GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels float64 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
O14965	Q02224	1	phosphorylation	down-regulates activity	0.48	Aurora A also phosphorylates and inhibits the centromere-associated kinesin CENP-E involved in efficient chromosome congression ( xref ; xref ).	SIGNOR-280187
Q96J92	O95747	1	phosphorylation	up-regulates activity	0.48	In addition, WNK4 phosphorylates and activates Ste20-type kinases SPAK and OSR1, which in turn phosphorylate and activate NCC [ xref ; xref ].\|Later studies also indicate that WNK4 phosphorylates and activates Ste20-type kinases SPAK and OSR1, which in turn phosphorylates and activates NCC ; ].	SIGNOR-278389
P06213	P53004	1	phosphorylation	up-regulates activity	0.479	Human BVR (hBVR) also reduces the hemeoxygenase activity product biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK).\|in addition to Y198 in the YMKM motif, 2 other tyrosines, Y228 in the YLSF motif and Y291 in the C-terminus of the protein, are directly phosphorylated by IRK	SIGNOR-275514
O43474	P40424	1	binding	up-regulates activity	0.479	We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4.	SIGNOR-267237
P12931	Q14721	1	phosphorylation	up-regulates	0.479	In the present study we show that an n-terminal tyrosine of kv2.1 (y124), which is a known target of src kinase, is critical for the apoptotic current surge..Kv2.1-mediated k+ currents are also enhanced during non-injurious conditions through direct phosphorylation of intracellular n-terminal residue tyrosine 124 (y124) by src kinase	SIGNOR-187201
Q15139	Q8WYL5	1	phosphorylation	down-regulates	0.479	Pkd-mediated phosphorylation of serines 937 and 978 regulates ssh1l subcellular localization by binding of 14-3-3 proteins 14-3-3 proteins associate with ssh1l when phosphorylated at serines 937 and 978, thereby sequestering ssh1l in the cytoplasm and preventing translocation of the phosphatase to f-actin_rich membrane protrusions	SIGNOR-186471
Q7KZF4	P42226	1	binding	up-regulates activity	0.479	STAT6 interacted with p100 in vitro and in vivo. Here, we show that the TAD of STAT6 is interacting with p100. p100 was found to enhance the STAT6-mediated transcription [.].	SIGNOR-259134
P98171	P63000	1	gtpase-activating protein	down-regulates activity	0.479	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-260460
P06493	Q13950	1	phosphorylation	up-regulates	0.479	In vitro kinase assays using recombinant cdc2 kinase showed that runx2 was phosphorylated at ser(451) the cdc2 inhibitor roscovitine dose dependently inhibited in vivo runx2 dna-binding activity during mitosis and the runx2 mutant s451a exhibited lower dna-binding activity and reduced stimulation of anchorage-independent growth relative to wild type runx2.	SIGNOR-143586
P49841	Q9Y4K3	1	phosphorylation	down-regulates quantity by destabilization	0.479	TRAF6 was phosphorylated at Thr266 by GSK3B in most clinical CRC, which triggered K48-linked polyubiquitination and degradation of TRAF6 and thereby attenuated its inhibitory activity towards the autophagy-dependent CTNNB1 signaling.	SIGNOR-277438
Q7Z5J4	O15516	1	transcriptional regulation	up-regulates quantity by expression	0.479	RAI1 Transcriptionally Activates CLOCK via an Intron 1 Enhancer Element. data suggest that RAI1 binds, directly or in a complex, to the first intron of CLOCK and enhances its transcriptional activity in vitro, supporting RAI1 as a positive regulator of CLOCK and an important part of the circadian loop of transcription. Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others.	SIGNOR-266839
Q13285	P11511	1	transcriptional regulation	up-regulates quantity by expression	0.479	The in vivo existence of an SF-1 corepressor complex consisting of DAX-1, RNF31, and SMRT at the steroidogenic promoters of the human StAR and CYP19 genes. We demonstrate that RNF31 is necessary for the stable association of the DAX-1 corepressor complex with chromatin-bound SF-1, thereby inhibiting the recruitment of coactivators and Pol II and controlling basal transcription levels of SF-1 target genes.	SIGNOR-271787
O43791	Q9Y6Q9	1	binding	down-regulates quantity by destabilization	0.479	Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations.	SIGNOR-272827
P12931	P43403	1	phosphorylation	up-regulates activity	0.479	In the cluster, Zap70 will be rapidly phosphorylated by active Src and slowly phosphorylated by autoinhibited, inactive Src.\|We provide evidence that clusters harbor a positive feedback loop among Zap70, LAT, and Src-family kinases that binds phosphorylated LAT and further activates Zap70.	SIGNOR-279126
P62714	P28482	1	dephosphorylation	down-regulates activity	0.479	Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines\|Protein phosphatase-2A was the only vanadate-insensitive phosphatase acting on Thr 183 of p42mapk or on MAPKK to be detected in PC12 cell extracts.	SIGNOR-248590
Q9Y6X0	Q01105	1	binding	up-regulates	0.479	Setbp1 was shown to form a complex with set and pp2a, enhancing the stability of set and its inhibition of pp2a.	SIGNOR-197324
P27361	Q05682	1	phosphorylation	down-regulates	0.478	The actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759. This phosphorylation leads to markedly diminished actin affinity.	SIGNOR-86741
Q92753	O00327	1	transcriptional regulation	up-regulates quantity by expression	0.478	RORβ and RORγ are also able to induce Bmal1 activity; however, RORα4 appears the most effective in inducing this activity. The ROREs in the Bmal1 promoter also bind ROR receptors. Overexpression of RORα1 and RORα4 induces Bmal1-promoter activity by interacting with these ROREs	SIGNOR-266852
Q5JTC6	O75581	1	binding	up-regulates activity	0.478	Knockdown of Amer1 reduces Wnt-induced LRP6 phosphorylation, Axin translocation to the plasma membrane and formation of LRP6 signalosomesThe generation of PtdIns(4,5)P2 in regions of receptor activity triggers the recruitment of Amer1 proteins, which in turn promote LRP6 phosphorylation by recruiting Axin/GSK3_ and CK1gamma to LRP6.	SIGNOR-24265
P41134	P15172	1	binding	down-regulates activity	0.478	Id1 and Id2 interacted strongly with MyoD and Myf-5.Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-240265
Q15139	Q8WUI4	1	phosphorylation	down-regulates	0.478	We show for the first time that vegf stimulated phosphorylation of hdac7 at the sites of ser178, ser344, and ser479we found that phospholipase cgamma/protein kinase c/protein kinase d1 (pkd1)-dependent signal pathway mediated hdac7 phosphorylation and cytoplasmic accumulation by vegf.	SIGNOR-179430
Q9UNE7	P10275	1	ubiquitination	down-regulates quantity by destabilization	0.478	Via this mechanism, CHIP ubiquitinates and degrades glucocorticoid receptor (GR), androgen receptor (AR), estrogen receptor (ER), ErbB2, and alpha-synuclein, only when bound to Hsp .	SIGNOR-278782
Q15306	O43353	1	binding	down-regulates activity	0.478	These studies demonstrate that inhibition of RICK (RIPK2) polyubiquitination by IRF4 involves polyubiquitination of the kinase domain of RICK and this inhibition is facilitated by binding of IRF4 to the kinase and/or intermediate domains of RICK.	SIGNOR-280454
