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
P40337	Q9H257	2	binding	down-regulates activity	0.393	We found that pVHL associates with the NF-kappaB agonist Card9 but does not target Card9 for destruction. Instead, pVHL serves as an adaptor that promotes the phosphorylation of the Card9 C terminus by CK2.	SIGNOR-257603
P55072	O14965	2	binding	down-regulates activity	0.313	The UBXN-2/p37/p47 adaptors of CDC-48/p97 regulate mitosis by limiting the centrosomal recruitment of Aurora A.\|We found that UBXN-2 and CDC-48 coimmunoprecipitated with AIR-1 from embryonic extracts	SIGNOR-265044
P13945	P38405	2	binding	up-regulates activity	0.448	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-256896
Q68EM7	P63000	1	guanine nucleotide exchange factor	up-regulates activity	0.566	ARHGAP17 is a Rho GTPase-activating protein of Rac1	SIGNOR-272166
P31751	Q01860	1	phosphorylation	up-regulates quantity by stabilization	0.255	Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG.	SIGNOR-242097
Q00987	Q96AQ6	1	polyubiquitination	down-regulates quantity by destabilization	0.29	. Accordingly, we identified the microtubule-associated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1.	SIGNOR-272850
Q9NZQ7	Q8NEZ4	0	transcriptional regulation	up-regulates quantity by expression	0.2	MLL3 enhances the transcription of PD-L1 and regulates anti-tumor immunity. We found that MLL3 bound to the enhancer of PD-L1.	SIGNOR-260040
P24752	P48735	1	acetylation	down-regulates activity	0.287	Mitochondrial acetyltransferase ACAT1 and deacetylase SIRT3 are responsible for acetylation and deacetylation, respectively, at K413 of mIDH2\|K413 acetylation inhibits mIDH2 by simultaneously attenuating dimer formation from monomers and destabilizing dimers for conversion to monomers	SIGNOR-267627
Q99759	Q99759	2	phosphorylation	up-regulates	0.2	Phosphorylation of serine 526 is required for mekk3 activity, and association with 14-3-3 blocks dephosphorylationautophosphorylation of mekk3 at ser526	SIGNOR-143647
Q15418	Q15831	1	phosphorylation	down-regulates activity	0.288	Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cellsBRAFV600E activates downstream molecules, including ERK and p90 ribosomal S6 kinase (RSK), and leads to the phosphorylation of LKB-1 at Ser428 by these kinases. This cascade results in the dissociation of LKB1 from AMPK.	SIGNOR-209871
O60825	P17612	0	phosphorylation	up-regulates activity	0.444	PFK-2 that was phosphorylated on Ser466, but not Ser483, by PKA did not bind to 14-3-3s‚	SIGNOR-250025
O94827	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.771	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-260566
Q86YT6	P53355	1	polyubiquitination	down-regulates quantity by destabilization	0.437	Transient expression of DIP-1 in HeLa cells antagonizes the anti-apoptotic function of DAPK to promote a caspase-dependent apoptosis. These studies also demonstrate that DAPK is an in vitro and in vivo target for ubiquitination by DIP-1, thereby providing a mechanism by which DAPK activities can be regulated through proteasomal degradation.	SIGNOR-272602
P04637	P62140	0	dephosphorylation	down-regulates activity	0.286	Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities\|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.	SIGNOR-248572
Q15078	P07384	0	cleavage	up-regulates activity	0.571	Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain	SIGNOR-251583
P29597	P23458	0	phosphorylation	up-regulates	0.527	These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055 and that this phosphorylation requires another kinase, most likely jak1.	SIGNOR-43080
P20701	P12931	0	phosphorylation	down-regulates activity	0.421	PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role.	SIGNOR-254741
P04150	Q16539	0	phosphorylation	up-regulates	0.511	We found serine 211 of the human gr to be a substrate for p38 mapk both in vitro and intracellularly. Mutation of this site to alanine greatly diminished gr-driven gene transcription and apoptosis.	SIGNOR-135198
Q05086	P33993	1	polyubiquitination	down-regulates quantity by destabilization	0.401	The characterization of this interaction in turn led to the discovery that Mcm7 is a substrate for both E6-AP-dependent and -independent ubiquitination and is specifically targeted for degradation by the 26 S proteasome.	SIGNOR-272543
Q13315	Q96RU2	1	phosphorylation	up-regulates activity	0.311	These novel findings establish a direct connection between the ubiquitination of UCK1 by KLHL2 and phosphorylation of USP28 and UCK1 by ATM, which are involved in mediating drug resistance against 5'-AZA in AML patients.	SIGNOR-279007
P06493	Q9Y3Z3	1	phosphorylation	down-regulates	0.492	Cyclin a2/cdk1 phosphorylates samhd1 at the threonine 592 residue both in vitro and in vivo. Phosphorylation of samhd1 thr592 correlates with loss of its ability to restrict hiv-1.	SIGNOR-201913
Q8N0Z6	Q8N9B5	2	binding	up-regulates activity	0.531	DNA damage activates ATM kinase which then phosphorylates Strap at Ser 203 (red circles). Phosphorylated Strap is stabilized and undergoes nuclear accumulation where it assembles into a co-activator complex, which includes p300 and cofactors such as JMY	SIGNOR-262647
O14733	Q13387	2	binding	up-regulates	0.678	Thus, both jip1 and jip2 selectively bind the mapkk isoform mkk7.	SIGNOR-59944
O60729	Q93008	1	dephosphorylation	down-regulates quantity by destabilization	0.2	Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms' tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis.	SIGNOR-275613
O43921	P54756	2	binding	up-regulates	0.818	Ephrin-a ligands (named ephrin-a1_ephrin-a5) are anchored in the plasma membrane through a gpi-linkage, and each can bind any of the epha subclass of receptors (epha1_epha8)	SIGNOR-65416
P49841	Q13887	1	phosphorylation	down-regulates	0.368	Stability of the klf5 is mediated by proteasomal degradation via phosphorylation by glycogen synthase kinase 3_ (gsk3_) and recognition by f-box and wd repeat domain-containing 7 (fbw7) of a phosphodegron sequence surrounding serine 303 in klf5	SIGNOR-203627
P09471	P46663	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-257237
O00628	O75381	2	binding	up-regulates activity	0.89	The peroxisomal docking complex is a key component of the import machinery for matrix proteins. The core protein of this complex, Pex14, is thought to represent the initial docking site for the import receptors Pex5 and Pex7.	SIGNOR-253028
