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
P09429	P14653	2	binding	up-regulates activity	0.298	We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein.	SIGNOR-219853
Q92918	Q13094	1	phosphorylation	up-regulates	0.778	The serine/threonine kinase hpk-1 phosphorylates serine 376 of slp-76 and induces the interaction with 14-3-3 proteins	SIGNOR-153613
P0C0S5	Q86Y13	0	monoubiquitination	up-regulates activity	0.2	2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271748
P05556	Q9Y5H9	2	binding	up-regulates activity	0.2	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion.	SIGNOR-265661
Q00610	Q13492	2	binding	up-regulates	0.749	Calm interacts with the clathrin heavy chain through its c-terminal third and with phophoinositides through its ap180 n-terminal homology (anth) domain, promoting assembly of clathrin triskelia into clathrin cagesin vitro	SIGNOR-144683
Q9NS91	P12004	1	ubiquitination	up-regulates activity	0.846	Second, these findings suggest the following model (XREF_FIG) : upon replication fork stalling at cisplatin induced DNA lesions, the RAD18 and RAD6 complex ubiquitylates PCNA on Lys164.\|The DNA damage-activated E3 ubiquitin ligase RAD18 promotes repair of interstrand DNA cross-links by ubiquitylating PCNA and recruiting FANCL to chromatin.	SIGNOR-278612
P10586	P06239	1	dephosphorylation	up-regulates	0.364	We confirmed that lar dephosphorylated the phosphorylated tyrosine residues of lck..Activation Of lck and fyn involves tyrosine dephosphorylation of the cooh-terminal regulatory domain of kinases, followed by autophosphorylation of the kinase domain.	SIGNOR-96771
Q15465	Q9Y625	2	binding	up-regulates activity	0.451	Based on results from in vitro experiments, we had previously proposed that GPC6 stimulates Hh signaling by interacting with Hh and Patched1 (Ptc1), and facilitating/stabilizing their interaction.	SIGNOR-264029
Q01638	O43318	2	binding	up-regulates activity	0.2	The activated heterodimer complex recruits downstream signaling components, including myeloid differentiation primary response protein 88 (MyD88), IL-1 receptor (IL-1R)–associated kinase, tumor necrosis factor (TNF) receptor–associated factor 6 (TRAF6), and transforming growth factor (TGF)-β–activated kinase 1 (TAK1) complex, resulting in TAK1 activation. TAK1 subsequently activates downstream kinases inhibitor of nuclear factor kappa-B kinase subunit alpha (IKKα) and IKKβ, which phosphorylate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibitor (IκB) proteins. These events ultimately lead to activation of the transcription factor NF-κB and induction of downstream effector genes	SIGNOR-277716
P16104	Q9H4B4	0	phosphorylation	up-regulates activity	0.2	Phosphorylation of H2AX at serine 139 was catalyzed by hyperosmotic stress-induced activation of Plk3.\|Osmotic stress induced phosphorylation of H2AX by polo like kinase 3 affects cell cycle progression in human corneal epithelial cells.\|Our results for the first time reveal that hyperosmotic stress-activated Plk3 elicited \u03b3H2AX.	SIGNOR-280073
O95239	P53350	0	phosphorylation	down-regulates activity	0.467	Moreover, phosphorylation of KIF4 and condensin I by Aurora B and polo like kinase 1 (Plk1) is important for KIF4 and condensin I localization to the chromosome.\|These results suggest that Plk1 negatively regulates the loading of both KIF4 and condensin to the chromosome.	SIGNOR-280069
P51955	P36873	1	phosphorylation	down-regulates	0.488	Pp1 is a substrate for nek2 and phosphorylation of pp1gamma(1) on two c-terminal sites reduces its phosphatase activity.	SIGNOR-78603
Q969V1	P08754	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-257180
Q13526	P45984	0	phosphorylation	up-regulates quantity by stabilization	0.2	Mechanistically, the JNK kinases directly bind to and phosphorylate PIN1 at Ser115, and this phosphorylation prevents PIN1 mono-ubiquitination at Lys117 and its proteasomal degradation.	SIGNOR-277563
P38936	P49841	0	phosphorylation	down-regulates quantity by destabilization	0.4	Glycogen synthase kinase 3beta phosphorylates p21waf1/cip1 for proteasomal degradation after uv irradiationhere, we show that ser-114 phosphorylation of p21 protein by glycogen synthase kinase 3beta (gsk-3beta) is required for its degradation in response to uv irradiation	SIGNOR-152941
Q2TAL8	Q9BW92	1	transcriptional regulation	up-regulates quantity by expression	0.2	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269407
P56524	Q13950	1	deacetylation	down-regulates activity	0.524	HDAC4 and HDAC5 deacetylate Runx2, allowing the protein to undergo Smurf-mediated degradation	SIGNOR-227547
P07949	Q14451	2	binding	up-regulates	0.571	Grb7 and grb10, likely relay signals emanating from ret to other, as yet, unidentified targets within the cell	SIGNOR-41765
P18848	Q9P2J5	1	transcriptional regulation	up-regulates quantity by expression	0.2	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269420
O15530	O14920	1	phosphorylation	up-regulates activity	0.474	We found that PDK1 directly phosphorylates IKKbeta at the Ser(181) residue in the activation loop, leading to NF-kappaB nuclear translocation and NF-kappaB-dependent anti-apoptotic gene expression.	SIGNOR-279088
P43146	Q8IZJ1	2	binding	down-regulates activity	0.658	In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists.	SIGNOR-268166
Q9UJ55	A8K0Z3	2	binding	up-regulates activity	0.2	Our mechanistic studies uncovered that K63-linked ubiquitination of WASH K220 by MAGE-L2-TRIM27 is required for endosomal F-actin nucleation and retrograde transport. These results suggest that K63-linked ubiquitination of WASH K220 by TRIM27 is required for WASH function in retrograde transport.	SIGNOR-253515
P52333	O14543	2	binding	down-regulates activity	0.699	SOCS proteins bind to janus kinase and to certain cytokine receptors and signaling molecules, thereby suppressing further signaling events. Studies have shown that SOCS proteins are key physiological regulators of inflammation. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of adaptive immunity.Both SOCS1 and SOCS3 can inhibit JAK tyrosine kinase activity directly through their kinase inhibitory regions (KIR).	SIGNOR-238645
P23443	Q6R327	1	phosphorylation	down-regulates	0.715	Phosphorylation of rictor on thr1135 did not affect mtorc2 assembly, kinase activity, or cellular localization. However, cells expressing a rictor t1135a mutant were found to have increased mtorc2-dependent phosphorylation of akt	SIGNOR-161995
P00451	P04275	2	binding	up-regulates activity	0.789	Binding of FVIII to VWF is needed to maintain appropriate plasma levels, as FVIII plasma levels and half-life are remarkably reduced in the absence of VWF	SIGNOR-251967