P17612	P35222	1	phosphorylation	up-regulates activity	0.478	Although pka did not affect the formation of a complex between glycogen synthase kinase 3beta (gsk-3beta), beta-catenin, and axin, phosphorylation of beta-catenin by pka inhibited ubiquitination of beta-catenin in intact cells and in vitro.	SIGNOR-140902
P61073	P08754	1	binding	up-regulates activity	0.478	Using this model, we have reported that CXCL12 activates Gi1, Gi2, or Gi3 heterotrimeric G proteins in a concentration-dependent manner	SIGNOR-278104
P28482	Q15746	1	phosphorylation	up-regulates activity	0.478	Inhibition of ERK2 impaired phosphorylation of MLCK and insulin stimulated glucose uptake.\|These findings suggest that ERK2 activates MLCK which then mediates the phosphorylation of RLC of MyoIIA.	SIGNOR-279226
O94916	P26447	1	transcriptional regulation	up-regulates quantity by expression	0.478	As expected, the depletion of NFAT5 decreased the S100A4 and LCN2 mRNA levels (Figure 3a). In addition, chromatin immunoprecipitation (ChIP) assay using NFAT5 antibody indicated that NFAT5 was bound to the S100A4 and LCN2 promoters (Figure 3b, Supplementary Figure S3), as expected (Chen et al., 2009).	SIGNOR-274115
Q92843	Q07812	1	binding	down-regulates	0.478	Bcl-w may protect largely via its ability to associate with bax because it could efficiently protect xem from tbid and bid, bad, hrk, and bmf bh3 peptides	SIGNOR-154518
Q9NYY3	P37840	1	phosphorylation	down-regulates activity	0.478	Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation. Pathological serine 129 phosphorylation regulates membrane accumulation of mutant alpha-synuclein.	SIGNOR-182155
P22681	P16234	1	ubiquitination	down-regulates quantity by destabilization	0.478	Cbl overexpression in nih3t3 cells enhanced the ubiquitination and degradation of the platelet-derived growth factor receptor-alpha (pdgfralpha)	SIGNOR-68024
P30968	O95837	1	binding	up-regulates activity	0.478	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-257331
Q9H2X6	P51608	1	phosphorylation	up-regulates activity	0.478	Here, we identify the homeodomain-interacting protein kinase 2 (HIPK2) as a kinase that binds MeCP2 and phosphorylates it at Ser 80 in vitro and in vivo.	SIGNOR-264549
P06493	Q92993	1	phosphorylation	up-regulates	0.478	Moreover, app stabilized tip60 through cdk-dependent phosphorylation	SIGNOR-139653
P17612	Q92736	1	phosphorylation	up-regulates activity	0.478	PKA-mediated hyperphosphorylation of a conserved serine, Ser-2843 in skeletal RyR and Ser-2809 in cardiac RyR, results in an aberrant SR function during heart failure. hyperphosphorylated RyRs are leaky and therefore lead to a reduced SR Ca2+ load and impaired contractile function in heart failure	SIGNOR-250079
P26045	P55072	1	dephosphorylation	down-regulates activity	0.478	Identification of VCP as a substrate of PTPH1in vivo.\|The tyrosines (Tyr796 and Tyr805) at the C terminus of VCP have been reported to be the major sites of phosphorylation, with Tyr805 accounting for more than 90% of the tyrosine phosphorylation on the protein \|The Y796F/Y805F VCP mutant was not associated with any of the PTPH1 constructs.	SIGNOR-248460
P56278	P31749	1	binding	up-regulates	0.478	Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation	SIGNOR-81671
Q96Q05	Q99558	1	binding	up-regulates activity	0.478	We demonstrated by immunohistochemistry that NIBP expression in the brain is localized to neurons. NIBP physically interacts with NIK, IKK(beta), but not IKK(alpha) or IKK(gamma). NIBP overexpression potentiates tumor necrosis factor-alpha-induced NF-kappaB activation through increased phosphorylation of the IKK complex and its downstream I(kappa)B(alpha) and p65 substrates.	SIGNOR-269672
P00519	Q99638	1	phosphorylation	up-regulates activity	0.477	The SH3 domain of c-Abl interacts directly with the C-terminal region of Rad9. c-Abl phosphorylates the Rad9 Bcl-2 homology 3 domain (Tyr-28) in vitro and in cells exposed to DNA-damaging agents. \| c-Abl-mediated phosphorylation of Rad9 induces binding of Rad9 to Bcl-xL \|these findings indicate that Rad9 is regulated by a c-Abl-dependent mechanism in the apoptotic response to genotoxic stress.	SIGNOR-260843
P25101	P63092	1	binding	up-regulates activity	0.477	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-256780
P24941	P03372	1	phosphorylation	up-regulates	0.477	The pi3k/akt pathway is necessary to activate cdk2, which phosphorylates eralphaser294, and mediates the binding between pin1 and eralpha	SIGNOR-200867
P29317	O14493	1	phosphorylation	down-regulates activity	0.477	EphA2 associates with claudin-4 via their extracellular domains. This association, in turn, leads to phosphorylation of the cytoplasmic carboxyl terminus of claudin-4 at Tyr-208. The tyrosine phosphorylation of claudin-4 attenuates association of claudin-4 with ZO-1, decreasing integration of claudin-4 into sites of cell-cell contact and enhancing paracellular permeability. These results indicate that EphA2 moderates the function of tight junctions via phosphorylation of claudin-4.	SIGNOR-262859
P50458	P28360	2	binding	down-regulates activity	0.477	Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity	SIGNOR-241327
P59768	P42336	1	binding	up-regulates	0.477	Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt.	SIGNOR-145122
Q8WU17	O15503	1	ubiquitination	down-regulates quantity	0.477	TRC8/RNF139 encodes an endoplasmic reticulum-resident E3 ubiquitin ligase that inhibits growth in a RING- and ubiquitylation-dependent manner. TRC8 also contains a predicted sterol-sensing domain. Here, we report that TRC8 protein levels are sterol responsive and that it binds and stimulates ubiquitylation of the endoplasmic reticulum anchor protein INSIG. Thus, we conclude that INSIG-1 and 2 physically interact with TRC8, and that TRC8 enhances ubiquitylation of INSIG-1 in a RING-dependent manner	SIGNOR-271955
Q8WU17	Q12772	1	ubiquitination	down-regulates quantity	0.477	Induction of TRC8 destabilized the precursor forms of the transcription factors SREBP-1 and SREBP-2. TRC8 destablizes SREBP precursors in a RING and proteasome-dependent manner	SIGNOR-271958
O95372	P17677	1	deacetylation	down-regulates quantity by destabilization	0.477	Acyl-protein thioesterase 2 catalyzes the deacylation of peripheral membrane-associated GAP-43. In this work, we investigated the deacylation of growth-associated protein-43 (GAP-43), a dually acylated protein at cysteine residues 3 and 4. Thus, the results demonstrate that APT-2 is the protein thioesterase involved in the acylation/deacylation cycle operating in GAP-43 subcellular distribution.we demonstrated that the reduction in the protein level was abrogated when cells were also treated with proteasome inhibitors (chloroquine, MG132 and lactacystin) which strongly suggest that GAP-43 deacylation is an early and necessary step for its later ubiquitination and degradation by the proteasome. In addition, it also suggests that acyl-protein thioesterase levels not only regulate palmitate turnover but also global protein turnover of GAP-43.	SIGNOR-266768