Q9HBW1	Q96CW9	2	binding	up-regulates activity	0.73	The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively.	SIGNOR-264048
O95837	P29275	2	binding	up-regulates activity	0.275	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-257414
P17542	Q96AE4	1	transcriptional regulation	up-regulates quantity by expression	0.2	TAL1 directly activates the FUBP1 promoter, leading to increased FUBP1 expression during erythroid differentiation.	SIGNOR-259131
P49674	Q13114	1	phosphorylation	up-regulates activity	0.307	CK1ɛ interacted with and phosphorylated TRAF3 at Ser349, which thereby promoted the Lys63 (K63)-linked ubiquitination of TRAF3 and subsequent recruitment of the kinase TBK1 to TRAF3.	SIGNOR-277212
Q9Y2R2	Q96P20	1	dephosphorylation	up-regulates activity	0.356	Further, this explains how loss of PTPN22 and subsequent enhanced NLRP3 phosphorylation mediate a decrease in NLRP3 inflammasome activation.\|Upon NLRP3 activation, PTPN22 dephosphorylates NLRP3 and thereby protects it from degradation, allowing robust inflammasome activity (summarized in Fig.S6).	SIGNOR-277056
P08754	Q9UNW8	2	binding	up-regulates activity	0.2	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257074
O00571	P06493	0	phosphorylation	down-regulates	0.297	Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis.	SIGNOR-141569
P07900	O94826	2	binding	up-regulates activity	0.2	The Tom70 receptor is a membrane-localized cochaperone that integrates the Hsp70/Hsp90 chaperones with mitochondrial preprotein targeting and translocation. In mammals, preprotein in the cytosol is associated with both Hsp90 and Hsp70 in a multichaperone complex, and docking of Hsp90 and/or Hsp70 onto Tom70 is essential for preprotein targeting.	SIGNOR-261379
Q93034	P10523	2	binding	up-regulates quantity by stabilization	0.412	Here we report that NEDD4-1, a HECT domain-containing E3 ubiquitin ligase, binds via its HECT domain directly with SAG's C-terminal RING domain and ubiquitylates SAG for proteasome-mediated. We also found that SAG bridges NEDD4-1 via its C-terminus and CUL-5 via its N-terminus to form a NEDD4-1/SAG/CUL-5 tri-complex. Biologically, NEDD4-1 overexpression sensitizes cancer cells to etoposide-induced apoptosis by reducing SAG levels through targeted degradation. Thus, SAG is added to a growing list of NEDD4-1 substrates and mediates its biological function. degradation.	SIGNOR-272844
O60341	Q99814	0	transcriptional regulation	down-regulates quantity by repression	0.28	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-271588
Q13291	Q86YJ5	0	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-271537
P19086	Q13639	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-257309
P63096	P21554	2	binding	up-regulates activity	0.541	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-256724
O15111	O43524	1	phosphorylation	down-regulates	0.572	Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation.	SIGNOR-124203
P67775	P27707	1	dephosphorylation	down-regulates activity	0.2	Protein phosphatase 2A regulates deoxycytidine kinase activity via Ser-74 dephosphorylation\|Deoxycytidine kinase (dCK) is a critical enzyme for activation of anticancer nucleoside analogs. Its activity is controlled via Ser-74 phosphorylation. Here, we investigated which Ser/Thr phosphatase dephosphorylates Ser-74. In cells, the PP1/PP2A inhibitor okadaic acid increased both dCK activity and Ser-74 phosphorylation	SIGNOR-275803
Q15208	Q15208	2	phosphorylation	up-regulates	0.2	We found that ndr1 autophosphorylates in vitro predominantly on ser-281 and to a lesser extent on thr-74 and thr-444. All of these residues proved to be crucial also for ndr1 activity in vivo	SIGNOR-96687
P10451	Q13950	0	transcriptional regulation	up-regulates quantity	0.488	Ets-1 and Runx2 are critical transcriptional regulators of OPN expression in CT26 colorectal cancer cells. Suppression of these transcription factors results in significant down-regulation of the OPN metastasis protein.	SIGNOR-245336
Q6ZVD8	P31749	1	dephosphorylation	down-regulates	0.773	Here, we identify a protein phosphatase, ph domain leucine-rich repeat protein phosphatase (phlpp), that specifically dephosphorylates the hydrophobic motif of akt (ser473 in akt1), triggering apoptosis and suppressing tumor growth.[...] These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt.	SIGNOR-252602
Q96EB6	P15172	1	null	down-regulates activity	0.621	Sir2 forms a complex with the acetyltransferase PCAF and MyoD and, when overexpressed, retards muscle differentiation	SIGNOR-241963
P43403	Q6ISU1	2	binding	up-regulates activity	0.285	Stimulation of the T-cell antigen receptor (TCR) leads to tyrosine phosphorylation of a number of cellular proteins, including phospholipase C (PLC) gamma 1 and the TCR zeta chain. We describe here a 70-kDa tyrosine phosphoprotein (ZAP-70) that associates with zeta within 15 sec following TCR stimulation. The phosphorylation of ZAP-70 and its association with zeta is independent of the other TCR chains	SIGNOR-134325
Q15831	Q9H093	1	phosphorylation	up-regulates	0.273	A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold.	SIGNOR-122717
O15123	Q03112	0	transcriptional regulation	up-regulates quantity by expression	0.2	We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2	SIGNOR-266060
P50148	P21731	2	binding	up-regulates activity	0.654	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-256887
O00192	P22223	2	binding	up-regulates quantity by stabilization	0.327	To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member.	SIGNOR-252127
Q96CG3	O14965	0	phosphorylation	up-regulates activity	0.2	Here, we report that Aurora A is essential for Thr9 phosphorylation of the TRAF-interacting protein TIFA, triggering activation of the NF-κB survival pathway in AML.	SIGNOR-273551
P60484	Q13224	1	dephosphorylation	down-regulates activity	0.296	GluN2B Y1472 site is dephosphorylated by PTEN .	SIGNOR-277165
O14757	P30307	1	phosphorylation	down-regulates quantity by destabilization	0.85	The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216).	SIGNOR-163158
P49792	Q92973	2	binding	up-regulates activity	0.455	Nup358(806–1306), but not other regions, efficiently recruits importin β and transportin 1	SIGNOR-262111