Q13261	P23458	1	null	up-regulates	0.462	Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated	SIGNOR-256227
Q5JVS0	Q05513	0	phosphorylation	down-regulates activity	0.292	We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. \| This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. \| Ki-1/57 Exits the Nucleus upon PMA Activation	SIGNOR-249257
P00533	P15514	2	binding	up-regulates activity	0.771	ErbB ligands include: EGF, transforming growth factor (TGF)_, and amphiregulin which only bind ErbB1	SIGNOR-67000
Q5JVS0	Q04759	0	phosphorylation	down-regulates activity	0.303	We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. \| This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. \| Ki-1/57 Exits the Nucleus upon PMA Activation	SIGNOR-249256
P01106	Q13177	0	phosphorylation	down-regulates activity	0.649	Here we demonstrate that Pak2 phosphorylates Myc at three sites (T358, S373, and T400) and affects Myc functions both in vitro and in vivo.	SIGNOR-278489
Q9NQL2	Q8N122	2	binding	up-regulates	0.905	Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor	SIGNOR-162093
P48507	Q16236	0	transcriptional regulation	up-regulates quantity by expression	0.439	NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification.Importantly, GCLC, GCLM, GSS, and GSR are transcriptional targets of NFE2L2. Their upregulation is implicated in conferring resistance to ferroptosis across various contexts, including chemotherapy and radiation therapy	SIGNOR-279869
P46019	P22612	0	phosphorylation	down-regulates activity	0.325	Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme.	SIGNOR-267414
P29317	P31749	0	phosphorylation	up-regulates activity	0.355	As non-canonical EphA2 activation requires phosphorylation of EphA2 at serine 897 by pAkt (Fig.\u00a02b), we sought to determine the effect of PTEN-mediated Akt regulation on invasion.	SIGNOR-279787
Q6WKZ4	Q7KZI7	0	phosphorylation	up-regulates quantity	0.341	We have now found that MARK2 phosphorylates Rab11-FIP1B/C at serine 234 in a consensus site similar to that previously identified in Rab11-FIP2.	SIGNOR-273676
Q14807	Q96EP1	0	ubiquitination	down-regulates quantity by destabilization	0.399	Chfr ubiquitinates Kif22 and promotes its degradation.	SIGNOR-271469
Q13315	Q9UPU5	1	phosphorylation	up-regulates activity	0.25	Taken together, these data suggest that the ATM kinase mediated phosphorylation of USP24 is involved in USP24 stabilization/up regulation following UV irradiation.\|Taken together, these data suggest that the ATM kinase-mediated phosphorylation of USP24 is involved in USP24 stabilization/up-regulation following UV irradiation.	SIGNOR-280043
Q9UL51	P12931	0	phosphorylation	up-regulates activity	0.267	We identified a highly conserved tyrosine residue in the C-linker of HCN channels (Tyr476 in HCN2) that confers modulation by Src. Replacement of this tyrosine by phenylalanine in HCN2 or HCN4 abolished sensitivity to Src inhibitors. Mass spectrometry confirmed that Tyr476 is phosphorylated by Src. Our results have functional implications for HCN channel gating. Furthermore, they indicate that tyrosine phosphorylation contributes in vivo to the fine tuning of HCN channel activity.	SIGNOR-263199
A6NFN3	Q12857	0	transcriptional regulation	up-regulates quantity	0.261	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268911
P40189	P42702	2	binding	up-regulates	0.605	The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3).	SIGNOR-204850
Q9P296	P01031	2	binding	up-regulates	0.662	Here we report that the orphan receptor c5l2/gpr77, which shares 35% amino acid identity with cd88, binds c5a with high affinity.	SIGNOR-113558
Q15750	O15105	2	binding	down-regulates	0.58	Smad6 interacts with tak1 and tab1, and smad7 with tab1. The interaction of i-smads with tak1 and/or tab1 implies that several mechanisms exist underlying the repression of the tak1-p38 kinase pathway by i-smads.	SIGNOR-112645
P05771	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-276234
Q14680	O43524	1	phosphorylation	down-regulates quantity	0.362	Further analysis indicated that FOXO1 and FOXO3, two known transcriptional regulators of p21, were phosphorylated by MELK and thus be involved in the induction of p21 after MELK inhibition.\|Our findings revealed that siRNA mediated MELK knockdown increased protein levels of FOXO1 and FOXO3, which might increase p21 transcriptional level in a p53 independent manner.	SIGNOR-279375
Q9NWD9	P53350	0	phosphorylation	up-regulates activity	0.2	In addition, the inhibition of PLK1 activity by BI2536 treatment sharply reduced BEX4 protein, which was localized at the centrosomes in the HeLa cells or the GFP-BEX4 stable cell lines.\|PLK1 directly phosphorylates BEX4 at T107 and contributes to BEX4-induced aneuploidy.	SIGNOR-279550
P12004	P08069	0	phosphorylation	up-regulates activity	0.2	In vitro MS analysis of PCNA co-incubated with the IGF-1R kinase indicated tyrosine residues 60, 133, and 250 in PCNA as IGF-1R targets, and PCNA phosphorylation was followed by mono- and polyubiquitination.	SIGNOR-277252
Q13043	P52945	1	phosphorylation	down-regulates activity	0.2	MST1 directly phosphorylated PDX1 at Thr11, resulting in its ubiquitination, degradation and impaired insulin secretion.\|Thus, kinase activity is required for MST1 induced PDX1 degradation.	SIGNOR-278303
Q15418	Q92882	1	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
Q9NWS0	P49959	2	binding	up-regulates activity	0.2	Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689.	SIGNOR-265898
Q99814	P41229	1	transcriptional regulation	up-regulates quantity by expression	0.278	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271579
P25963	O14920	0	phosphorylation	down-regulates activity	0.922	Tak1 become activated and then phosphorilates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation	SIGNOR-235400
P14923	P12931	0	phosphorylation	up-regulates activity	0.668	Tyrosine phosphorylation of plakoglobin causes contrary effects on its association with desmosomes and adherens junction components and modulates beta-catenin-mediated transcriptionFor instance, Src, which mainly phosphorylates Tyr86 in beta-catenin, modifies Tyr643 in plakoglobin, decreasing the interaction with E-cadherin and alpha-catenin and increasing the interaction with the alpha-catenin-equivalent protein in desmosomes, desmoplakin.	SIGNOR-247310
O96017	Q13049	1	phosphorylation	up-regulates activity	0.2	We show that CHK2 binds and phosphorylates TRIM32 at the S55 site, which then mediates K63-linked ubiquitination of ATG7 at the K45 site to initiate autophagy.	SIGNOR-277790