Q6ZMU5	P35568	1	ubiquitination	down-regulates quantity by destabilization	0.477	Here, we demonstrate that MG53 induces IRS-1 ubiquitination with the help of the E2 enzyme UBE2H during skeletal myogenesis by examining MG53 disrupted skeletal muscle cells and tissues.\|The IRS-1 protein level was decreased by MG53 in a concentration dependent manner and was restored by the addition of MG132, a proteasome inhibitor (XREF_FIG; XREF_SUPPLEMENTARY).	SIGNOR-278520
P28360	P50458	2	binding	down-regulates activity	0.477	Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity	SIGNOR-241330
O00255	P31269	1	methylation	up-regulates quantity by expression	0.477	Men1 excision causes reduction of Hoxa9 expression, colony formation by hematopoietic progenitors, and the peripheral white blood cell count. Menin directly activates Hoxa9 expression, at least in part, by binding to the Hoxa9 locus, facilitating methylation of H3K4, and recruiting the methylated H3K4 binding protein chd1 to the locus.	SIGNOR-255894
O60882	P16112	1	cleavage	down-regulates quantity by destabilization	0.477	Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)\|It has been suggested that MMPs play a role in the hydrolysis of COMP and, therefore, compromise the integrity of the cartilage ECM structure leading to the ultimate loss of joint function	SIGNOR-266981
P11678	P12724	1	post translational modification	up-regulates activity	0.477	Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism.	SIGNOR-261705
P42345	P19484	1	phosphorylation	down-regulates activity	0.477	Our data points to the lysosome as the site where mTORC1-dependent phosphorylation of TFEB occurs. [...]Our study has revealed a specific role for phosphorylation of TFEB S211 in the negative regulation of the nuclear abundance of TFEB. This occurs through the promotion of 14-3-3 binding and the masking of the nearby NLS on TFEB.	SIGNOR-248270
P49137	Q6JBY9	1	phosphorylation	down-regulates activity	0.477	Human CapZIP was phosphorylated at Ser-179 and Ser-244 by MAPKAP-K2 (mitogen-activated protein kinase-activated protein kinase 2) or MAPKAP-K3 in vitro. In the present paper we have identified CapZIP as a protein that is phosphorylated exceptionally rapidly by several SAPKs in vitro (Figure 4), and which is expressed in muscles and immune cells. Both MAPKAP-K2 and MAPKAP-K3 phosphorylated CapZIP at Ser-179 in vitro. An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.	SIGNOR-263080
Q13535	Q01831	1	binding	up-regulates	0.477	Atrand atm physically interacted with xpc and promptly localized to the uv damage sites.	SIGNOR-201112
Q9UHC6	Q12860	1	relocalization	up-regulates activity	0.477	These results suggest that the targeting of contactin to different axonal domains may be determined, in part, via its association with Caspr.	SIGNOR-269074
P12931	O15162	1	phosphorylation	up-regulates activity	0.476	Plscr1 is phosphorylated by c-src, within the tandem repeat sequence 68vynqpvynqp77.\|The EGF-mediated Interaction between PLSCR1 and Shc Requires Phosphorylation of Tyr69 and Tyr74 in PLSCR1	SIGNOR-103773
P11678	P10153	1	post translational modification	up-regulates activity	0.476	Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism.	SIGNOR-261704
P24941	Q99626	1	phosphorylation	down-regulates quantity by destabilization	0.476	Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation\|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo.	SIGNOR-250729
P48039	P63096	1	binding	up-regulates activity	0.476	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-256706
P43403	Q16539	2	phosphorylation	up-regulates activity	0.476	Lck, Fyn, and Zap70 activate p38 even in the absence of Tyr182 phosphorylation.p38 is a substrate for Fyn, Lck and Zap70.Thus, T cell Src family kinases and Zap70 activate p38 by phosphorylating Tyr323.	SIGNOR-276030
Q00987	P46531	1	ubiquitination	up-regulates	0.476	Although the interaction between notch1 and mdm2 results in ubiquitination of notch1, this does not result in degradation of notch1, but instead leads to activation of the intracellular domain of notch1.	SIGNOR-200197
P49459	P12004	1	ubiquitination	up-regulates	0.476	Pcna is mono-ubiquitinated through rad6 and rad18, modified by lysine-63-linked multi-ubiquitination--which additionally requires mms2, ubc13 and rad5--and is conjugated to sumo by ubc9. The first of these is monoubiquitination of lysine 164 on one or more of the pcna subunits by the e2-e3 complex of rad6-rad18.	SIGNOR-92737
O95198	Q9BYP7	1	binding	down-regulates quantity by destabilization	0.476	We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body.	SIGNOR-272121
P29350	P04629	1	dephosphorylation	down-regulates activity	0.476	Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675.	SIGNOR-248468
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
P49841	Q9UBK2	1	phosphorylation	down-regulates quantity	0.476	GSK3\u03b2 is an important serine/threonine kinase to regulate PPAR\u03b3 coactivator-1\u03b1 degradation. , GSK3\u03b2 reduces PPAR\u03b3 coactivator-1\u03b1 levels by phosphorylating PPAR\u03b3 coactivator-1\u03b1 and subsequently stimulating PPAR\u03b3 coactivator-1\u03b1 degradation by the ubiquitin-proteasomal system.\|Within them, GSK3beta, which can phosphorylate PGC-1alpha and promote its ubiquitin mediated degradation , , was upregulated significantly in mnd2 mouse brain and spinal cord compared with that in wide-type mice (XREF_FIG).	SIGNOR-279723
Q9NRI5	P43034	1	binding	up-regulates activity	0.476	Disrupted-In-Schizophrenia 1 (DISC1) is a candidate gene for susceptibility to schizophrenia. DISC1 is reported to interact with NudE-like (NUDEL), which forms a complex with lissencephaly-1 (LIS1) and 14-3-3ε. 14-3-3ε is involved in the proper localization of NUDEL and LIS1 in axons. the association with NUDEL and LIS1 supports the notion that DISC1 contributes to the neuronal development and morphology	SIGNOR-252163
P78362	Q9UKV3	1	phosphorylation	up-regulates	0.476	Here, we show that srpk2 binds and phosphorylates acinus, an sr protein essential for rna splicing, and redistributes it from the nuclear speckles to the nucleoplasm, resulting in cyclin a1 but not a2 up-regulation. Acinus s422d, an srpk2 phosphorylation mimetic, enhances cyclin a1 transcription, whereas acinus s422a, an unphosphorylatable mutant, blocks the stimulatory effect of srpk2	SIGNOR-179006
Q13882	P31749	1	phosphorylation	up-regulates	0.476	Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6.	SIGNOR-252622
P46934	Q13571	1	ubiquitination	up-regulates activity	0.476	These results suggest that LAPTM5 ubiquitination is mediated by Nedd4.\|Thus, Nedd4 promotes the recruitment of GGA3 to LAPTM5, allowing LAPTM5 translocation from the Golgi to the lysosome with the aid of GGA3.	SIGNOR-278768
P49841	Q14195	1	phosphorylation	up-regulates activity	0.475	Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro	SIGNOR-146011
Q9UHC7	O14746	1	polyubiquitination	down-regulates quantity by destabilization	0.475	MKRN1 functions as an E3 ubiquitin-ligase for hTERT in vitro and in vivo. Furthermore, we have used the yeast two-hybrid method to identify a novel RING finger gene (MKRN1) encoding an E3 ligase that mediates ubiquitination of hTERT. Overexpression of MKRN1 in telomerase-positive cells promotes the degradation of hTERT and decreases telomerase activity and subsequently telomere length.	SIGNOR-271529