Q06830	P11802	0	phosphorylation	down-regulates	0.226	Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%.Prx i was also phosphorylated, with an efficiency similar to that observed with cdc2, when incubated in vitro with cdk2, cdk4, or cdk6 that had been immunoprecipitated from hela cell lysates with specific antibodies (data not shown).	SIGNOR-87105
Q13485	O75925	0	sumoylation	up-regulates	0.394	These data demonstrate that pias1 protein positively modulates tgf-beta responses as a sumo e3 ligase for smad4	SIGNOR-123462
O60516	P42345	0	phosphorylation	up-regulates	0.358	While promoting initiation of protein translation through mtor, eukaryoticinitiation factor 4e, and the ribosomal p70-s6 kinase.	SIGNOR-122035
O75531	P60510	0	dephosphorylation	up-regulates	0.2	Herein, we demonstrate we demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. We have identified the major phosphatase responsible for dephosphorylation of ser-4 to be protein phosphatase 4 catalytic subunit.	SIGNOR-203281
P51608	Q7Z2K8	1	post transcriptional regulation	up-regulates quantity by expression	0.298	MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1.	SIGNOR-264679
O95600	P68871	1	transcriptional regulation	down-regulates quantity by repression	0.2	These results establish KLF8 as a CACCC-box binding protein that associates with CtBP and represses transcription.	SIGNOR-266052
P46531	O75056	2	binding	up-regulates activity	0.379	Furthermore, we show that Syndecan-3 interacts with Notch and is required for Notch processing by ADAM17/tumor necrosis factor-converting enzyme (TACE) and signal transduction. Together, our data support the conclusion that Syndecan-3 and Notch cooperate in regulating homeostasis of the satellite cell population and myofiber size.	SIGNOR-244072
P06493	P60510	0	dephosphorylation	down-regulates activity	0.397	PP4c efficiently dephosphorylates Cdk1 sites of NDEL1 but does not dephosphorylate the Aurora A site.\|We also found that PP4c negatively regulates Cdk1 activity in interphase.	SIGNOR-277162
P35813	Q9UHD2	1	dephosphorylation	down-regulates activity	0.41	Furthermore, PPM1A, but not PPM1B, serves as an efficient phosphatase to dephosphorylate Ser 172 residue of both TBK1 and IKKepsilon kinases, which is critical for their kinase activities.\|In a similar in vitro phosphatase assay, incubation of PPM1A also eliminated TBK1 and IKKepsilon phosphorylation at Ser 172 residue, evidenced by phospho-S172 immunoblotting (XREF_FIG, F and G).\|These observations suggest that PPM1A may block kinase activities of TBK1 and IKKepsilon.	SIGNOR-276966
P03372	P06850	1	transcriptional regulation	up-regulates quantity by expression	0.34	Evidence of direct estrogenic regulation of human corticotropin-releasing hormone gene expression. Potential implications for the sexual dimophism of the stress response and immune/inflammatory reaction.\|Gel retardation and immunoprecipitation demonstrated specific association between the perfect half-palindromic EREs of hCRH gene and the DNA binding domain of hER in vitro.	SIGNOR-268721
P06213	Q05209	0	dephosphorylation	down-regulates	0.378	Interestingly, all PTPs that were tested could completely dephosphorylate the receptor, given sufficient time, including a negative control (PTP-PEST) that failed to bind IRK as a trapping mutant.	SIGNOR-75894
P21580	Q9Y4K3	1	deubiquitination	down-regulates activity	0.702	A20 is a deubiquitinating enzyme (dub) for lys63-linked polyubiquitinated signaling mediators such as traf6	SIGNOR-160223
O75116	Q16555	1	phosphorylation	up-regulates	0.383	Rho-kinase phosphorylated crmp-2 at thr-555 in vitro.we demonstrated that crmp-2 is phosphorylated by rho-kinase in drg neurons during lpa-induced growth cone collapse.	SIGNOR-77543
Q9NRM7	P61981	1	phosphorylation	up-regulates	0.331	Phosphorylation of 14-3-3_ on s59 by lats2. Ser(58) phosphorylation and lys(49) acetylation of 14-3-3_ occur in a coordinated time-dependent manner to regulate 14-3-3_ homodimerization. 14-3-3_ ser(58) phosphorylation is required for star interactions under control conditions,	SIGNOR-205247
P00533	P42566	2	phosphorylation	up-regulates	0.755	Earlier studies have shown that eps15 at tyr-849 is phosphorylated in egf-stimulated cells and partly controls the internalization of mono-ubiquitinated egfr via uim domains of eps15 [10]. It has also been shown that active egfr phosphorylates tyr-849 directly;	SIGNOR-203311
P31146	Q00535	0	phosphorylation	up-regulates activity	0.288	We here show that phosphorylation of coronin 1 on Thr(418/424) by cyclin-dependent kinase (CDK) 5 activity was responsible for coronin 1-G_s association and the modulation of cAMP production. Together these results show an essential role for CDK5 activity in promoting the coronin 1-dependent cAMP/PKA pathway.	SIGNOR-245187
P24941	Q99741	1	phosphorylation	down-regulates activity	0.942	Hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)\|An HsCdc6A1A2A3 mutant, which mimics unphosphorylated HsCdc6, is exclusively nuclear, and its expression inhibits initiation of DNA replication. An HsCdc6E1E2E3 mutant, which mimics phosphorylated HsCdc6, is exclusively cytoplasmic and is not associated with the chromatin/nuclear matrix fraction.	SIGNOR-67544
P63000	Q38SD2	0	phosphorylation	up-regulates activity	0.292	In vitro kinase assays confirmed that recombinant Lrrk1 phosphorylated RAC1-GST protein, and immunoprecipitation showed that the interaction of Lrrk1 with RAC1 occurred within 10 min after RANKL treatment.\|Lrrk1 phosphorylates and activates RAC1 and Cdc42 small GTPase proteins in osteoclasts.	SIGNOR-279626
P62993	Q13191	2	binding	up-regulates activity	0.567	Here we show that in unstimulated Jurkat cells Cbl is co-immunoprecipitated with monoclonal antibody against Grb2.	SIGNOR-236051
Q13309	P38936	1	ubiquitination	down-regulates	0.772	Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase.	SIGNOR-138490
P55196	Q13671	2	binding	up-regulates activity	0.2	Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors.	SIGNOR-220926
P16473	P01222	2	binding	up-regulates	0.722	Two novel human glycoprotein hormonelike genes, alpha2 (a2) and beta5 (b5), recently have been identified. Using a yeast two-hybrid assay, the two subunits were found as potential heterodimerization partners.	SIGNOR-88653