Q9NXK8	P30838	2	binding	down-regulates quantity by destabilization	0.32	We now show that SCFFBXL12 is an authentic E3 for the ALDH3 family of enzymes. We now show that the ubiquitin-dependent degradation of ALDH3 mediated by FBXL12 (F box and leucine-rich repeat protein 12) is essential for execution of the differentiation program of trophoblast stem cells (TSCs). FBXL12 is present only in eutherian mammals, and its expression is largely restricted to the placenta during mouse embryogenesis. FBXL12 was found to interact specifically with members of the ALDH3 family and to mediate their polyubiquitylation. Finally, coimmunoprecipitation analysis revealed that FBXL12 interacted efficiently only with members of the ALDH3 family (ALDH3A1, ALDH3A2, and ALDH3B1), showing little if any association with those of the ALDH1 family (ALDH1A1, ALDH1A2, and ALDH1A3) (Fig. 2H). Collectively, these results suggested that SCFFBXL12 is an authentic E3 specific for ALDH3 family members.	SIGNOR-272813
Q07021	P02747	2	binding	down-regulates activity	0.399	Previous studies have shown that gC1qR inhibits aggregated IgG-mediated complement activation by binding to the gC1q site on C1q, thereby preventing IgG from binding to the gh’s (28), suggesting that the binding sites for gC1qR and IgG on C1q may be identical or at least overlapping.	SIGNOR-263404
Q9UKC9	Q9UK99	2	binding	down-regulates quantity by destabilization	0.549	F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. The SCF complex is composed of F-box protein, Skp1, Cullin1 (Cul1) and ROC1. Fbxo3, whose substrates are few, forms SCF Fbxo3 ubiquitin ligase and regulates the degradations of Fbxl2, p62, HIPK2 and p300 through the ubiquitin-proteasome pathway.	SIGNOR-272445
Q13043	P42336	1	phosphorylation	down-regulates activity	0.2	MST1/2 and HGK inhibit catalytic activity of p110α through phosphorylation at T1061	SIGNOR-277920
P25098	P41143	1	phosphorylation	down-regulates activity	0.2	Taken together, we have demonstrated that agonist-induced opioid receptor phosphorylation occurs exclusively at two phosphate acceptor sites (T358 and S363) of GRK2 at the DOR carboxyl terminus.	SIGNOR-249660
P00533	P62993	2	binding	up-regulates activity	0.923	Adaptor protein Grb2 binds phosphotyrosines in the epidermal growth factor (EGF) receptor (EGFR) and thereby links receptor activation to intracellular signaling cascades.	SIGNOR-267725
P63092	O60503	2	binding	up-regulates activity	0.628	Adenylyl cyclase 9 (AC9) is a membrane-bound enzyme that converts ATP into cAMP. The enzyme is weakly activated by forskolin, fully activated by the G protein Gαs subunit and is autoinhibited by the AC9 C-terminus.	SIGNOR-278883
Q13153	Q02750	1	phosphorylation	up-regulates activity	0.582	We find that adhesion to fibronectin induces pak1-dependent phosphorylation of mek1 on s298 and that this phosphorylation is necessary for efficient activation of mek1 and subsequent mapk activation.	SIGNOR-236002
P17252	P26927	0	phosphorylation	up-regulates activity	0.2	Thus, the phosphorylation of PKCα at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKCα.	SIGNOR-277179
Q96ME1	Q9UJT9	2	binding	down-regulates quantity by destabilization	0.652	F-box protein Fbxl18 mediates polyubiquitylation and proteasomal degradation of the pro-apoptotic SCF subunit Fbxl7.. Here, we identified that an orphan F-box protein, Fbxl18, targets Fbxl7 for its polyubiquitylation and proteasomal degradation. Lys 109 within Fbxl7 is an essential acceptor site for ubiquitin conjugation by Fbxl18.	SIGNOR-272448
P35637	P00519	0	phosphorylation	down-regulates activity	0.325	Abl kinase-mediated FUS Tyr526 phosphorylation alters nucleocytoplasmic FUS localization in FTLD-FUS.	SIGNOR-280168
P57682	O95600	1	transcriptional regulation	down-regulates quantity by repression	0.255	Here we report that Klf8 is repressed by Klf3 in vivo and is up-regulated by Klf1. Transcript analysis indicates that Klf8 has two promoters, both containing multiple CACCC elements. Transactivation assays and chromatin immunoprecipitation experiments indicate that Klf3 represses Klf8 directly and that Klf1 activates Klf8 directly.	SIGNOR-266049
P15260	O60674	2	binding	up-regulates	0.714	The only type ii ifn, ifn-, binds a distinct cell-surface receptor, which is known as the type ii ifn receptor. This receptor is also composed of two subunits, ifngr1 and ifngr2, which are associated with jak1 and jak2, respectively. Activation of the jaks that are associated with the type i ifn receptor results in tyrosine phosphorylation of stat2	SIGNOR-135955
P25101	P05305	2	binding	up-regulates	0.881	Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors.	SIGNOR-145759
P42574	Q14790	0	cleavage	up-regulates activity	0.726	Triggering of the DISC leads to caspase-8 activation. Active caspase-8 cleaves caspase-3 which, in type I cells, leads to cell death induction.	SIGNOR-171767
Q13469	Q08209	0	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
Q96JY6	Q04206	1	polyubiquitination	down-regulates quantity by destabilization	0.347	Here we report that PDLIM2 negatively regulated NF-kappaB activity, acting as a nuclear ubiquitin E3 ligase targeting the p65 subunit of NF-kappaB. PDLIM2 bound to p65 and promoted p65 polyubiquitination.	SIGNOR-271651
P28335	P30679	2	binding	up-regulates activity	0.503	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-257355
Q96QT6	Q04724	2	binding	up-regulates activity	0.2	We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE.	SIGNOR-266994
Q15116	Q9NZQ7	2	binding	up-regulates	0.936	Pd-l1, was found to bind pd-1 specifically. The functional significance of this interaction has been demonstrated in t cell assays, in which engagement of pd-1 by pd-l1 leads to the inhibition of tcr-mediated lymphocyte proliferation and cytokine secretion.	SIGNOR-82604
P63000	P52735	0	guanine nucleotide exchange factor	up-regulates	0.761	Vav2 activates rac1 / vav2 is an exchange factor for rho family gtpases.	SIGNOR-81645
Q14493	Q93077	1	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265400
Q13153	P10398	1	phosphorylation	up-regulates	0.267	Phosphorylation of endogenous a-raf, b-raf and raf-1 on the homologous pak phosphorylation sites (serine 299, serine 445, or serine 338 respectively)we found that the phosphorylation of a-raf on serine 299 was also stimulated by egf, although the duration of phosphorylation on this site was much shorter than for raf-1. Thus, by analogy with raf-1, phosphorylation of this site may play an important role in the a-raf activation mechanism.	SIGNOR-236342
P09629	P09038	1	transcriptional regulation	up-regulates quantity by expression	0.396	Band shift and cotransfection experiments showed that HOXB7 directly transactivates the hFGF gene through one out of five putative homeodomain binding sites present in its promoter.	SIGNOR-261639