P27361	P49137	1	phosphorylation	up-regulates	0.475	Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase	SIGNOR-201687
O95136	P63096	1	binding	up-regulates	0.475	Edg-3 and edg-5 couple not only to gibut also to gqand g13.	SIGNOR-70664
P30872	P08754	1	binding	up-regulates activity	0.475	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-256822
Q9NXK8	Q14012	1	ubiquitination	down-regulates quantity	0.475	Here, we show that a ubiquitin E3 ligase component, F-box protein Fbxl12, mediates CaMKI degradation via a proteasome-directed pathway leading to disruption of cyclin D1/cdk4 complex. Endogenous Fbxl12 and CaMKI interacted as demonstrated after Fbxl12 immuno-precipitation followed by immunoblot analysis with CaMKI antibodies assembly and resultantG1 arrest in lung epithelia. Fbxl12 targets CaMKI for ubiquitination.	SIGNOR-261193
P41145	P63096	1	binding	up-regulates activity	0.475	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-256710
P07948	Q01344	1	phosphorylation	up-regulates activity	0.475	Lyn activate and expand IL-5RA intracellular signaling through FIP1L1-PDGFRA/JAK2/Lyn/Akt network complex, provoking eosinophils proliferation and exaggerated activation manifested as CEL.\|We further delineated that Lyn can induce IL-5RA tyrosine phosphorylation and physically associate with IL-5RA in F/P expressing cells.	SIGNOR-279059
P06239	Q16539	1	phosphorylation	up-regulates activity	0.475	Lck, Fyn, and Zap70 activate p38 even in the absence of Tyr182 phosphorylation.p38 is a substrate for Fyn, Lck and Zap70.Thus, T cell Src family kinases and Zap70 activate p38 by phosphorylating Tyr323.	SIGNOR-276029
Q969V5	P31749	1	ubiquitination	down-regulates quantity by destabilization	0.475	The results of the functional studies suggest that the degradation of Akt by MULAN suppresses cell proliferation and viability.	SIGNOR-252437
Q9UL17	P01579	1	transcriptional regulation	up-regulates quantity by expression	0.475	T-bet Transactivates the IFNγ Gene and Represses the IL-2 Gene in EL4 Cells	SIGNOR-266234
Q8IW41	O43524	1	phosphorylation	up-regulates activity	0.475	Analysis of mutant alleles of FoxO3a showed that MK5 phosphorylated FoxO3a predominantly at S215, but that mutation of four of the identified sites was required to essentially abolish phosphorylation of FoxO3a by MK5 (\u201c4A\u201d) ( Figure\u00a04 C and data not shown).\|MK5 phosphorylates and activates the transcription factor FoxO3a and potentially other FoxO factors.	SIGNOR-279469
O75030	P10415	1	transcriptional regulation	up-regulates quantity by expression	0.475	MITF directly occupies the BCL2 promoter in vivo and this suggest that BCL2 may be a direct transcriptional target of MITF	SIGNOR-249618
Q9H4B4	Q99986	1	phosphorylation	up-regulates	0.474	Vrk1 does not phosphorylate plk3, but plk3 phosphorylates the c-terminal region of vrk1 in ser342. Vrk1 with substitutions in s342 is catalytically active but blocks golgi fragmentation, indicating that its specific phosphorylation is necessary for this process.	SIGNOR-182858
P28482	P20749	1	phosphorylation	up-regulates activity	0.474	Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.	SIGNOR-277361
Q13164	P29590	1	phosphorylation	down-regulates activity	0.474	Big MAP kinase 1 (BMK1) also phosphorylates PML at two sites : S403 and T409.\|Mutational analysis demonstrated that BMK1 drives suppression of PML directly through its phosphorylation.	SIGNOR-279074
P62820	Q96LT7	2	binding	up-regulates activity	0.474	Thus, our data identify C9orf72 as a novel Rab1a effector in the regulation of autophagy and indicate that C9orf72 haploinsufficiency and associated reductions in autophagy might be the underlying cause of C9ALS/FTD-associated p62 pathology.	SIGNOR-261282
Q13315	P37275	1	phosphorylation	up-regulates activity	0.474	Mechanistically, ATM kinase phosphorylates and stabilizes ZEB1 in response to DNA damage, and ZEB1 in turn directly interacts with USP7 and enhances its ability to deubiquitinate and stabilize CHK1, thereby promoting homologous recombination-dependent DNA repair and resistance to radiation.\|Therefore, ATM dependent phosphorylation of ZEB1 at S585 is crucial for IR induced stabilization of ZEB1 but not the interaction between ZEB1 and USP7.	SIGNOR-278329
P43250	Q15722	1	phosphorylation	down-regulates activity	0.474	Thr(308) is a major residue involved in GRK6-mediated desensitization of BLT1 signaling.	SIGNOR-251213
Q8TCY5	P41968	1	binding	down-regulates activity	0.474	We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members.	SIGNOR-252366
P53778	P04637	1	phosphorylation	up-regulates activity	0.474	Furthermore, upon activation by oncogenic ras, p38gamma stimulated the transcriptional activity of p53 by phosphorylating p53 at Ser(33), suggesting that the ability of p38gamma to mediate senescence is at least partly achieved through p53.	SIGNOR-280026
O15111	Q13568	1	phosphorylation	down-regulates activity	0.474	These data indicate that in context of MyD88 signaling pathway IKKalpha suppresses IRF-5 activation.\|These data showed that the IKK\u03b1 phosphorylates IRF-5 and that IKK\u03b1 mediated phosphorylation stimulates formation of IRF-5 dimers.	SIGNOR-278293
Q13233	Q15796	1	phosphorylation	up-regulates activity	0.474	As yet, the apparent discrepancy between these and above data is not clear, but obviously the type of cell under study and the cellular context may play an important role.In endothelial cells, Smad2 activity is stimulated by MEKK1, a component of the Stress Activated Protein Kinase and c-Jun N terminal kinase (SAPK and JNK) pathway.\|Phosphorylation of Smad2 by MEKK1 increased its association with Smad4, its nuclear accumulation and its transcription induction activity .	SIGNOR-279064
Q96M94	Q99708	1	binding	down-regulates quantity by destabilization	0.474	Here, we identify the Cullin3 E3 ligase substrate adaptor Kelch-like protein 15 (KLHL15) as a new interaction partner of CtIP and show that KLHL15 promotes CtIP protein turnover via the ubiquitin-proteasome pathway.	SIGNOR-272410
P06493	Q5FWF5	1	phosphorylation	down-regulates	0.474	We show here that eco1 degradation requires the sequential actions of cdk1 and two additional kinases , cdc7-dbf4 and the gsk-3 homolog mck1.	SIGNOR-200400
P06493	P49792	1	phosphorylation	up-regulates activity	0.474	Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment.	SIGNOR-259118
O14867	O60675	1	binding	up-regulates activity	0.474	Bach1 forms a heterodimer with the small Maf oncoproteins and binds to the Maf-recognition element (MARE) to inhibit target genes	SIGNOR-226409
Q8N100	Q12837	1	transcriptional regulation	up-regulates quantity by expression	0.474	Thus, these data suggest that the expression of Brn3b can be activated directly by Math5 and that it is also subject to positive feedback regulation by Brn3 proteins.	SIGNOR-261567
P41743	Q9H8V3	1	phosphorylation	up-regulates	0.474	Our data support a model in which pkc?-Mediated phosphorylation regulates ect2 binding to the oncogenic pkc?-Par6 complex thereby activating rac1 activity and driving transformed growth and invasion.	SIGNOR-170790
P30968	P50148	1	binding	up-regulates activity	0.474	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-257265