O75533	P24941	0	phosphorylation	up-regulates	0.346	To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptide). Three phosphorylation sites were identified as thr244, thr248, and thr313	SIGNOR-90434
P53350	Q8NHV4	1	phosphorylation	up-regulates activity	0.619	Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation.	SIGNOR-272992
Q16620	Q06124	0	dephosphorylation	down-regulates activity	0.707	Conversely, PTPN11 knockdown lead to increased Y 515 phosphorylation of TrkB compared to the scramble control in the neuronal cells.\|This study established that TrkB activation as demonstrated by receptor phosphorylation at Tyr 515 in the SH-SY5Y cells is negatively regulated by PTPN11 actions.	SIGNOR-277123
Q9HC98	O14757	0	phosphorylation	down-regulates activity	0.237	Nek6 is also directly phosphorylated by the checkpoint kinases Chk1 and Chk2 in vitro .	SIGNOR-279403
P51812	P11362	1	phosphorylation	down-regulates quantity	0.357	Both in vitro and in vivo experiments confirmed the interaction and we show that phosphorylated RSK2 binds to and phosphorylates serine 789 in the C-terminal tail of FGFR1.prevention of FGFR1 phosphorylation by inhibition of RSK2 activity or mutation of serine 789 to alanine reduced FGFR1 endocytosis and ubiquitination explaining mechanistically the prolonged signaling activity.	SIGNOR-276599
P48740	P0C0L4	1	cleavage	up-regulates activity	0.606	The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.\|Activation of C4 by Ct sand MASP-2 on western blots.	SIGNOR-263438
P15407	P05412	0	transcriptional regulation	up-regulates quantity by expression	0.826	Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription.	SIGNOR-261604
Q9NXA8	Q15067	1	catalytic activity	down-regulates activity	0.26	SIRT5‐mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation.	SIGNOR-261210
Q13464	P19105	1	phosphorylation	up-regulates activity	0.561	Phosphorylation of myosin II regulatory light chain (MRLC) is important for cell motility and cytokinesis in nonmuscle cells. Although the regulation of monophosphorylated MRLC at serine 19 throughout the cell cycle was examined in detail, MRLC diphosphorylation at both threonine 18 and serine 19 is still unclear. Here we found that Rho-kinase has an activity for MRLC diphosphorylation in nonmuscle cells using sequential column chromatographies.	SIGNOR-263074
P27361	P17480	1	phosphorylation	down-regulates	0.579	Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna	SIGNOR-112817
P47712	Q8IW41	0	phosphorylation	up-regulates activity	0.334	The p38-activated protein kinases MNK1, MSK1, and PRAK1 phosphorylate cPLA2 in vitro uniquely on Ser-727. By using Chinese hamster ovary, HeLa, and HEK293 cells stably transfected with wild type and phosphorylation site mutant forms of cPLA2, we show that phosphorylation of cPLA2 at both Ser-505 and Ser-727 and elevation of Ca(2+) leads to its activation in agonist-stimulated cells.	SIGNOR-250162
P31749	P35226	1	phosphorylation	up-regulates activity	0.437	The polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate	SIGNOR-252559
P24864	Q96PU4	0	ubiquitination	down-regulates quantity by destabilization	0.332	We found that NIRF directly ubiquitinated cyclins D1 and E1, as evidenced by the appearance of the tail (Fig. 4B). In summary, the above findings suggest that NIRF tightly cooperates with the core cell cycle machinery and induces G1 arrest, which is accompanied by ubiquitination of cyclins D1 and E1.	SIGNOR-271886
Q5S007	Q14155	2	phosphorylation	up-regulates	0.456	Arhgef7 is interacting with lrrk2 in vitro and in vivo. Lrrk2 phosphorylates arhgef7 in vitro.Two Threonine residues, t107 and t143, within the arhgef7 n-terminus were identified with high confidence	SIGNOR-169221
Q9ULU4	P15692	1	transcriptional regulation	down-regulates quantity by repression	0.2	Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported	SIGNOR-262041
P23219	Q86UZ6	0	transcriptional regulation	up-regulates quantity by expression	0.2	ZBTB46 acts as a transcriptional coactivator that binds to the promoter of prostaglandin-endoperoxide synthase 1 (PTGS1) and transcriptionally regulated PTGS1 levels.	SIGNOR-277991
P46531	P06239	2	binding	up-regulates	0.456	Endogenous notch-1 associates with p56(lck) and pi3k. p56(lck) is required for the notch-1-mediated activation of akt/pkb function	SIGNOR-118902
P04049	Q9C004	2	binding	down-regulates activity	0.433	Here we show that mammalian Sprouty4 suppresses vascular epithelial growth factor (VEGF)-induced, Ras-independent activation of Raf1 but does not affect epidermal growth factor (EGF)-induced, Ras-dependent activation of Raf1. Sprouty4 binds to Raf1 through its carboxy-terminal cysteine-rich domain, and this binding is necessary for the inhibitory activity of Sprouty4.	SIGNOR-253033
Q13315	Q99708	1	phosphorylation	down-regulates	0.828	Atm phosphorylates ctip at serine residues 664 and 745 our study suggests another dna damage-response pathway in which the signal is transmitted through phosphorylation of ctip by atm, leading to dissociation of the ctip_ctbp repressor complex from brca1, which in turn, activate transcription of gadd45	SIGNOR-79872
P63096	Q9UPC5	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-256688
Q16236	O00625	2	transcriptional regulation	up-regulates quantity by expression	0.2	The activation of NFE2L2 is pivotal in protecting cells from ferroptotic death. To achieve this protective function, NFE2L2 regulates a broad spectrum of genes involved in multiple cellular pathways, including those that modulate ROS, detoxify harmful agents, and repair damaged proteins. In human pancreatic cancer cell lines, the expression of PIR is upregulated by NFE2L2 in response to ferroptosis-inducing agents (erastin or RSL3)	SIGNOR-279850
Q05513	Q9NPB6	1	phosphorylation	up-regulates quantity by stabilization	0.841	APKC associates and phosphorylates Par6 on S345. aPKC expression stabilizes Par6 protein levels. We show that the aPKC, PKCι, interacts with TGF-β receptors through Par6 and that these proteins localize to the leading edge of migrating cells. Furthermore, Par6 phosphorylation on serine 345 by TGF-β receptors is enhanced in the presence of aPKC. aPKC kinase activity, as well as an association with Par6, were found to be important for Par6 phosphorylation.	SIGNOR-276433

