosphorylated GRK2 showed a single site of phosphorylation, which was identified as serine 29 by HPLC-MS. A S29A mutant of GRK2 was not phosphorylated by PKC in vitro and showed no phorbol ester-stimulated phosphorylation when transfected into human embryonic kidney (HEK)293 cells.

SIGNOR-249058

P0DTC2

P07711

0

cleavage

up-regulates activity

0.2

SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines.

SIGNOR-260737

Q05655

P49840

1

phosphorylation

down-regulates

0.342

Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway.

SIGNOR-115722

Q7Z2Y5

Q9UNE7

0

polyubiquitination

down-regulates quantity by destabilization

0.2

Our results indicate that Nrk is ubiquitinated by CHIP in a chaperone-dependent manner, resulting in its proteasomal degradation.

SIGNOR-274110

P27986

P42336

2

binding

up-regulates activity

0.936

Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival

SIGNOR-242637

O14763

P50591

2

binding

up-regulates

0.934

Tumour necrosis factor-related apoptosis inducing ligand (trail) receptor 2 (trail-r2) also known as tnfrsf10b (tumour necrosis factor receptor (tnfr) super family 10b) or killer/dr5, a member of the tnfr family, is a promising candidate tumour suppressor gene at 8p21-22.

SIGNOR-134524

Q9UL51

Q13237

0

phosphorylation

down-regulates activity

0.2

Here, we show for the first time that in the HCN2 channel cGMP can also exert an inhibitory effect on gating via cGMP-dependent protein kinase II (cGKII)-mediated phosphorylation.We identify the proximal C-terminus of HCN2 as binding region of cGKII and show that cGKII phosphorylates HCN2 at a specific serine residue (S641) in the C-terminal end of the CNBD. The cGKII shifts the voltage-dependence of HCN2 activation to 2-5 mV more negative voltages and, hence, counteracts the stimulatory effect of cGMP on gating.

SIGNOR-263185

O14640

Q9GZV5

2

binding

down-regulates

0.358

Taz binds to dvl proteins, thereby inhibiting dvl phosphorylation by casein kinase 1-delta and -epsilon kinases (ck1d/e), thus promoting beta-catenin degradation.

SIGNOR-195212

Q5JWF2

P41968

0

null

up-regulates activity

0.547

We hypothesize that XLŒ±s may be involved in this regulatory loop by coupling to melanocortin receptors 3 and 4 in the hypothalamus.

SIGNOR-253068

O00429

Q9UM11

0

ubiquitination

down-regulates quantity

0.349

Here we demonstrate that changes in mitochondrial dynamics as cells exit mitosis are driven in part through ubiquitylation of Drp1 catalyzed by the APC/Ccdh1 (anaphase-promoting complex/cyclosome and its coactivator (Cdh1) E3 ubiquiting ligase complex

SIGNOR-274127

P17252

O15350

1

phosphorylation

up-regulates activity

0.2

Here, we report that p73 is able to induce cell cycle arrest independently of its amino-terminal transactivation domain, whereas this domain is crucial for p73 proapoptotic functions. its activity is regulated throughout the cell cycle and modified by protein kinase C-dependent phosphorylation at serine residue 388.

SIGNOR-276235

Q9UPT9

P06493

0

phosphorylation

up-regulates activity

0.47

On the other hand, CDK1 enhances USP22 activity to stabilize CCNB1 during the G2/M phase.|Phosphorylation of USP22 by CDK1 enhances its activity in deubiquitinating CCNB1.

SIGNOR-278241

P27361

P06401

1

phosphorylation

down-regulates

0.561

Specifically, down-regulation of mature prs occurs by a mechanism in which ligand binding activates pr phosphorylation by mapks at a unique serine residue, which then targets the receptors for degradation.

SIGNOR-74716

O00755

P03956

1

transcriptional regulation

up-regulates quantity by expression

0.261

Because MMP1 is also another direct target of the canonical Wnt pathway (22), Wnt7a overexpression upregulated MMP1/10 to degrade the extracellular matrix and to facilitate UBC cell invasion.

SIGNOR-278868

P52306

P15153

2

binding

up-regulates

0.5

Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob

SIGNOR-171421

Q15131

P15036

1

phosphorylation

down-regulates quantity by destabilization

0.528

Altogether, these results suggest that CDK10/cyclin M directly controls ETS2 degradation through the phosphorylation of these two serines.

SIGNOR-260914

Q5VTR2

Q13315

0

phosphorylation

up-regulates

0.522

E3 ubiquitin ligase, a heterodimeric complex of the ringfinger rfn20/rfn40 is phosphorylated by atm.

SIGNOR-174949

P12931

P42681

1

phosphorylation

up-regulates activity

0.348

We further demonstrate that Rlk can be phosphorylated and activated by Src kinases, leading to a decrease in its half-life. A specific tyrosine in the activation loop of Rlk, Y420, is required for phosphorylation and activation, as well as for decreased stability, but is not required for lipid RAFT association.

SIGNOR-247346