O14965

Q02224

1

phosphorylation

down-regulates activity

0.48

Aurora A also phosphorylates and inhibits the centromere-associated kinesin CENP-E involved in efficient chromosome congression ( xref ; xref ).

SIGNOR-280187

Q96J92

O95747

1

phosphorylation

up-regulates activity

0.48

In addition, WNK4 phosphorylates and activates Ste20-type kinases SPAK and OSR1, which in turn phosphorylate and activate NCC [ xref ; xref ].|Later studies also indicate that WNK4 phosphorylates and activates Ste20-type kinases SPAK and OSR1, which in turn phosphorylates and activates NCC ; ].

SIGNOR-278389

P06213

P53004

1

phosphorylation

up-regulates activity

0.479

Human BVR (hBVR) also reduces the hemeoxygenase activity product biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK).|in addition to Y198 in the YMKM motif, 2 other tyrosines, Y228 in the YLSF motif and Y291 in the C-terminus of the protein, are directly phosphorylated by IRK

SIGNOR-275514

O43474

P40424

1

binding

up-regulates activity

0.479

We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4.

SIGNOR-267237

P12931

Q14721

1

phosphorylation

up-regulates

0.479

In the present study we show that an n-terminal tyrosine of kv2.1 (y124), which is a known target of src kinase, is critical for the apoptotic current surge..Kv2.1-mediated k+ currents are also enhanced during non-injurious conditions through direct phosphorylation of intracellular n-terminal residue tyrosine 124 (y124) by src kinase

SIGNOR-187201

Q15139

Q8WYL5

1

phosphorylation

down-regulates

0.479

Pkd-mediated phosphorylation of serines 937 and 978 regulates ssh1l subcellular localization by binding of 14-3-3 proteins 14-3-3 proteins associate with ssh1l when phosphorylated at serines 937 and 978, thereby sequestering ssh1l in the cytoplasm and preventing translocation of the phosphatase to f-actin_rich membrane protrusions

SIGNOR-186471

Q7KZF4

P42226

1

binding

up-regulates activity

0.479

STAT6 interacted with p100 in vitro and in vivo. Here, we show that the TAD of STAT6 is interacting with p100. p100 was found to enhance the STAT6-mediated transcription [.].

SIGNOR-259134

P98171

P63000

1

gtpase-activating protein

down-regulates activity

0.479

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-260460

P06493

Q13950

1

phosphorylation

up-regulates

0.479

In vitro kinase assays using recombinant cdc2 kinase showed that runx2 was phosphorylated at ser(451) the cdc2 inhibitor roscovitine dose dependently inhibited in vivo runx2 dna-binding activity during mitosis and the runx2 mutant s451a exhibited lower dna-binding activity and reduced stimulation of anchorage-independent growth relative to wild type runx2.

SIGNOR-143586

P49841

Q9Y4K3

1

phosphorylation

down-regulates quantity by destabilization

0.479

TRAF6 was phosphorylated at Thr266 by GSK3B in most clinical CRC, which triggered K48-linked polyubiquitination and degradation of TRAF6 and thereby attenuated its inhibitory activity towards the autophagy-dependent CTNNB1 signaling.

SIGNOR-277438

Q7Z5J4

O15516

1

transcriptional regulation

up-regulates quantity by expression

0.479

RAI1 Transcriptionally Activates CLOCK via an Intron 1 Enhancer Element. data suggest that RAI1 binds, directly or in a complex, to the first intron of CLOCK and enhances its transcriptional activity in vitro, supporting RAI1 as a positive regulator of CLOCK and an important part of the circadian loop of transcription. Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others.

SIGNOR-266839

Q13285

P11511

1

transcriptional regulation

up-regulates quantity by expression

0.479

The in vivo existence of an SF-1 corepressor complex consisting of DAX-1, RNF31, and SMRT at the steroidogenic promoters of the human StAR and CYP19 genes. We demonstrate that RNF31 is necessary for the stable association of the DAX-1 corepressor complex with chromatin-bound SF-1, thereby inhibiting the recruitment of coactivators and Pol II and controlling basal transcription levels of SF-1 target genes.

SIGNOR-271787

O43791

Q9Y6Q9

1

binding

down-regulates quantity by destabilization

0.479

Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations.

SIGNOR-272827

P12931

P43403

1

phosphorylation

up-regulates activity

0.479

In the cluster, Zap70 will be rapidly phosphorylated by active Src and slowly phosphorylated by autoinhibited, inactive Src.|We provide evidence that clusters harbor a positive feedback loop among Zap70, LAT, and Src-family kinases that binds phosphorylated LAT and further activates Zap70.

SIGNOR-279126

P62714

P28482

1

dephosphorylation

down-regulates activity

0.479

Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines|Protein phosphatase-2A was the only vanadate-insensitive phosphatase acting on Thr 183 of p42mapk or on MAPKK to be detected in PC12 cell extracts.

SIGNOR-248590

Q9Y6X0

Q01105

1

binding

up-regulates

0.479

Setbp1 was shown to form a complex with set and pp2a, enhancing the stability of set and its inhibition of pp2a.

SIGNOR-197324

P27361

Q05682

1

phosphorylation

down-regulates

0.478

The actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759. This phosphorylation leads to markedly diminished actin affinity.

SIGNOR-86741

Q92753

O00327

1

transcriptional regulation

up-regulates quantity by expression

0.478

RORβ and RORγ are also able to induce Bmal1 activity; however, RORα4 appears the most effective in inducing this activity. The ROREs in the Bmal1 promoter also bind ROR receptors. Overexpression of RORα1 and RORα4 induces Bmal1-promoter activity by interacting with these ROREs

SIGNOR-266852

Q5JTC6

O75581

1

binding

up-regulates activity

0.478

Knockdown of Amer1 reduces Wnt-induced LRP6 phosphorylation, Axin translocation to the plasma membrane and formation of LRP6 signalosomesThe generation of PtdIns(4,5)P2 in regions of receptor activity triggers the recruitment of Amer1 proteins, which in turn promote LRP6 phosphorylation by recruiting Axin/GSK3_ and CK1gamma to LRP6.

SIGNOR-24265

P41134

P15172

1

binding

down-regulates activity

0.478

Id1 and Id2 interacted strongly with MyoD and Myf-5.Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.

SIGNOR-240265

Q15139

Q8WUI4

1

phosphorylation

down-regulates

0.478

We show for the first time that vegf stimulated phosphorylation of hdac7 at the sites of ser178, ser344, and ser479we found that phospholipase cgamma/protein kinase c/protein kinase d1 (pkd1)-dependent signal pathway mediated hdac7 phosphorylation and cytoplasmic accumulation by vegf.

SIGNOR-179430

Q9UNE7

P10275

1

ubiquitination

down-regulates quantity by destabilization

0.478

Via this mechanism, CHIP ubiquitinates and degrades glucocorticoid receptor (GR), androgen receptor (AR), estrogen receptor (ER), ErbB2, and alpha-synuclein, only when bound to Hsp .

SIGNOR-278782

Q15306

O43353

1

binding

down-regulates activity

0.478

These studies demonstrate that inhibition of RICK (RIPK2) polyubiquitination by IRF4 involves polyubiquitination of the kinase domain of RICK and this inhibition is facilitated by binding of IRF4 to the kinase and/or intermediate domains of RICK.