P40337

Q9H257

2

binding

down-regulates activity

0.393

We found that pVHL associates with the NF-kappaB agonist Card9 but does not target Card9 for destruction. Instead, pVHL serves as an adaptor that promotes the phosphorylation of the Card9 C terminus by CK2.

SIGNOR-257603

P55072

O14965

2

binding

down-regulates activity

0.313

The UBXN-2/p37/p47 adaptors of CDC-48/p97 regulate mitosis by limiting the centrosomal recruitment of Aurora A.|We found that UBXN-2 and CDC-48 coimmunoprecipitated with AIR-1 from embryonic extracts

SIGNOR-265044

P13945

P38405

2

binding

up-regulates activity

0.448

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-256896

Q68EM7

P63000

1

guanine nucleotide exchange factor

up-regulates activity

0.566

ARHGAP17 is a Rho GTPase-activating protein of Rac1

SIGNOR-272166

P31751

Q01860

1

phosphorylation

up-regulates quantity by stabilization

0.255

Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG.

SIGNOR-242097

Q00987

Q96AQ6

1

polyubiquitination

down-regulates quantity by destabilization

0.29

. Accordingly, we identified the microtubule-associated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1.

SIGNOR-272850

Q9NZQ7

Q8NEZ4

0

transcriptional regulation

up-regulates quantity by expression

0.2

MLL3 enhances the transcription of PD-L1 and regulates anti-tumor immunity. We found that MLL3 bound to the enhancer of PD-L1.

SIGNOR-260040

P24752

P48735

1

acetylation

down-regulates activity

0.287

Mitochondrial acetyltransferase ACAT1 and deacetylase SIRT3 are responsible for acetylation and deacetylation, respectively, at K413 of mIDH2|K413 acetylation inhibits mIDH2 by simultaneously attenuating dimer formation from monomers and destabilizing dimers for conversion to monomers

SIGNOR-267627

Q99759

2

phosphorylation

up-regulates

0.2

Phosphorylation of serine 526 is required for mekk3 activity, and association with 14-3-3 blocks dephosphorylationautophosphorylation of mekk3 at ser526

SIGNOR-143647

Q15418

Q15831

1

phosphorylation

down-regulates activity

0.288

Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cellsBRAFV600E activates downstream molecules, including ERK and p90 ribosomal S6 kinase (RSK), and leads to the phosphorylation of LKB-1 at Ser428 by these kinases. This cascade results in the dissociation of LKB1 from AMPK.

SIGNOR-209871

O60825

P17612

0

phosphorylation

up-regulates activity

0.444

PFK-2 that was phosphorylated on Ser466, but not Ser483, by PKA did not bind to 14-3-3s‚

SIGNOR-250025

O94827

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.771

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-260566

Q86YT6

P53355

1

polyubiquitination

down-regulates quantity by destabilization

0.437

Transient expression of DIP-1 in HeLa cells antagonizes the anti-apoptotic function of DAPK to promote a caspase-dependent apoptosis. These studies also demonstrate that DAPK is an in vitro and in vivo target for ubiquitination by DIP-1, thereby providing a mechanism by which DAPK activities can be regulated through proteasomal degradation.

SIGNOR-272602

P04637

P62140

0

dephosphorylation

down-regulates activity

0.286

Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.

SIGNOR-248572

Q15078

P07384

0

cleavage

up-regulates activity

0.571

Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain

SIGNOR-251583

P29597

P23458

0

phosphorylation

up-regulates

0.527

These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055 and that this phosphorylation requires another kinase, most likely jak1.

SIGNOR-43080

P20701

P12931

0

phosphorylation

down-regulates activity

0.421

PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role.

SIGNOR-254741

P04150

Q16539

0

phosphorylation

up-regulates

0.511

We found serine 211 of the human gr to be a substrate for p38 mapk both in vitro and intracellularly. Mutation of this site to alanine greatly diminished gr-driven gene transcription and apoptosis.

SIGNOR-135198

Q05086

P33993

1

polyubiquitination

down-regulates quantity by destabilization

0.401

The characterization of this interaction in turn led to the discovery that Mcm7 is a substrate for both E6-AP-dependent and -independent ubiquitination and is specifically targeted for degradation by the 26 S proteasome.

SIGNOR-272543

Q13315

Q96RU2

1

phosphorylation

up-regulates activity

0.311

These novel findings establish a direct connection between the ubiquitination of UCK1 by KLHL2 and phosphorylation of USP28 and UCK1 by ATM, which are involved in mediating drug resistance against 5'-AZA in AML patients.

SIGNOR-279007

P06493

Q9Y3Z3

1

phosphorylation

down-regulates

0.492

Cyclin a2/cdk1 phosphorylates samhd1 at the threonine 592 residue both in vitro and in vivo. Phosphorylation of samhd1 thr592 correlates with loss of its ability to restrict hiv-1.

SIGNOR-201913

Q8N0Z6

Q8N9B5

2

binding

up-regulates activity

0.531

DNA damage activates ATM kinase which then phosphorylates Strap at Ser 203 (red circles). Phosphorylated Strap is stabilized and undergoes nuclear accumulation where it assembles into a co-activator complex, which includes p300 and cofactors such as JMY

SIGNOR-262647

O14733

Q13387

2

binding

up-regulates

0.678

Thus, both jip1 and jip2 selectively bind the mapkk isoform mkk7.

SIGNOR-59944

O60729

Q93008

1

dephosphorylation

down-regulates quantity by destabilization

0.2

Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms' tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis.

SIGNOR-275613

O43921

P54756

2

binding

up-regulates

0.818

Ephrin-a ligands (named ephrin-a1_ephrin-a5) are anchored in the plasma membrane through a gpi-linkage, and each can bind any of the epha subclass of receptors (epha1_epha8)

SIGNOR-65416

P49841

Q13887

1

phosphorylation

down-regulates

0.368

Stability of the klf5 is mediated by proteasomal degradation via phosphorylation by glycogen synthase kinase 3_ (gsk3_) and recognition by f-box and wd repeat domain-containing 7 (fbw7) of a phosphodegron sequence surrounding serine 303 in klf5

SIGNOR-203627

P09471

P46663

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-257237

O00628

O75381

2

binding

up-regulates activity

0.89

The peroxisomal docking complex is a key component of the import machinery for matrix proteins. The core protein of this complex, Pex14, is thought to represent the initial docking site for the import receptors Pex5 and Pex7.