O00443	P06493	0	phosphorylation	down-regulates activity	0.281	Mitotic and stress-induced phosphorylation of HsPI3K-C2alpha targets the protein for degradation. Stress-dependent and mitotic phosphorylation of hspik3-c2alpha occurs on the same serine residue (ser259) within a recognition motif for proline-directed kinases. Mitotic phosphorylation of hspik3-c2alpha can be attributed to cdc2 activity, and stress-induced phosphorylation of hspik3-c2alpha is mediated by jnk/sapk	SIGNOR-100903
Q12933	Q13546	1	ubiquitination	up-regulates activity	0.895	Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2.	SIGNOR-59689
Q15796	O95405	0	relocalization	up-regulates activity	0.908	Smad anchor for receptor activation (SARA) is known as Smad cofactor that interacts directly with Smad2/3 and functions to recruit Smad2/3 to the TGF-beta receptor.	SIGNOR-165786
Q9BYX4	P36873	0	dephosphorylation	up-regulates activity	0.247	Exogenous PP1alpha or PP1gamma substantially decreased the S88 phosphorylation of Flag-MDA5\|we identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation.	SIGNOR-264579
Q13418	Q96C90	1	phosphorylation	up-regulates activity	0.398	We conclude that ILK may activate smooth-muscle contraction both directly, via phosphorylation of myosin, and indirectly, via phosphorylation and activation of CPI-17 and PHI-1, leading to inhibition of MLCP.\|CPI-17 and PHI-1 thiophosphorylated by ILK at Thr(38) or Thr(57) respectively inhibited myosin light-chain phosphatase (MLCP) activity bound to myosin	SIGNOR-265741
Q14674	O60216	1	cleavage	down-regulates quantity by destabilization	0.78	In order to segregate sister chromatids to opposite poles in anaphase, cohesin has to be removed from chromosomes. In budding yeast, the prevalent mode of cohesin removal is by proteolytic cleavage of the Scc1 subunit at the onset of anaphase by the endopeptidase separase	SIGNOR-275537
Q8TEA8	O00311	0	phosphorylation	up-regulates activity	0.321	Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D).	SIGNOR-273967
Q9Y5B0	P19784	0	phosphorylation	down-regulates activity	0.374	We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.\| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. \| Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified	SIGNOR-250986
P18848	O75807	1	transcriptional regulation	up-regulates quantity by expression	0.657	ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress.	SIGNOR-260172
Q16539	P43403	2	phosphorylation	down-regulates activity	0.476	We have found that T cell p38 MAP kinase (MAPK), which is directly phosphorylated and activated by ZAP-70 downstream of the TCR, in turn phosphorylates Thr-293 in the interdomain B region of ZAP-70. These results identify a tight negative feedback loop in which ZAP-70-activated p38 reciprocally phosphorylates ZAP-70 and destabilizes the signaling complex.	SIGNOR-277384
P50613	P24941	2	phosphorylation	up-regulates activity	0.571	Phosphorylation of monomeric human CDK2 by CAK1 is more efficient than phosphorylation of the binary CDK2-cyclin A complex. Phosphorylated CDK2 exhibits histone H1 kinase activity corresponding to approximately 0.3% of that observed with the fully activated phosphorylated CDK2-cyclin A complex. Fluorescence measurements have shown that Thr160 phosphorylation increases the affinity of CDK2 for both histone substrate and ATP and decreases its affinity for ADP.	SIGNOR-250768
Q9H5J4	P36956	0	transcriptional regulation	up-regulates quantity by expression	0.45	These data demonstrated that Elovl-6 is regulated directly and primarily by SREBP-1c.	SIGNOR-267943
P27037	P36896	1	phosphorylation	up-regulates	0.687	In this complex, the actrii??/Iib kinase phosphorylates alk4 within a glycine- and serine-rich region called the gs domain, and this phosphorylation event activates the alk4 kinase	SIGNOR-99995
Q14118	P12931	0	phosphorylation	down-regulates	0.55	Tyrosine 892 is now thought to be the principal site for recognition by the c-src tyrosine kinase;. We show that upon tyrosine phosphorylation, beta-dystroglycan undergoes a profound change in its sub-cellular localization (e.g., from the plasma membrane to an internal membrane compartment). One possibility is that the net negative charge at position 892 causes the redistribution of beta-dystroglycan to this intracellular vesicular location	SIGNOR-101655
Q9NRD9	P17612	0	phosphorylation	up-regulates	0.2	We analyzed the duox1 phosphorylation state with an anti-rxx(ps/pt) antibody that could potentially recognize phosphorylation on ser955 and ser1217 but not on thr1007. duox1 but not duox2 activity is stimulated by forskolin (ec50 = 0.1 _m) via protein kinase a-mediated duox1 phosphorylation on serine 955. duox1 is positively regulated by the camp-dependent protein kinase a (pka)6 cascade	SIGNOR-183449
Q14457	P31749	0	phosphorylation	down-regulates activity	0.564	In addition, pharmacological inhibition of AKT1 enhanced BECN1 stability in both assays, leaving about twice the amount of BECN1 at 90 min compared to control (Fig. 4i\u2013l).\|The oncogenic kinase AKT1 phosphorylates BECN1 at positions S234, S295, which leads to sequestration of this peripheral membrane binding protein xref to the cytoskeleton with the result of inhibition of autophagy xref .	SIGNOR-279666
P29320	P12931	2	binding	up-regulates	0.528	We propose src kinase as a downstream effector that mediates the neuron's response to eph receptor activation.	SIGNOR-58139
Q9UKP6	P38405	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-256922
Q9Y4K3	P03186	0	deubiquitination	down-regulates activity	0.2	EBV-encoded BPLF1 interacts with and deubiquitinates TRAF6 to inhibit NF-κB signaling during lytic infection. Once lytic replication is induced, BPLF1 then deubiquitinates and inactivates TRAF6 to further block NF-κB signaling, promoting efficient viral genome replication.	SIGNOR-266739
Q9Y6C5	Q14623	2	binding	down-regulates activity	0.791	Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH.	SIGNOR-61314
P45983	P10415	1	phosphorylation	down-regulates	0.582	G(2)/m-phase cells proved more susceptible to death signals, and phosphorylation of bcl-2 appeared to be responsible, as a ser70ala substitution restored resistance to apoptosis. We noted that ask1 and jnk1 were normally activated at g(2)/m phase, and jnk was capable of phosphorylating bcl-2..	SIGNOR-72361
Q06330	P46531	2	binding	up-regulates	0.95	The intracellular part of the notch receptor is cleaved off and translocates to the nucleus, where it binds to the transcription factor rbp-j.	SIGNOR-183510
Q00526	P46531	1	phosphorylation	down-regulates quantity by destabilization	0.243	Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues	SIGNOR-273167

