GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
P04908	Q9H3R0	demethylation	down-regulates activity	0.2	As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation	SIGNOR-263862
O95863	Q8NEZ5	ubiquitination	down-regulates quantity by destabilization	0.2	FBXO22 elicits its antimetastatic effects by targeting SNAIL, a master regulator of EMT and breast cancer metastasis, for ubiquitin-mediated proteasomal degradation in a glycogen synthase kinase 3β phosphorylation-dependent manner.	SIGNOR-273446
Q9H0X6	P11474	transcriptional regulation	up-regulates quantity by expression	0.2	Furthermore, RNF208 was induced by 17β-estradiol (E2) treatment in an estrogen receptor alpha (ΕRα)-dependent manner	SIGNOR-269052
P51532	P48730	phosphorylation	down-regulates quantity by destabilization	0.2	We reveal that CK1δ phosphorylates Brg1 at Ser31/Ser35 residues to facilitate the binding of Brg1 to FBW7, leading to ubiquitination-mediated degradation.	SIGNOR-277407
P35575	Q53ET0	transcriptional regulation	up-regulates quantity	0.2	Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB	SIGNOR-256103
P08754	Q99677	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-257170
Q99574	Q86TM6	polyubiquitination	down-regulates quantity by destabilization	0.2	In this study, we demonstrate that two ER-associated E3 ligases, Hrd1 and gp78, are involved in the ubiquitination and degradation of mutant neuroserpin.	SIGNOR-272757
P32314	P51812	phosphorylation	down-regulates quantity by destabilization	0.2	Importantly, we identified RSK2 kinase as the upstream kinase for the FOXN2 phosphodegron. The Ser365 and Ser369 sites in a conserved DSGYAS motif are responsible for the ubiquitination of FOXN2 by β-Trcp.	SIGNOR-273841
O60260	P68036	ubiquitination	up-regulates activity	0.2	Only UbcH5 and Related Class I E2s Support Ubiquitination of S5a—UbcH5 belongs to the Class I family of E2s which contains a catalytic core (UBC domain) without a distinct Ub binding domain (38). To test whether other Class I E2s can also support ubiquitination of S5a, we assayed the ubiquitination of S5a with UbcH7 and the E3s, Nedd4, or Parkin. With either of these E3s, UbcH7 supported ubiquitination of S5a (Fig. 8, A and B). In addition, another Class I E2, Ubc4, a close homolog of UbcH5, supported ubiquitination of S5a by the APC, a multimeric Ring finger E3 responsible for cell cycle progression through mitosis (39) (Fig. 8C). Thus, multiple Class I E2s can support ubiquitination of S5a by various types of E3s (Table 1).	SIGNOR-272734
Q6NUN9	O60260	polyubiquitination	down-regulates quantity by destabilization	0.2	. Parkin ubiquitinates and regulates the ubiquitin proteasomal degradation of PARIS	SIGNOR-272758
Q04206	P11309	phosphorylation	up-regulates	0.2	In this study we show that phosphorylation of rela/p65 at ser276 prevents its degradation by ubiquitin-mediated proteolysis. importantly, we identify pim-1 as a further kinase responsible for the phosphorylation of rela/p65 at ser276.	SIGNOR-189125
Q9H267	P18433	dephosphorylation	down-regulates activity	0.2	Here, we report that VPS33B, a host protein involved in vesicle trafficking, is dephosphorylated by PtpA leading to a block of phagosome maturation by M. tuberculosis.\|These data suggest that M. tuberculosis PtpA inhibits phagosome maturation.To assess the role of VPS33B in phagosome maturation, we attenuated the expression of endogenous VPS33B expression in THP-1 cells using a siRNA based approach.	SIGNOR-277015
P11940	Q13064	ubiquitination	down-regulates activity	0.2	MKRN3-mediated ubiquitination was found to attenuate the binding of PABPs to the poly(A) tails of mRNA\|Altogether, it is thus clear that the ubiquitination of PABPC1 or PABPC4 by MKRN3 negatively regulates the formation of translation initiation complex (TIC), attenuates their binding to poly (A)-tail contained mRNAs, and leads to the shortened poly (A) tail-length of GNRH1 mRNA.	SIGNOR-278764
Q99708	P14618	phosphorylation	up-regulates activity	0.2	Here, we uncover an unexpected mechanism through which pyruvate kinase M2 (PKM2), the highly expressed PK isoform in cancer cells and a master regulator of cancer metabolic reprogramming, integrates with the DDR to directly promote DNA double-strand break (DSB) repair. In response to ionizing radiation and oxidative stress, ATM phosphorylates PKM2 at T328 resulting in its nuclear accumulation.	SIGNOR-277413