SIGNOR-253028

Q9HBW1

Q96CW9

2

binding

up-regulates activity

0.73

The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively.

SIGNOR-264048

O95837

P29275

2

binding

up-regulates activity

0.275

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-257414

P17542

Q96AE4

1

transcriptional regulation

up-regulates quantity by expression

0.2

TAL1 directly activates the FUBP1 promoter, leading to increased FUBP1 expression during erythroid differentiation.

SIGNOR-259131

P49674

Q13114

1

phosphorylation

up-regulates activity

0.307

CK1ɛ interacted with and phosphorylated TRAF3 at Ser349, which thereby promoted the Lys63 (K63)-linked ubiquitination of TRAF3 and subsequent recruitment of the kinase TBK1 to TRAF3.

SIGNOR-277212

Q9Y2R2

Q96P20

1

dephosphorylation

up-regulates activity

0.356

Further, this explains how loss of PTPN22 and subsequent enhanced NLRP3 phosphorylation mediate a decrease in NLRP3 inflammasome activation.|Upon NLRP3 activation, PTPN22 dephosphorylates NLRP3 and thereby protects it from degradation, allowing robust inflammasome activity (summarized in Fig.S6).

SIGNOR-277056

P08754

Q9UNW8

2

binding

up-regulates activity

0.2

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

SIGNOR-257074

O00571

P06493

0

phosphorylation

down-regulates

0.297

Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis.

SIGNOR-141569

P07900

O94826

2

binding

up-regulates activity

0.2

The Tom70 receptor is a membrane-localized cochaperone that integrates the Hsp70/Hsp90 chaperones with mitochondrial preprotein targeting and translocation. In mammals, preprotein in the cytosol is associated with both Hsp90 and Hsp70 in a multichaperone complex, and docking of Hsp90 and/or Hsp70 onto Tom70 is essential for preprotein targeting.

SIGNOR-261379

Q93034

P10523

2

binding

up-regulates quantity by stabilization

0.412

Here we report that NEDD4-1, a HECT domain-containing E3 ubiquitin ligase, binds via its HECT domain directly with SAG's C-terminal RING domain and ubiquitylates SAG for proteasome-mediated. We also found that SAG bridges NEDD4-1 via its C-terminus and CUL-5 via its N-terminus to form a NEDD4-1/SAG/CUL-5 tri-complex. Biologically, NEDD4-1 overexpression sensitizes cancer cells to etoposide-induced apoptosis by reducing SAG levels through targeted degradation. Thus, SAG is added to a growing list of NEDD4-1 substrates and mediates its biological function. degradation.

SIGNOR-272844

O60341

Q99814

0

transcriptional regulation

down-regulates quantity by repression

0.28

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-271588

Q13291

Q86YJ5

0

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-271537

P19086

Q13639

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-257309

P63096

P21554

2

binding

up-regulates activity

0.541

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-256724

O15111

O43524

1

phosphorylation

down-regulates

0.572

Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation.

SIGNOR-124203

P67775

P27707

1

dephosphorylation

down-regulates activity

0.2

Protein phosphatase 2A regulates deoxycytidine kinase activity via Ser-74 dephosphorylation|Deoxycytidine kinase (dCK) is a critical enzyme for activation of anticancer nucleoside analogs. Its activity is controlled via Ser-74 phosphorylation. Here, we investigated which Ser/Thr phosphatase dephosphorylates Ser-74. In cells, the PP1/PP2A inhibitor okadaic acid increased both dCK activity and Ser-74 phosphorylation

SIGNOR-275803

Q15208

2

phosphorylation

up-regulates

0.2

We found that ndr1 autophosphorylates in vitro predominantly on ser-281 and to a lesser extent on thr-74 and thr-444. All of these residues proved to be crucial also for ndr1 activity in vivo

SIGNOR-96687

P10451

Q13950

0

transcriptional regulation

up-regulates quantity

0.488

Ets-1 and Runx2 are critical transcriptional regulators of OPN expression in CT26 colorectal cancer cells. Suppression of these transcription factors results in significant down-regulation of the OPN metastasis protein.

SIGNOR-245336

Q6ZVD8

P31749

1

dephosphorylation

down-regulates

0.773

Here, we identify a protein phosphatase, ph domain leucine-rich repeat protein phosphatase (phlpp), that specifically dephosphorylates the hydrophobic motif of akt (ser473 in akt1), triggering apoptosis and suppressing tumor growth.[...] These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt.

SIGNOR-252602

Q96EB6

P15172

1

null

down-regulates activity

0.621

Sir2 forms a complex with the acetyltransferase PCAF and MyoD and, when overexpressed, retards muscle differentiation

SIGNOR-241963

P43403

Q6ISU1

2

binding

up-regulates activity

0.285

Stimulation of the T-cell antigen receptor (TCR) leads to tyrosine phosphorylation of a number of cellular proteins, including phospholipase C (PLC) gamma 1 and the TCR zeta chain. We describe here a 70-kDa tyrosine phosphoprotein (ZAP-70) that associates with zeta within 15 sec following TCR stimulation. The phosphorylation of ZAP-70 and its association with zeta is independent of the other TCR chains

SIGNOR-134325

Q15831

Q9H093

1

phosphorylation

up-regulates

0.273

A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold.

SIGNOR-122717

O15123

Q03112

0

transcriptional regulation

up-regulates quantity by expression

0.2

We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2

SIGNOR-266060

P50148

P21731

2

binding

up-regulates activity

0.654

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-256887

O00192

P22223

2

binding

up-regulates quantity by stabilization

0.327

To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member.

SIGNOR-252127

Q96CG3

O14965

0

phosphorylation

up-regulates activity

0.2

Here, we report that Aurora A is essential for Thr9 phosphorylation of the TRAF-interacting protein TIFA, triggering activation of the NF-κB survival pathway in AML.

SIGNOR-273551

P60484

Q13224

1

dephosphorylation

down-regulates activity

0.296

GluN2B Y1472 site is dephosphorylated by PTEN .