SIGNOR-280454

P17612

P35222

1

phosphorylation

up-regulates activity

0.478

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

SIGNOR-140902

P61073

P08754

1

binding

up-regulates activity

0.478

Using this model, we have reported that CXCL12 activates Gi1, Gi2, or Gi3 heterotrimeric G proteins in a concentration-dependent manner

SIGNOR-278104

P28482

Q15746

1

phosphorylation

up-regulates activity

0.478

Inhibition of ERK2 impaired phosphorylation of MLCK and insulin stimulated glucose uptake.|These findings suggest that ERK2 activates MLCK which then mediates the phosphorylation of RLC of MyoIIA.

SIGNOR-279226

O94916

P26447

1

transcriptional regulation

up-regulates quantity by expression

0.478

As expected, the depletion of NFAT5 decreased the S100A4 and LCN2 mRNA levels (Figure 3a). In addition, chromatin immunoprecipitation (ChIP) assay using NFAT5 antibody indicated that NFAT5 was bound to the S100A4 and LCN2 promoters (Figure 3b, Supplementary Figure S3), as expected (Chen et al., 2009).

SIGNOR-274115

Q92843

Q07812

1

binding

down-regulates

0.478

Bcl-w may protect largely via its ability to associate with bax because it could efficiently protect xem from tbid and bid, bad, hrk, and bmf bh3 peptides

SIGNOR-154518

Q9NYY3

P37840

1

phosphorylation

down-regulates activity

0.478

Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation. Pathological serine 129 phosphorylation regulates membrane accumulation of mutant alpha-synuclein.

SIGNOR-182155

P22681

P16234

1

ubiquitination

down-regulates quantity by destabilization

0.478

Cbl overexpression in nih3t3 cells enhanced the ubiquitination and degradation of the platelet-derived growth factor receptor-alpha (pdgfralpha)

SIGNOR-68024

P30968

O95837

1

binding

up-regulates activity

0.478

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-257331

Q9H2X6

P51608

1

phosphorylation

up-regulates activity

0.478

Here, we identify the homeodomain-interacting protein kinase 2 (HIPK2) as a kinase that binds MeCP2 and phosphorylates it at Ser 80 in vitro and in vivo.

SIGNOR-264549

P06493

Q92993

1

phosphorylation

up-regulates

0.478

Moreover, app stabilized tip60 through cdk-dependent phosphorylation

SIGNOR-139653

P17612

Q92736

1

phosphorylation

up-regulates activity

0.478

PKA-mediated hyperphosphorylation of a conserved serine, Ser-2843 in skeletal RyR and Ser-2809 in cardiac RyR, results in an aberrant SR function during heart failure. hyperphosphorylated RyRs are leaky and therefore lead to a reduced SR Ca2+ load and impaired contractile function in heart failure

SIGNOR-250079

P26045

P55072

1

dephosphorylation

down-regulates activity

0.478

Identification of VCP as a substrate of PTPH1in vivo.|The tyrosines (Tyr796 and Tyr805) at the C terminus of VCP have been reported to be the major sites of phosphorylation, with Tyr805 accounting for more than 90% of the tyrosine phosphorylation on the protein |The Y796F/Y805F VCP mutant was not associated with any of the PTPH1 constructs.

SIGNOR-248460

P56278

P31749

1

binding

up-regulates

0.478

Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation

SIGNOR-81671

Q96Q05

Q99558

1

binding

up-regulates activity

0.478

We demonstrated by immunohistochemistry that NIBP expression in the brain is localized to neurons. NIBP physically interacts with NIK, IKK(beta), but not IKK(alpha) or IKK(gamma). NIBP overexpression potentiates tumor necrosis factor-alpha-induced NF-kappaB activation through increased phosphorylation of the IKK complex and its downstream I(kappa)B(alpha) and p65 substrates.

SIGNOR-269672

P00519

Q99638

1

phosphorylation

up-regulates activity

0.477

The SH3 domain of c-Abl interacts directly with the C-terminal region of Rad9. c-Abl phosphorylates the Rad9 Bcl-2 homology 3 domain (Tyr-28) in vitro and in cells exposed to DNA-damaging agents. | c-Abl-mediated phosphorylation of Rad9 induces binding of Rad9 to Bcl-xL |these findings indicate that Rad9 is regulated by a c-Abl-dependent mechanism in the apoptotic response to genotoxic stress.

SIGNOR-260843

P25101

P63092

1

binding

up-regulates activity

0.477

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

SIGNOR-256780

P24941

P03372

1

phosphorylation

up-regulates

0.477

The pi3k/akt pathway is necessary to activate cdk2, which phosphorylates eralphaser294, and mediates the binding between pin1 and eralpha

SIGNOR-200867

P29317

O14493

1

phosphorylation

down-regulates activity

0.477

EphA2 associates with claudin-4 via their extracellular domains. This association, in turn, leads to phosphorylation of the cytoplasmic carboxyl terminus of claudin-4 at Tyr-208. The tyrosine phosphorylation of claudin-4 attenuates association of claudin-4 with ZO-1, decreasing integration of claudin-4 into sites of cell-cell contact and enhancing paracellular permeability. These results indicate that EphA2 moderates the function of tight junctions via phosphorylation of claudin-4.

SIGNOR-262859

P50458

P28360

2

binding

down-regulates activity

0.477

Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity

SIGNOR-241327

P59768

P42336

1

binding

up-regulates

0.477

Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt.

SIGNOR-145122

Q8WU17

O15503

1

ubiquitination

down-regulates quantity

0.477

TRC8/RNF139 encodes an endoplasmic reticulum-resident E3 ubiquitin ligase that inhibits growth in a RING- and ubiquitylation-dependent manner. TRC8 also contains a predicted sterol-sensing domain. Here, we report that TRC8 protein levels are sterol responsive and that it binds and stimulates ubiquitylation of the endoplasmic reticulum anchor protein INSIG. Thus, we conclude that INSIG-1 and 2 physically interact with TRC8, and that TRC8 enhances ubiquitylation of INSIG-1 in a RING-dependent manner

SIGNOR-271955

Q8WU17

Q12772

1

ubiquitination

down-regulates quantity

0.477

Induction of TRC8 destabilized the precursor forms of the transcription factors SREBP-1 and SREBP-2. TRC8 destablizes SREBP precursors in a RING and proteasome-dependent manner

SIGNOR-271958

O95372

P17677

1

deacetylation

down-regulates quantity by destabilization

0.477

Acyl-protein thioesterase 2 catalyzes the deacylation of peripheral membrane-associated GAP-43. In this work, we investigated the deacylation of growth-associated protein-43 (GAP-43), a dually acylated protein at cysteine residues 3 and 4. Thus, the results demonstrate that APT-2 is the protein thioesterase involved in the acylation/deacylation cycle operating in GAP-43 subcellular distribution.we demonstrated that the reduction in the protein level was abrogated when cells were also treated with proteasome inhibitors (chloroquine, MG132 and lactacystin) which strongly suggest that GAP-43 deacylation is an early and necessary step for its later ubiquitination and degradation by the proteasome. In addition, it also suggests that acyl-protein thioesterase levels not only regulate palmitate turnover but also global protein turnover of GAP-43.

SIGNOR-266768

Q6ZMU5

P35568

1

ubiquitination

down-regulates quantity by destabilization

0.477

Here, we demonstrate that MG53 induces IRS-1 ubiquitination with the help of the E2 enzyme UBE2H during skeletal myogenesis by examining MG53 disrupted skeletal muscle cells and tissues.|The IRS-1 protein level was decreased by MG53 in a concentration dependent manner and was restored by the addition of MG132, a proteasome inhibitor (XREF_FIG; XREF_SUPPLEMENTARY).