P09429

P14653

2

binding

up-regulates activity

0.298

We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein.

SIGNOR-219853

Q92918

Q13094

1

phosphorylation

up-regulates

0.778

The serine/threonine kinase hpk-1 phosphorylates serine 376 of slp-76 and induces the interaction with 14-3-3 proteins

SIGNOR-153613

P0C0S5

Q86Y13

0

monoubiquitination

up-regulates activity

0.2

2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.

SIGNOR-271748

P05556

Q9Y5H9

2

binding

up-regulates activity

0.2

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

SIGNOR-265661

Q00610

Q13492

2

binding

up-regulates

0.749

Calm interacts with the clathrin heavy chain through its c-terminal third and with phophoinositides through its ap180 n-terminal homology (anth) domain, promoting assembly of clathrin triskelia into clathrin cagesin vitro

SIGNOR-144683

Q9NS91

P12004

1

ubiquitination

up-regulates activity

0.846

Second, these findings suggest the following model (XREF_FIG) : upon replication fork stalling at cisplatin induced DNA lesions, the RAD18 and RAD6 complex ubiquitylates PCNA on Lys164.|The DNA damage-activated E3 ubiquitin ligase RAD18 promotes repair of interstrand DNA cross-links by ubiquitylating PCNA and recruiting FANCL to chromatin.

SIGNOR-278612

P10586

P06239

1

dephosphorylation

up-regulates

0.364

We confirmed that lar dephosphorylated the phosphorylated tyrosine residues of lck..Activation Of lck and fyn involves tyrosine dephosphorylation of the cooh-terminal regulatory domain of kinases, followed by autophosphorylation of the kinase domain.

SIGNOR-96771

Q15465

Q9Y625

2

binding

up-regulates activity

0.451

Based on results from in vitro experiments, we had previously proposed that GPC6 stimulates Hh signaling by interacting with Hh and Patched1 (Ptc1), and facilitating/stabilizing their interaction.

SIGNOR-264029

Q01638

O43318

2

binding

up-regulates activity

0.2

The activated heterodimer complex recruits downstream signaling components, including myeloid differentiation primary response protein 88 (MyD88), IL-1 receptor (IL-1R)–associated kinase, tumor necrosis factor (TNF) receptor–associated factor 6 (TRAF6), and transforming growth factor (TGF)-β–activated kinase 1 (TAK1) complex, resulting in TAK1 activation. TAK1 subsequently activates downstream kinases inhibitor of nuclear factor kappa-B kinase subunit alpha (IKKα) and IKKβ, which phosphorylate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibitor (IκB) proteins. These events ultimately lead to activation of the transcription factor NF-κB and induction of downstream effector genes

SIGNOR-277716

P16104

Q9H4B4

0

phosphorylation

up-regulates activity

0.2

Phosphorylation of H2AX at serine 139 was catalyzed by hyperosmotic stress-induced activation of Plk3.|Osmotic stress induced phosphorylation of H2AX by polo like kinase 3 affects cell cycle progression in human corneal epithelial cells.|Our results for the first time reveal that hyperosmotic stress-activated Plk3 elicited \u03b3H2AX.

SIGNOR-280073

O95239

P53350

0

phosphorylation

down-regulates activity

0.467

Moreover, phosphorylation of KIF4 and condensin I by Aurora B and polo like kinase 1 (Plk1) is important for KIF4 and condensin I localization to the chromosome.|These results suggest that Plk1 negatively regulates the loading of both KIF4 and condensin to the chromosome.

SIGNOR-280069

P51955

P36873

1

phosphorylation

down-regulates

0.488

Pp1 is a substrate for nek2 and phosphorylation of pp1gamma(1) on two c-terminal sites reduces its phosphatase activity.

SIGNOR-78603

Q969V1

P08754

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-257180

Q13526

P45984

0

phosphorylation

up-regulates quantity by stabilization

0.2

Mechanistically, the JNK kinases directly bind to and phosphorylate PIN1 at Ser115, and this phosphorylation prevents PIN1 mono-ubiquitination at Lys117 and its proteasomal degradation.

SIGNOR-277563

P38936

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.4

Glycogen synthase kinase 3beta phosphorylates p21waf1/cip1 for proteasomal degradation after uv irradiationhere, we show that ser-114 phosphorylation of p21 protein by glycogen synthase kinase 3beta (gsk-3beta) is required for its degradation in response to uv irradiation

SIGNOR-152941

Q2TAL8

Q9BW92

1

transcriptional regulation

up-regulates quantity by expression

0.2

QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.

SIGNOR-269407

P56524

Q13950

1

deacetylation

down-regulates activity

0.524

HDAC4 and HDAC5 deacetylate Runx2, allowing the protein to undergo Smurf-mediated degradation

SIGNOR-227547

P07949

Q14451

2

binding

up-regulates

0.571

Grb7 and grb10, likely relay signals emanating from ret to other, as yet, unidentified targets within the cell

SIGNOR-41765

P18848

Q9P2J5

1

transcriptional regulation

up-regulates quantity by expression

0.2

QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.

SIGNOR-269420

O15530

O14920

1

phosphorylation

up-regulates activity

0.474

We found that PDK1 directly phosphorylates IKKbeta at the Ser(181) residue in the activation loop, leading to NF-kappaB nuclear translocation and NF-kappaB-dependent anti-apoptotic gene expression.

SIGNOR-279088

P43146

Q8IZJ1

2

binding

down-regulates activity

0.658

In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists.

SIGNOR-268166

Q9UJ55

A8K0Z3

2

binding

up-regulates activity

0.2

Our mechanistic studies uncovered that K63-linked ubiquitination of WASH K220 by MAGE-L2-TRIM27 is required for endosomal F-actin nucleation and retrograde transport. These results suggest that K63-linked ubiquitination of WASH K220 by TRIM27 is required for WASH function in retrograde transport.

SIGNOR-253515

P52333

O14543

2

binding

down-regulates activity

0.699

SOCS proteins bind to janus kinase and to certain cytokine receptors and signaling molecules, thereby suppressing further signaling events. Studies have shown that SOCS proteins are key physiological regulators of inflammation. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of adaptive immunity.Both SOCS1 and SOCS3 can inhibit JAK tyrosine kinase activity directly through their kinase inhibitory regions (KIR).