Q8NHM5	Q99814	transcriptional regulation	up-regulates quantity by expression	0.2	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-271582
P19544	Q93008	deubiquitination	up-regulates quantity by stabilization	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-275614
P48058	Q9BYB0	binding	up-regulates quantity	0.2	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264604
Q9Y653	P02461	binding	up-regulates activity	0.2	Using the N-terminal fragment of GPR56 (GPR56(N)) as a probe, we have recently demonstrated that collagen III is the ligand of GPR56 in the developing brain. In this report, we discover a new functional domain in GPR56(N), the ligand binding domain.	SIGNOR-253979
O75015	Q05481	transcriptional regulation	down-regulates quantity by repression	0.2	Thus, these results indicate that these cloned ZNF140 and ZNF91 proteins function as repressors for the human Fc gamma RIIB transcription.	SIGNOR-266215
Q99714	O60260	ubiquitination	down-regulates quantity by destabilization	0.2	This study identifies the multifunctional PD-related mitochondrial matrix enzyme 17-β hydroxysteroid dehydrogenase type 10 (HSD17B10) as a new Parkin substrate.	SIGNOR-272823
Q96J84	P06241	phosphorylation	up-regulates activity	0.2	Here we have characterized Neph1, another SD component, as a novel substrate of SFK. Fyn interacts with and phosphorylates the cytoplasmic domain of Neph1 in vitro and in intact cells. Both tyrosine 637 and 638 of Neph1 are crucial for Neph1-Grb2 binding.	SIGNOR-262746
Q99501	P51955	phosphorylation	up-regulates activity	0.2	Nek2A mediates G2/M phosphorylation of GAS2L1. GAS2L1 and its Ser352 phosphorylation are required for proper spindle organization and chromosome segregation.	SIGNOR-273683
O60610	O14757	phosphorylation	down-regulates activity	0.2	Chk1 Phosphorylates Drf1 for beta-Trcp-Dependent Degradation.\|From this we conclude that Chk1 inhibits Drf1, but not the other three limiting factors at the MBT.	SIGNOR-279026
Q9NZQ7	Q9UNE7	destabilization	down-regulates quantity by destabilization	0.2	Deletion of STUB1 resulted in a more profound increase in PD-L1 levels in CMTM6 deficient than in CMTM6 proficient cells, identifying STUB1 as an E3 ligase that causes destabilization of PD-L1 (Fig. 4f,g), either by direct modification of one of the lysines in the PD-L1 cytoplasmic domain or indirectly	SIGNOR-274979
Q9UPS8	Q01196	transcriptional regulation	down-regulates quantity by repression	0.2	In healthy individual, RUNX1/FLI1 complex negatively regulates ANKRD26 gene expression in MKs.	SIGNOR-266069
P30559	O15530	phosphorylation	up-regulates activity	0.2	We found that Ser261 in OXTR was phosphorylated by protein kinase D1 (PKD1).\|In HEK293A cells, the PKD1-mediated phosphorylation of OXTR promoted its binding to Gq protein and, in turn, OXTR-mediated phosphorylation of PKD1, indicating a positive feedback loop.	SIGNOR-268577
P09211	P05771	phosphorylation	up-regulates activity	0.2	Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently	SIGNOR-276023
Q5JPH6	Q2TAL8	transcriptional regulation	up-regulates quantity by expression	0.2	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269402
P49674	Q2M2I3	binding	up-regulates quantity	0.2	We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates.	SIGNOR-273763
Q07812	O15297	dephosphorylation	down-regulates activity	0.2	34 In this study, a novel function of Wip1 was identified, that is, its ability to dephosphorylate directly and thus inactivate apoptotic BAX protein in response to gamma irradiation.\|To ascertain whether Wip1 dephosphorylates BAX, recombinant Wip1 was incubated with previously reported BAX-derived phosphopeptides containing Ser87, Ser163, Thr167, and Ser184 in an in vitro phosphatase assay. xref , xref Peptides containing phospho-Thr180 from p38 MAPK and phospho-Thr31 from UNG2 were used as a positive and negative control, respectively. xref As shown in xref , purified Wip1 did not dephosphorylate the four BAX-derived phosphopeptides.	SIGNOR-276993
Q8NFG4	P0DMV8	binding	up-regulates quantity by stabilization	0.2	These data suggest that inhibition of Hsp70 does not lead to an increase in misfolded FLCN but instead to its degradation.	SIGNOR-256506