SIGNOR-278520

P28360

P50458

2

binding

down-regulates activity

0.477

Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity

SIGNOR-241330

O00255

P31269

1

methylation

up-regulates quantity by expression

0.477

Men1 excision causes reduction of Hoxa9 expression, colony formation by hematopoietic progenitors, and the peripheral white blood cell count. Menin directly activates Hoxa9 expression, at least in part, by binding to the Hoxa9 locus, facilitating methylation of H3K4, and recruiting the methylated H3K4 binding protein chd1 to the locus.

SIGNOR-255894

O60882

P16112

1

cleavage

down-regulates quantity by destabilization

0.477

Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)|It has been suggested that MMPs play a role in the hydrolysis of COMP and, therefore, compromise the integrity of the cartilage ECM structure leading to the ultimate loss of joint function

SIGNOR-266981

P11678

P12724

1

post translational modification

up-regulates activity

0.477

Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism.

SIGNOR-261705

P42345

P19484

1

phosphorylation

down-regulates activity

0.477

Our data points to the lysosome as the site where mTORC1-dependent phosphorylation of TFEB occurs. [...]Our study has revealed a specific role for phosphorylation of TFEB S211 in the negative regulation of the nuclear abundance of TFEB. This occurs through the promotion of 14-3-3 binding and the masking of the nearby NLS on TFEB.

SIGNOR-248270

P49137

Q6JBY9

1

phosphorylation

down-regulates activity

0.477

Human CapZIP was phosphorylated at Ser-179 and Ser-244 by MAPKAP-K2 (mitogen-activated protein kinase-activated protein kinase 2) or MAPKAP-K3 in vitro. In the present paper we have identified CapZIP as a protein that is phosphorylated exceptionally rapidly by several SAPKs in vitro (Figure 4), and which is expressed in muscles and immune cells. Both MAPKAP-K2 and MAPKAP-K3 phosphorylated CapZIP at Ser-179 in vitro. An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.

SIGNOR-263080

Q13535

Q01831

1

binding

up-regulates

0.477

Atrand atm physically interacted with xpc and promptly localized to the uv damage sites.

SIGNOR-201112

Q9UHC6

Q12860

1

relocalization

up-regulates activity

0.477

These results suggest that the targeting of contactin to different axonal domains may be determined, in part, via its association with Caspr.

SIGNOR-269074

P12931

O15162

1

phosphorylation

up-regulates activity

0.476

Plscr1 is phosphorylated by c-src, within the tandem repeat sequence 68vynqpvynqp77.|The EGF-mediated Interaction between PLSCR1 and Shc Requires Phosphorylation of Tyr69 and Tyr74 in PLSCR1

SIGNOR-103773

P11678

P10153

1

post translational modification

up-regulates activity

0.476

Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism.

SIGNOR-261704

P24941

Q99626

1

phosphorylation

down-regulates quantity by destabilization

0.476

Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo.

SIGNOR-250729

P48039

P63096

1

binding

up-regulates activity

0.476

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-256706

P43403

Q16539

2

phosphorylation

up-regulates activity

0.476

Lck, Fyn, and Zap70 activate p38 even in the absence of Tyr182 phosphorylation.p38 is a substrate for Fyn, Lck and Zap70.Thus, T cell Src family kinases and Zap70 activate p38 by phosphorylating Tyr323.

SIGNOR-276030

Q00987

P46531

1

ubiquitination

up-regulates

0.476

Although the interaction between notch1 and mdm2 results in ubiquitination of notch1, this does not result in degradation of notch1, but instead leads to activation of the intracellular domain of notch1.

SIGNOR-200197

P49459

P12004

1

ubiquitination

up-regulates

0.476

Pcna is mono-ubiquitinated through rad6 and rad18, modified by lysine-63-linked multi-ubiquitination--which additionally requires mms2, ubc13 and rad5--and is conjugated to sumo by ubc9. The first of these is monoubiquitination of lysine 164 on one or more of the pcna subunits by the e2-e3 complex of rad6-rad18.

SIGNOR-92737

O95198

Q9BYP7

1

binding

down-regulates quantity by destabilization

0.476

We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body.

SIGNOR-272121

P29350

P04629

1

dephosphorylation

down-regulates activity

0.476

Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675.

SIGNOR-248468

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

P49841

Q9UBK2

1

phosphorylation

down-regulates quantity

0.476

GSK3\u03b2 is an important serine/threonine kinase to regulate PPAR\u03b3 coactivator-1\u03b1 degradation. , GSK3\u03b2 reduces PPAR\u03b3 coactivator-1\u03b1 levels by phosphorylating PPAR\u03b3 coactivator-1\u03b1 and subsequently stimulating PPAR\u03b3 coactivator-1\u03b1 degradation by the ubiquitin-proteasomal system.|Within them, GSK3beta, which can phosphorylate PGC-1alpha and promote its ubiquitin mediated degradation , , was upregulated significantly in mnd2 mouse brain and spinal cord compared with that in wide-type mice (XREF_FIG).

SIGNOR-279723

Q9NRI5

P43034

1

binding

up-regulates activity

0.476

Disrupted-In-Schizophrenia 1 (DISC1) is a candidate gene for susceptibility to schizophrenia. DISC1 is reported to interact with NudE-like (NUDEL), which forms a complex with lissencephaly-1 (LIS1) and 14-3-3ε. 14-3-3ε is involved in the proper localization of NUDEL and LIS1 in axons. the association with NUDEL and LIS1 supports the notion that DISC1 contributes to the neuronal development and morphology

SIGNOR-252163

P78362

Q9UKV3

1

phosphorylation

up-regulates

0.476

Here, we show that srpk2 binds and phosphorylates acinus, an sr protein essential for rna splicing, and redistributes it from the nuclear speckles to the nucleoplasm, resulting in cyclin a1 but not a2 up-regulation. Acinus s422d, an srpk2 phosphorylation mimetic, enhances cyclin a1 transcription, whereas acinus s422a, an unphosphorylatable mutant, blocks the stimulatory effect of srpk2

SIGNOR-179006

Q13882

P31749

1

phosphorylation

up-regulates

0.476

Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6.

SIGNOR-252622

P46934

Q13571

1

ubiquitination

up-regulates activity

0.476

These results suggest that LAPTM5 ubiquitination is mediated by Nedd4.|Thus, Nedd4 promotes the recruitment of GGA3 to LAPTM5, allowing LAPTM5 translocation from the Golgi to the lysosome with the aid of GGA3.

SIGNOR-278768

P49841

Q14195

1

phosphorylation

up-regulates activity

0.475

Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro

SIGNOR-146011

Q9UHC7

O14746

1

polyubiquitination

down-regulates quantity by destabilization

0.475

MKRN1 functions as an E3 ubiquitin-ligase for hTERT in vitro and in vivo. Furthermore, we have used the yeast two-hybrid method to identify a novel RING finger gene (MKRN1) encoding an E3 ligase that mediates ubiquitination of hTERT. Overexpression of MKRN1 in telomerase-positive cells promotes the degradation of hTERT and decreases telomerase activity and subsequently telomere length.

SIGNOR-271529

P27361

P49137

1

phosphorylation

up-regulates

0.475

Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase

SIGNOR-201687

O95136

P63096

1

binding

up-regulates

0.475

Edg-3 and edg-5 couple not only to gibut also to gqand g13.