SIGNOR-238645

P23443

Q6R327

1

phosphorylation

down-regulates

0.715

Phosphorylation of rictor on thr1135 did not affect mtorc2 assembly, kinase activity, or cellular localization. However, cells expressing a rictor t1135a mutant were found to have increased mtorc2-dependent phosphorylation of akt

SIGNOR-161995

P00451

P04275

2

binding

up-regulates activity

0.789

Binding of FVIII to VWF is needed to maintain appropriate plasma levels, as FVIII plasma levels and half-life are remarkably reduced in the absence of VWF

SIGNOR-251967

Q13261

P23458

1

null

up-regulates

0.462

Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated

SIGNOR-256227

Q5JVS0

Q05513

0

phosphorylation

down-regulates activity

0.292

We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation

SIGNOR-249257

P00533

P15514

2

binding

up-regulates activity

0.771

ErbB ligands include: EGF, transforming growth factor (TGF)_, and amphiregulin which only bind ErbB1

SIGNOR-67000

Q5JVS0

Q04759

0

phosphorylation

down-regulates activity

0.303

We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation

SIGNOR-249256

P01106

Q13177

0

phosphorylation

down-regulates activity

0.649

Here we demonstrate that Pak2 phosphorylates Myc at three sites (T358, S373, and T400) and affects Myc functions both in vitro and in vivo.

SIGNOR-278489

Q9NQL2

Q8N122

2

binding

up-regulates

0.905

Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor

SIGNOR-162093

P48507

Q16236

0

transcriptional regulation

up-regulates quantity by expression

0.439

NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification.Importantly, GCLC, GCLM, GSS, and GSR are transcriptional targets of NFE2L2. Their upregulation is implicated in conferring resistance to ferroptosis across various contexts, including chemotherapy and radiation therapy

SIGNOR-279869

P46019

P22612

0

phosphorylation

down-regulates activity

0.325

Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme.

SIGNOR-267414

P29317

P31749

0

phosphorylation

up-regulates activity

0.355

As non-canonical EphA2 activation requires phosphorylation of EphA2 at serine 897 by pAkt (Fig.\u00a02b), we sought to determine the effect of PTEN-mediated Akt regulation on invasion.

SIGNOR-279787

Q6WKZ4

Q7KZI7

0

phosphorylation

up-regulates quantity

0.341

We have now found that MARK2 phosphorylates Rab11-FIP1B/C at serine 234 in a consensus site similar to that previously identified in Rab11-FIP2.

SIGNOR-273676

Q14807

Q96EP1

0

ubiquitination

down-regulates quantity by destabilization

0.399

Chfr ubiquitinates Kif22 and promotes its degradation.

SIGNOR-271469

Q13315

Q9UPU5

1

phosphorylation

up-regulates activity

0.25

Taken together, these data suggest that the ATM kinase mediated phosphorylation of USP24 is involved in USP24 stabilization/up regulation following UV irradiation.|Taken together, these data suggest that the ATM kinase-mediated phosphorylation of USP24 is involved in USP24 stabilization/up-regulation following UV irradiation.

SIGNOR-280043

Q9UL51

P12931

0

phosphorylation

up-regulates activity

0.267

We identified a highly conserved tyrosine residue in the C-linker of HCN channels (Tyr476 in HCN2) that confers modulation by Src. Replacement of this tyrosine by phenylalanine in HCN2 or HCN4 abolished sensitivity to Src inhibitors. Mass spectrometry confirmed that Tyr476 is phosphorylated by Src. Our results have functional implications for HCN channel gating. Furthermore, they indicate that tyrosine phosphorylation contributes in vivo to the fine tuning of HCN channel activity.

SIGNOR-263199

A6NFN3

Q12857

0

transcriptional regulation

up-regulates quantity

0.261

For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)

SIGNOR-268911

P40189

P42702

2

binding

up-regulates

0.605

The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3).

SIGNOR-204850

Q9P296

P01031

2

binding

up-regulates

0.662

Here we report that the orphan receptor c5l2/gpr77, which shares 35% amino acid identity with cd88, binds c5a with high affinity.

SIGNOR-113558

Q15750

O15105

2

binding

down-regulates

0.58

Smad6 interacts with tak1 and tab1, and smad7 with tab1. The interaction of i-smads with tak1 and/or tab1 implies that several mechanisms exist underlying the repression of the tak1-p38 kinase pathway by i-smads.

SIGNOR-112645

P05771

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-276234

Q14680

O43524

1

phosphorylation

down-regulates quantity

0.362

Further analysis indicated that FOXO1 and FOXO3, two known transcriptional regulators of p21, were phosphorylated by MELK and thus be involved in the induction of p21 after MELK inhibition.|Our findings revealed that siRNA mediated MELK knockdown increased protein levels of FOXO1 and FOXO3, which might increase p21 transcriptional level in a p53 independent manner.

SIGNOR-279375

Q9NWD9

P53350

0

phosphorylation

up-regulates activity

0.2

In addition, the inhibition of PLK1 activity by BI2536 treatment sharply reduced BEX4 protein, which was localized at the centrosomes in the HeLa cells or the GFP-BEX4 stable cell lines.|PLK1 directly phosphorylates BEX4 at T107 and contributes to BEX4-induced aneuploidy.

SIGNOR-279550

P12004

P08069

0

phosphorylation

up-regulates activity

0.2

In vitro MS analysis of PCNA co-incubated with the IGF-1R kinase indicated tyrosine residues 60, 133, and 250 in PCNA as IGF-1R targets, and PCNA phosphorylation was followed by mono- and polyubiquitination.

SIGNOR-277252

Q13043

P52945

1

phosphorylation

down-regulates activity

0.2

MST1 directly phosphorylated PDX1 at Thr11, resulting in its ubiquitination, degradation and impaired insulin secretion.|Thus, kinase activity is required for MST1 induced PDX1 degradation.

SIGNOR-278303

Q15418

Q92882

1

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

Q9NWS0

P49959

2

binding

up-regulates activity

0.2

Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689.

SIGNOR-265898

Q99814

P41229

1

transcriptional regulation

up-regulates quantity by expression

0.278

To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.

SIGNOR-271579

P25963

O14920

0

phosphorylation

down-regulates activity

0.922

Tak1 become activated and then phosphorilates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation

SIGNOR-235400

P14923

P12931

0

phosphorylation

up-regulates activity

0.668

Tyrosine phosphorylation of plakoglobin causes contrary effects on its association with desmosomes and adherens junction components and modulates beta-catenin-mediated transcriptionFor instance, Src, which mainly phosphorylates Tyr86 in beta-catenin, modifies Tyr643 in plakoglobin, decreasing the interaction with E-cadherin and alpha-catenin and increasing the interaction with the alpha-catenin-equivalent protein in desmosomes, desmoplakin.

SIGNOR-247310

O96017

Q13049

1

phosphorylation

up-regulates activity

0.2

We show that CHK2 binds and phosphorylates TRIM32 at the S55 site, which then mediates K63-linked ubiquitination of ATG7 at the K45 site to initiate autophagy.