SIGNOR-277165

O14757

P30307

1

phosphorylation

down-regulates quantity by destabilization

0.85

The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216).

SIGNOR-163158

P49792

Q92973

2

binding

up-regulates activity

0.455

Nup358(806–1306), but not other regions, efficiently recruits importin β and transportin 1

SIGNOR-262111

Q06830

P11802

0

phosphorylation

down-regulates

0.226

Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%.Prx i was also phosphorylated, with an efficiency similar to that observed with cdc2, when incubated in vitro with cdk2, cdk4, or cdk6 that had been immunoprecipitated from hela cell lysates with specific antibodies (data not shown).

SIGNOR-87105

Q13485

O75925

0

sumoylation

up-regulates

0.394

These data demonstrate that pias1 protein positively modulates tgf-beta responses as a sumo e3 ligase for smad4

SIGNOR-123462

O60516

P42345

0

phosphorylation

up-regulates

0.358

While promoting initiation of protein translation through mtor, eukaryoticinitiation factor 4e, and the ribosomal p70-s6 kinase.

SIGNOR-122035

O75531

P60510

0

dephosphorylation

up-regulates

0.2

Herein, we demonstrate we demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. We have identified the major phosphatase responsible for dephosphorylation of ser-4 to be protein phosphatase 4 catalytic subunit.

SIGNOR-203281

P51608

Q7Z2K8

1

post transcriptional regulation

up-regulates quantity by expression

0.298

MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1.

SIGNOR-264679

O95600

P68871

1

transcriptional regulation

down-regulates quantity by repression

0.2

These results establish KLF8 as a CACCC-box binding protein that associates with CtBP and represses transcription.

SIGNOR-266052

P46531

O75056

2

binding

up-regulates activity

0.379

Furthermore, we show that Syndecan-3 interacts with Notch and is required for Notch processing by ADAM17/tumor necrosis factor-converting enzyme (TACE) and signal transduction. Together, our data support the conclusion that Syndecan-3 and Notch cooperate in regulating homeostasis of the satellite cell population and myofiber size.

SIGNOR-244072

P06493

P60510

0

dephosphorylation

down-regulates activity

0.397

PP4c efficiently dephosphorylates Cdk1 sites of NDEL1 but does not dephosphorylate the Aurora A site.|We also found that PP4c negatively regulates Cdk1 activity in interphase.

SIGNOR-277162

P35813

Q9UHD2

1

dephosphorylation

down-regulates activity

0.41

Furthermore, PPM1A, but not PPM1B, serves as an efficient phosphatase to dephosphorylate Ser 172 residue of both TBK1 and IKKepsilon kinases, which is critical for their kinase activities.|In a similar in vitro phosphatase assay, incubation of PPM1A also eliminated TBK1 and IKKepsilon phosphorylation at Ser 172 residue, evidenced by phospho-S172 immunoblotting (XREF_FIG, F and G).|These observations suggest that PPM1A may block kinase activities of TBK1 and IKKepsilon.

SIGNOR-276966

P03372

P06850

1

transcriptional regulation

up-regulates quantity by expression

0.34

Evidence of direct estrogenic regulation of human corticotropin-releasing hormone gene expression. Potential implications for the sexual dimophism of the stress response and immune/inflammatory reaction.|Gel retardation and immunoprecipitation demonstrated specific association between the perfect half-palindromic EREs of hCRH gene and the DNA binding domain of hER in vitro.

SIGNOR-268721

P06213

Q05209

0

dephosphorylation

down-regulates

0.378

Interestingly, all PTPs that were tested could completely dephosphorylate the receptor, given sufficient time, including a negative control (PTP-PEST) that failed to bind IRK as a trapping mutant.

SIGNOR-75894

P21580

Q9Y4K3

1

deubiquitination

down-regulates activity

0.702

A20 is a deubiquitinating enzyme (dub) for lys63-linked polyubiquitinated signaling mediators such as traf6

SIGNOR-160223

O75116

Q16555

1

phosphorylation

up-regulates

0.383

Rho-kinase phosphorylated crmp-2 at thr-555 in vitro.we demonstrated that crmp-2 is phosphorylated by rho-kinase in drg neurons during lpa-induced growth cone collapse.

SIGNOR-77543

Q9NRM7

P61981

1

phosphorylation

up-regulates

0.331

Phosphorylation of 14-3-3_ on s59 by lats2. Ser(58) phosphorylation and lys(49) acetylation of 14-3-3_ occur in a coordinated time-dependent manner to regulate 14-3-3_ homodimerization. 14-3-3_ ser(58) phosphorylation is required for star interactions under control conditions,

SIGNOR-205247

P00533

P42566

2

phosphorylation

up-regulates

0.755

Earlier studies have shown that eps15 at tyr-849 is phosphorylated in egf-stimulated cells and partly controls the internalization of mono-ubiquitinated egfr via uim domains of eps15 [10]. It has also been shown that active egfr phosphorylates tyr-849 directly;

SIGNOR-203311

P31146

Q00535

0

phosphorylation

up-regulates activity

0.288

We here show that phosphorylation of coronin 1 on Thr(418/424) by cyclin-dependent kinase (CDK) 5 activity was responsible for coronin 1-G_s association and the modulation of cAMP production. Together these results show an essential role for CDK5 activity in promoting the coronin 1-dependent cAMP/PKA pathway.

SIGNOR-245187

P24941

Q99741

1

phosphorylation

down-regulates activity

0.942

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

SIGNOR-67544

P63000

Q38SD2

0

phosphorylation

up-regulates activity

0.292

In vitro kinase assays confirmed that recombinant Lrrk1 phosphorylated RAC1-GST protein, and immunoprecipitation showed that the interaction of Lrrk1 with RAC1 occurred within 10 min after RANKL treatment.|Lrrk1 phosphorylates and activates RAC1 and Cdc42 small GTPase proteins in osteoclasts.

SIGNOR-279626

P62993

Q13191

2

binding

up-regulates activity

0.567

Here we show that in unstimulated Jurkat cells Cbl is co-immunoprecipitated with monoclonal antibody against Grb2.

SIGNOR-236051

Q13309

P38936

1

ubiquitination

down-regulates

0.772

Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase.