SIGNOR-70664

P30872

P08754

1

binding

up-regulates activity

0.475

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-256822

Q9NXK8

Q14012

1

ubiquitination

down-regulates quantity

0.475

Here, we show that a ubiquitin E3 ligase component, F-box protein Fbxl12, mediates CaMKI degradation via a proteasome-directed pathway leading to disruption of cyclin D1/cdk4 complex. Endogenous Fbxl12 and CaMKI interacted as demonstrated after Fbxl12 immuno-precipitation followed by immunoblot analysis with CaMKI antibodies assembly and resultantG1 arrest in lung epithelia. Fbxl12 targets CaMKI for ubiquitination.

SIGNOR-261193

P41145

P63096

1

binding

up-regulates activity

0.475

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-256710

P07948

Q01344

1

phosphorylation

up-regulates activity

0.475

Lyn activate and expand IL-5RA intracellular signaling through FIP1L1-PDGFRA/JAK2/Lyn/Akt network complex, provoking eosinophils proliferation and exaggerated activation manifested as CEL.|We further delineated that Lyn can induce IL-5RA tyrosine phosphorylation and physically associate with IL-5RA in F/P expressing cells.

SIGNOR-279059

P06239

Q16539

1

phosphorylation

up-regulates activity

0.475

Lck, Fyn, and Zap70 activate p38 even in the absence of Tyr182 phosphorylation.p38 is a substrate for Fyn, Lck and Zap70.Thus, T cell Src family kinases and Zap70 activate p38 by phosphorylating Tyr323.

SIGNOR-276029

Q969V5

P31749

1

ubiquitination

down-regulates quantity by destabilization

0.475

The results of the functional studies suggest that the degradation of Akt by MULAN suppresses cell proliferation and viability.

SIGNOR-252437

Q9UL17

P01579

1

transcriptional regulation

up-regulates quantity by expression

0.475

T-bet Transactivates the IFNγ Gene and Represses the IL-2 Gene in EL4 Cells

SIGNOR-266234

Q8IW41

O43524

1

phosphorylation

up-regulates activity

0.475

Analysis of mutant alleles of FoxO3a showed that MK5 phosphorylated FoxO3a predominantly at S215, but that mutation of four of the identified sites was required to essentially abolish phosphorylation of FoxO3a by MK5 (\u201c4A\u201d) ( Figure\u00a04 C and data not shown).|MK5 phosphorylates and activates the transcription factor FoxO3a and potentially other FoxO factors.

SIGNOR-279469

O75030

P10415

1

transcriptional regulation

up-regulates quantity by expression

0.475

MITF directly occupies the BCL2 promoter in vivo and this suggest that BCL2 may be a direct transcriptional target of MITF

SIGNOR-249618

Q9H4B4

Q99986

1

phosphorylation

up-regulates

0.474

Vrk1 does not phosphorylate plk3, but plk3 phosphorylates the c-terminal region of vrk1 in ser342. Vrk1 with substitutions in s342 is catalytically active but blocks golgi fragmentation, indicating that its specific phosphorylation is necessary for this process.

SIGNOR-182858

P28482

P20749

1

phosphorylation

up-regulates activity

0.474

Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.

SIGNOR-277361

Q13164

P29590

1

phosphorylation

down-regulates activity

0.474

Big MAP kinase 1 (BMK1) also phosphorylates PML at two sites : S403 and T409.|Mutational analysis demonstrated that BMK1 drives suppression of PML directly through its phosphorylation.

SIGNOR-279074

P62820

Q96LT7

2

binding

up-regulates activity

0.474

Thus, our data identify C9orf72 as a novel Rab1a effector in the regulation of autophagy and indicate that C9orf72 haploinsufficiency and associated reductions in autophagy might be the underlying cause of C9ALS/FTD-associated p62 pathology.

SIGNOR-261282

Q13315

P37275

1

phosphorylation

up-regulates activity

0.474

Mechanistically, ATM kinase phosphorylates and stabilizes ZEB1 in response to DNA damage, and ZEB1 in turn directly interacts with USP7 and enhances its ability to deubiquitinate and stabilize CHK1, thereby promoting homologous recombination-dependent DNA repair and resistance to radiation.|Therefore, ATM dependent phosphorylation of ZEB1 at S585 is crucial for IR induced stabilization of ZEB1 but not the interaction between ZEB1 and USP7.

SIGNOR-278329

P43250

Q15722

1

phosphorylation

down-regulates activity

0.474

Thr(308) is a major residue involved in GRK6-mediated desensitization of BLT1 signaling.

SIGNOR-251213

Q8TCY5

P41968

1

binding

down-regulates activity

0.474

We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members.

SIGNOR-252366

P53778

P04637

1

phosphorylation

up-regulates activity

0.474

Furthermore, upon activation by oncogenic ras, p38gamma stimulated the transcriptional activity of p53 by phosphorylating p53 at Ser(33), suggesting that the ability of p38gamma to mediate senescence is at least partly achieved through p53.

SIGNOR-280026

O15111

Q13568

1

phosphorylation

down-regulates activity

0.474

These data indicate that in context of MyD88 signaling pathway IKKalpha suppresses IRF-5 activation.|These data showed that the IKK\u03b1 phosphorylates IRF-5 and that IKK\u03b1 mediated phosphorylation stimulates formation of IRF-5 dimers.

SIGNOR-278293

Q13233

Q15796

1

phosphorylation

up-regulates activity

0.474

As yet, the apparent discrepancy between these and above data is not clear, but obviously the type of cell under study and the cellular context may play an important role.In endothelial cells, Smad2 activity is stimulated by MEKK1, a component of the Stress Activated Protein Kinase and c-Jun N terminal kinase (SAPK and JNK) pathway.|Phosphorylation of Smad2 by MEKK1 increased its association with Smad4, its nuclear accumulation and its transcription induction activity .

SIGNOR-279064

Q96M94

Q99708

1

binding

down-regulates quantity by destabilization

0.474

Here, we identify the Cullin3 E3 ligase substrate adaptor Kelch-like protein 15 (KLHL15) as a new interaction partner of CtIP and show that KLHL15 promotes CtIP protein turnover via the ubiquitin-proteasome pathway.

SIGNOR-272410

P06493

Q5FWF5

1

phosphorylation

down-regulates

0.474

We show here that eco1 degradation requires the sequential actions of cdk1 and two additional kinases , cdc7-dbf4 and the gsk-3 homolog mck1.

SIGNOR-200400

P06493

P49792

1

phosphorylation

up-regulates activity

0.474

Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment.

SIGNOR-259118

O14867

O60675

1

binding

up-regulates activity

0.474

Bach1 forms a heterodimer with the small Maf oncoproteins and binds to the Maf-recognition element (MARE) to inhibit target genes

SIGNOR-226409

Q8N100

Q12837

1

transcriptional regulation

up-regulates quantity by expression

0.474

Thus, these data suggest that the expression of Brn3b can be activated directly by Math5 and that it is also subject to positive feedback regulation by Brn3 proteins.

SIGNOR-261567

P41743

Q9H8V3

1

phosphorylation

up-regulates

0.474

Our data support a model in which pkc?-Mediated phosphorylation regulates ect2 binding to the oncogenic pkc?-Par6 complex thereby activating rac1 activity and driving transformed growth and invasion.

SIGNOR-170790

P30968

P50148

1

binding

up-regulates activity

0.474

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-257265