SIGNOR-277790

Q9NXK8

P30838

2

binding

down-regulates quantity by destabilization

0.32

We now show that SCFFBXL12 is an authentic E3 for the ALDH3 family of enzymes. We now show that the ubiquitin-dependent degradation of ALDH3 mediated by FBXL12 (F box and leucine-rich repeat protein 12) is essential for execution of the differentiation program of trophoblast stem cells (TSCs). FBXL12 is present only in eutherian mammals, and its expression is largely restricted to the placenta during mouse embryogenesis. FBXL12 was found to interact specifically with members of the ALDH3 family and to mediate their polyubiquitylation. Finally, coimmunoprecipitation analysis revealed that FBXL12 interacted efficiently only with members of the ALDH3 family (ALDH3A1, ALDH3A2, and ALDH3B1), showing little if any association with those of the ALDH1 family (ALDH1A1, ALDH1A2, and ALDH1A3) (Fig. 2H). Collectively, these results suggested that SCFFBXL12 is an authentic E3 specific for ALDH3 family members.

SIGNOR-272813

Q07021

P02747

2

binding

down-regulates activity

0.399

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

SIGNOR-263404

Q9UKC9

Q9UK99

2

binding

down-regulates quantity by destabilization

0.549

F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. The SCF complex is composed of F-box protein, Skp1, Cullin1 (Cul1) and ROC1. Fbxo3, whose substrates are few, forms SCF Fbxo3 ubiquitin ligase and regulates the degradations of Fbxl2, p62, HIPK2 and p300 through the ubiquitin-proteasome pathway.

SIGNOR-272445

Q13043

P42336

1

phosphorylation

down-regulates activity

0.2

MST1/2 and HGK inhibit catalytic activity of p110α through phosphorylation at T1061

SIGNOR-277920

P25098

P41143

1

phosphorylation

down-regulates activity

0.2

Taken together, we have demonstrated that agonist-induced opioid receptor phosphorylation occurs exclusively at two phosphate acceptor sites (T358 and S363) of GRK2 at the DOR carboxyl terminus.

SIGNOR-249660

P00533

P62993

2

binding

up-regulates activity

0.923

Adaptor protein Grb2 binds phosphotyrosines in the epidermal growth factor (EGF) receptor (EGFR) and thereby links receptor activation to intracellular signaling cascades.

SIGNOR-267725

P63092

O60503

2

binding

up-regulates activity

0.628

Adenylyl cyclase 9 (AC9) is a membrane-bound enzyme that converts ATP into cAMP. The enzyme is weakly activated by forskolin, fully activated by the G protein Gαs subunit and is autoinhibited by the AC9 C-terminus.

SIGNOR-278883

Q13153

Q02750

1

phosphorylation

up-regulates activity

0.582

We find that adhesion to fibronectin induces pak1-dependent phosphorylation of mek1 on s298 and that this phosphorylation is necessary for efficient activation of mek1 and subsequent mapk activation.

SIGNOR-236002

P17252

P26927

0

phosphorylation

up-regulates activity

0.2

Thus, the phosphorylation of PKCα at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKCα.

SIGNOR-277179

Q96ME1

Q9UJT9

2

binding

down-regulates quantity by destabilization

0.652

F-box protein Fbxl18 mediates polyubiquitylation and proteasomal degradation of the pro-apoptotic SCF subunit Fbxl7.. Here, we identified that an orphan F-box protein, Fbxl18, targets Fbxl7 for its polyubiquitylation and proteasomal degradation. Lys 109 within Fbxl7 is an essential acceptor site for ubiquitin conjugation by Fbxl18.

SIGNOR-272448

P35637

P00519

0

phosphorylation

down-regulates activity

0.325

Abl kinase-mediated FUS Tyr526 phosphorylation alters nucleocytoplasmic FUS localization in FTLD-FUS.

SIGNOR-280168

P57682

O95600

1

transcriptional regulation

down-regulates quantity by repression

0.255

Here we report that Klf8 is repressed by Klf3 in vivo and is up-regulated by Klf1. Transcript analysis indicates that Klf8 has two promoters, both containing multiple CACCC elements. Transactivation assays and chromatin immunoprecipitation experiments indicate that Klf3 represses Klf8 directly and that Klf1 activates Klf8 directly.

SIGNOR-266049

P15260

O60674

2

binding

up-regulates

0.714

The only type ii ifn, ifn-, binds a distinct cell-surface receptor, which is known as the type ii ifn receptor. This receptor is also composed of two subunits, ifngr1 and ifngr2, which are associated with jak1 and jak2, respectively. Activation of the jaks that are associated with the type i ifn receptor results in tyrosine phosphorylation of stat2

SIGNOR-135955

P25101

P05305

2

binding

up-regulates

0.881

Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors.

SIGNOR-145759

P42574

Q14790

0

cleavage

up-regulates activity

0.726

Triggering of the DISC leads to caspase-8 activation. Active caspase-8 cleaves caspase-3 which, in type I cells, leads to cell death induction.

SIGNOR-171767

Q13469

Q08209

0

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

Q96JY6

Q04206

1

polyubiquitination

down-regulates quantity by destabilization

0.347

Here we report that PDLIM2 negatively regulated NF-kappaB activity, acting as a nuclear ubiquitin E3 ligase targeting the p65 subunit of NF-kappaB. PDLIM2 bound to p65 and promoted p65 polyubiquitination.

SIGNOR-271651

P28335

P30679

2

binding

up-regulates activity

0.503

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-257355

Q96QT6

Q04724

2

binding

up-regulates activity

0.2

We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE.

SIGNOR-266994

Q15116

Q9NZQ7

2

binding

up-regulates

0.936

Pd-l1, was found to bind pd-1 specifically. The functional significance of this interaction has been demonstrated in t cell assays, in which engagement of pd-1 by pd-l1 leads to the inhibition of tcr-mediated lymphocyte proliferation and cytokine secretion.

SIGNOR-82604

P63000

P52735

0

guanine nucleotide exchange factor

up-regulates

0.761

Vav2 activates rac1 / vav2 is an exchange factor for rho family gtpases.

SIGNOR-81645

Q14493

Q93077

1

translation regulation

up-regulates quantity by expression

0.2

Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.

SIGNOR-265400

Q13153

P10398

1

phosphorylation

up-regulates

0.267

Phosphorylation of endogenous a-raf, b-raf and raf-1 on the homologous pak phosphorylation sites (serine 299, serine 445, or serine 338 respectively)we found that the phosphorylation of a-raf on serine 299 was also stimulated by egf, although the duration of phosphorylation on this site was much shorter than for raf-1. Thus, by analogy with raf-1, phosphorylation of this site may play an important role in the a-raf activation mechanism.