SIGNOR-138490

P55196

Q13671

2

binding

up-regulates activity

0.2

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

SIGNOR-220926

P16473

P01222

2

binding

up-regulates

0.722

Two novel human glycoprotein hormonelike genes, alpha2 (a2) and beta5 (b5), recently have been identified. Using a yeast two-hybrid assay, the two subunits were found as potential heterodimerization partners.

SIGNOR-88653

O75533

P24941

0

phosphorylation

up-regulates

0.346

To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptide). Three phosphorylation sites were identified as thr244, thr248, and thr313

SIGNOR-90434

P53350

Q8NHV4

1

phosphorylation

up-regulates activity

0.619

Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation.

SIGNOR-272992

Q16620

Q06124

0

dephosphorylation

down-regulates activity

0.707

Conversely, PTPN11 knockdown lead to increased Y 515 phosphorylation of TrkB compared to the scramble control in the neuronal cells.|This study established that TrkB activation as demonstrated by receptor phosphorylation at Tyr 515 in the SH-SY5Y cells is negatively regulated by PTPN11 actions.

SIGNOR-277123

Q9HC98

O14757

0

phosphorylation

down-regulates activity

0.237

Nek6 is also directly phosphorylated by the checkpoint kinases Chk1 and Chk2 in vitro .

SIGNOR-279403

P51812

P11362

1

phosphorylation

down-regulates quantity

0.357

Both in vitro and in vivo experiments confirmed the interaction and we show that phosphorylated RSK2 binds to and phosphorylates serine 789 in the C-terminal tail of FGFR1.prevention of FGFR1 phosphorylation by inhibition of RSK2 activity or mutation of serine 789 to alanine reduced FGFR1 endocytosis and ubiquitination explaining mechanistically the prolonged signaling activity.

SIGNOR-276599

P48740

P0C0L4

1

cleavage

up-regulates activity

0.606

The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots.

SIGNOR-263438

P15407

P05412

0

transcriptional regulation

up-regulates quantity by expression

0.826

Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription.

SIGNOR-261604

Q9NXA8

Q15067

1

catalytic activity

down-regulates activity

0.26

SIRT5‐mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation.

SIGNOR-261210

Q13464

P19105

1

phosphorylation

up-regulates activity

0.561

Phosphorylation of myosin II regulatory light chain (MRLC) is important for cell motility and cytokinesis in nonmuscle cells. Although the regulation of monophosphorylated MRLC at serine 19 throughout the cell cycle was examined in detail, MRLC diphosphorylation at both threonine 18 and serine 19 is still unclear. Here we found that Rho-kinase has an activity for MRLC diphosphorylation in nonmuscle cells using sequential column chromatographies.

SIGNOR-263074

P27361

P17480

1

phosphorylation

down-regulates

0.579

Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna

SIGNOR-112817

P47712

Q8IW41

0

phosphorylation

up-regulates activity

0.334

The p38-activated protein kinases MNK1, MSK1, and PRAK1 phosphorylate cPLA2 in vitro uniquely on Ser-727. By using Chinese hamster ovary, HeLa, and HEK293 cells stably transfected with wild type and phosphorylation site mutant forms of cPLA2, we show that phosphorylation of cPLA2 at both Ser-505 and Ser-727 and elevation of Ca(2+) leads to its activation in agonist-stimulated cells.

SIGNOR-250162

P31749

P35226

1

phosphorylation

up-regulates activity

0.437

The polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate

SIGNOR-252559

P24864

Q96PU4

0

ubiquitination

down-regulates quantity by destabilization

0.332

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

SIGNOR-271886

Q5S007

Q14155

2

phosphorylation

up-regulates

0.456

Arhgef7 is interacting with lrrk2 in vitro and in vivo. Lrrk2 phosphorylates arhgef7 in vitro.Two Threonine residues, t107 and t143, within the arhgef7 n-terminus were identified with high confidence

SIGNOR-169221

Q9ULU4

P15692

1

transcriptional regulation

down-regulates quantity by repression

0.2

Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported

SIGNOR-262041

P23219

Q86UZ6

0

transcriptional regulation

up-regulates quantity by expression

0.2

ZBTB46 acts as a transcriptional coactivator that binds to the promoter of prostaglandin-endoperoxide synthase 1 (PTGS1) and transcriptionally regulated PTGS1 levels.

SIGNOR-277991

P46531

P06239

2

binding

up-regulates

0.456

Endogenous notch-1 associates with p56(lck) and pi3k. p56(lck) is required for the notch-1-mediated activation of akt/pkb function

SIGNOR-118902

P04049

Q9C004

2

binding

down-regulates activity

0.433

Here we show that mammalian Sprouty4 suppresses vascular epithelial growth factor (VEGF)-induced, Ras-independent activation of Raf1 but does not affect epidermal growth factor (EGF)-induced, Ras-dependent activation of Raf1. Sprouty4 binds to Raf1 through its carboxy-terminal cysteine-rich domain, and this binding is necessary for the inhibitory activity of Sprouty4.

SIGNOR-253033

Q13315

Q99708

1

phosphorylation

down-regulates

0.828

Atm phosphorylates ctip at serine residues 664 and 745 our study suggests another dna damage-response pathway in which the signal is transmitted through phosphorylation of ctip by atm, leading to dissociation of the ctip_ctbp repressor complex from brca1, which in turn, activate transcription of gadd45

SIGNOR-79872

P63096

Q9UPC5

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-256688

Q16236

O00625

2

transcriptional regulation

up-regulates quantity by expression

0.2

The activation of NFE2L2 is pivotal in protecting cells from ferroptotic death. To achieve this protective function, NFE2L2 regulates a broad spectrum of genes involved in multiple cellular pathways, including those that modulate ROS, detoxify harmful agents, and repair damaged proteins. In human pancreatic cancer cell lines, the expression of PIR is upregulated by NFE2L2 in response to ferroptosis-inducing agents (erastin or RSL3)

SIGNOR-279850

Q05513

Q9NPB6

1

phosphorylation

up-regulates quantity by stabilization

0.841

APKC associates and phosphorylates Par6 on S345. aPKC expression stabilizes Par6 protein levels. We show that the aPKC, PKCι, interacts with TGF-β receptors through Par6 and that these proteins localize to the leading edge of migrating cells. Furthermore, Par6 phosphorylation on serine 345 by TGF-β receptors is enhanced in the presence of aPKC. aPKC kinase activity, as well as an association with Par6, were found to be important for Par6 phosphorylation.

SIGNOR-276433