SIGNOR-236342

P09629

P09038

1

transcriptional regulation

up-regulates quantity by expression

0.396

Band shift and cotransfection experiments showed that HOXB7 directly transactivates the hFGF gene through one out of five putative homeodomain binding sites present in its promoter.

SIGNOR-261639

O00443

P06493

0

phosphorylation

down-regulates activity

0.281

Mitotic and stress-induced phosphorylation of HsPI3K-C2alpha targets the protein for degradation. Stress-dependent and mitotic phosphorylation of hspik3-c2alpha occurs on the same serine residue (ser259) within a recognition motif for proline-directed kinases. Mitotic phosphorylation of hspik3-c2alpha can be attributed to cdc2 activity, and stress-induced phosphorylation of hspik3-c2alpha is mediated by jnk/sapk

SIGNOR-100903

Q12933

Q13546

1

ubiquitination

up-regulates activity

0.895

Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2.

SIGNOR-59689

Q15796

O95405

0

relocalization

up-regulates activity

0.908

Smad anchor for receptor activation (SARA) is known as Smad cofactor that interacts directly with Smad2/3 and functions to recruit Smad2/3 to the TGF-beta receptor.

SIGNOR-165786

Q9BYX4

P36873

0

dephosphorylation

up-regulates activity

0.247

Exogenous PP1alpha or PP1gamma substantially decreased the S88 phosphorylation of Flag-MDA5|we identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation.

SIGNOR-264579

Q13418

Q96C90

1

phosphorylation

up-regulates activity

0.398

We conclude that ILK may activate smooth-muscle contraction both directly, via phosphorylation of myosin, and indirectly, via phosphorylation and activation of CPI-17 and PHI-1, leading to inhibition of MLCP.|CPI-17 and PHI-1 thiophosphorylated by ILK at Thr(38) or Thr(57) respectively inhibited myosin light-chain phosphatase (MLCP) activity bound to myosin

SIGNOR-265741

Q14674

O60216

1

cleavage

down-regulates quantity by destabilization

0.78

In order to segregate sister chromatids to opposite poles in anaphase, cohesin has to be removed from chromosomes. In budding yeast, the prevalent mode of cohesin removal is by proteolytic cleavage of the Scc1 subunit at the onset of anaphase by the endopeptidase separase

SIGNOR-275537

Q8TEA8

O00311

0

phosphorylation

up-regulates activity

0.321

Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D).

SIGNOR-273967

Q9Y5B0

P19784

0

phosphorylation

down-regulates activity

0.374

We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified

SIGNOR-250986

P18848

O75807

1

transcriptional regulation

up-regulates quantity by expression

0.657

ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress.

SIGNOR-260172

Q16539

P43403

2

phosphorylation

down-regulates activity

0.476

We have found that T cell p38 MAP kinase (MAPK), which is directly phosphorylated and activated by ZAP-70 downstream of the TCR, in turn phosphorylates Thr-293 in the interdomain B region of ZAP-70. These results identify a tight negative feedback loop in which ZAP-70-activated p38 reciprocally phosphorylates ZAP-70 and destabilizes the signaling complex.

SIGNOR-277384

P50613

P24941

2

phosphorylation

up-regulates activity

0.571

Phosphorylation of monomeric human CDK2 by CAK1 is more efficient than phosphorylation of the binary CDK2-cyclin A complex. Phosphorylated CDK2 exhibits histone H1 kinase activity corresponding to approximately 0.3% of that observed with the fully activated phosphorylated CDK2-cyclin A complex. Fluorescence measurements have shown that Thr160 phosphorylation increases the affinity of CDK2 for both histone substrate and ATP and decreases its affinity for ADP.

SIGNOR-250768

Q9H5J4

P36956

0

transcriptional regulation

up-regulates quantity by expression

0.45

These data demonstrated that Elovl-6 is regulated directly and primarily by SREBP-1c.

SIGNOR-267943

P27037

P36896

1

phosphorylation

up-regulates

0.687

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

SIGNOR-99995

Q14118

P12931

0

phosphorylation

down-regulates

0.55

Tyrosine 892 is now thought to be the principal site for recognition by the c-src tyrosine kinase;. We show that upon tyrosine phosphorylation, beta-dystroglycan undergoes a profound change in its sub-cellular localization (e.g., from the plasma membrane to an internal membrane compartment). One possibility is that the net negative charge at position 892 causes the redistribution of beta-dystroglycan to this intracellular vesicular location

SIGNOR-101655

Q9NRD9

P17612

0

phosphorylation

up-regulates

0.2

We analyzed the duox1 phosphorylation state with an anti-rxx(ps/pt) antibody that could potentially recognize phosphorylation on ser955 and ser1217 but not on thr1007. duox1 but not duox2 activity is stimulated by forskolin (ec50 = 0.1 _m) via protein kinase a-mediated duox1 phosphorylation on serine 955. duox1 is positively regulated by the camp-dependent protein kinase a (pka)6 cascade

SIGNOR-183449

Q14457

P31749

0

phosphorylation

down-regulates activity

0.564

In addition, pharmacological inhibition of AKT1 enhanced BECN1 stability in both assays, leaving about twice the amount of BECN1 at 90 min compared to control (Fig. 4i\u2013l).|The oncogenic kinase AKT1 phosphorylates BECN1 at positions S234, S295, which leads to sequestration of this peripheral membrane binding protein xref to the cytoskeleton with the result of inhibition of autophagy xref .

SIGNOR-279666

P29320

P12931

2

binding

up-regulates

0.528

We propose src kinase as a downstream effector that mediates the neuron's response to eph receptor activation.

SIGNOR-58139

Q9UKP6

P38405

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-256922

Q9Y4K3

P03186

0

deubiquitination

down-regulates activity

0.2

EBV-encoded BPLF1 interacts with and deubiquitinates TRAF6 to inhibit NF-κB signaling during lytic infection. Once lytic replication is induced, BPLF1 then deubiquitinates and inactivates TRAF6 to further block NF-κB signaling, promoting efficient viral genome replication.

SIGNOR-266739

Q9Y6C5

Q14623

2

binding

down-regulates activity

0.791

Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH.

SIGNOR-61314

P45983

P10415

1

phosphorylation

down-regulates

0.582

G(2)/m-phase cells proved more susceptible to death signals, and phosphorylation of bcl-2 appeared to be responsible, as a ser70ala substitution restored resistance to apoptosis. We noted that ask1 and jnk1 were normally activated at g(2)/m phase, and jnk was capable of phosphorylating bcl-2..

SIGNOR-72361

Q06330

P46531

2

binding

up-regulates

0.95

The intracellular part of the notch receptor is cleaved off and translocates to the nucleus, where it binds to the transcription factor rbp-j.

SIGNOR-183510

Q00526

P46531

1

phosphorylation

down-regulates quantity by destabilization

0.243

Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues

SIGNOR-273167