P50148	Q99527	binding	up-regulates	0.2	However, grpr preferentially couples to galfaq proteins.	SIGNOR-195320
P19086	Q13153	phosphorylation	up-regulates	0.2	Phosphorylation of either ser(16) by pak1 or ser(27) by pkc decreased the affinity of galpha(z) for gbetagamma;phosphorylation of both residues by pkc caused no further effect. Pak1 thus regulates galpha(z) function by attenuating the inhibitory effects of both gaps and gbetagamma.	SIGNOR-48673
Q01860	P49137	phosphorylation	up-regulates activity	0.2	MK2 mediated OCT4 transcriptional activation is a novel mechanism for activating the MYC oncogene in progressive disease neuroblastoma that provides a therapeutic target.\|OCT4 phosphorylation at the S111 residue by MK2 was upstream of MYC transcriptional activation.	SIGNOR-279542
P16615	P45984	phosphorylation	up-regulates activity	0.2	JNK2 Enhances SERCA2 Function in a CaMKII-Independent Manner..\|We found that JNK2 and SERCA2 proteins are physically associated with each other, and that JNK2 directly elevates the maximal rate of the SERCA2 activity by phosphorylating SERCA2.	SIGNOR-279540
P54756	O00712	transcriptional regulation	up-regulates quantity	0.2	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268902
Q14164	Q9HCE1	binding	up-regulates activity	0.2	MOV10 enhances IRF3 activation and IRF3-mediated gene induction. This indicated that MOV10-mediated antiviral activity is most likely mediated through IKKε and not through TBK1. Involvement of IKKε was further established by examining the physical interaction of MOV10 and IKKε.	SIGNOR-261138
P78352	Q96NR3	binding	up-regulates quantity	0.2	Using Western blotting, we validated our MS approach confirming the binding of Dgl4 (also known as PSD95) and VPS35 to the recombinant Ptchd1 C terminus. Endogenous DLG4 and VPS35 from membrane and soluble mouse brain fractions were recovered specifically on the GST fusion proteins containing the cytoplasmic but not the extracellular, negative control sequences of Ptchd1 (Fig. 5E). Binding of DLG4 was dependent on the PDZ-binding motif in Ptchd1, whereas VPS35 binding was not (Fig. 5E). These results demonstrate a biochemical interaction of Ptchd1 with postsynaptic trafficking proteins in the mouse brain. Together, these data suggest that loss of Ptchd1 results in severe alterations in synaptic function in the dentate gyrus	SIGNOR-266652
P49585	Q02447	transcriptional regulation	up-regulates quantity by expression	0.2	Sp1 and Sp3 function as transcriptional activators of the Ctpct promoter	SIGNOR-266232
Q8N884	Q8WV44	ubiquitination	up-regulates activity	0.2	Our finding that RINCK positively regulates cGAS activation by mediating the monoubiquitination of cGAS uncovers the function of RINCK in cGAS mediated innate immunity.\|Together, these data suggest that RINCK mediates cGAS monoubiquitination.	SIGNOR-278794
Q92769	Q96KB5	phosphorylation	up-regulates activity	0.2	The results of in vitro studies further confirmed the effect of TOPK on HDAC activity by showing that TOPK overexpression significantly up-regulated p-HDAC1 and p-HDAC2, resulting in an increase in the acetylation of histones H3 and H4 in BV2 cells.\|These results indicated that TOPK overexpression resulted in the phosphorylation of HDAC1 and HDAC2, which might inactivate them and promote the acetylation of Histone 3 and Histone 4.	SIGNOR-279087
P08754	Q9UNW8	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
Q96PH1	Q9UQM7	phosphorylation	up-regulates activity	0.2	In vitro phosphorylation assays revealed that CAMKII can directly phosphorylate Nox5 on Thr494 and Ser498 as detected by phosphorylation state-specific antibodies. Mass spectrometry (MS) analysis revealed the phosphorylation of additional, novel sites at Ser475, Ser502, and Ser675. Of these phosphorylation sites, mutation of only Ser475 to alanine prevented CAMKII-induced increases in Nox5 activity. Together, these results suggest that CAMKII can positively regulate Nox5 activity via the phosphorylation of Ser475.	SIGNOR-276329
O43561	Q13043	phosphorylation	up-regulates activity	0.2	MST kinase phosphorylates and activates LATS kinase.	SIGNOR-279661
P38405	O00254	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-256904
Q14980	Q9UHD2	phosphorylation	up-regulates activity	0.2	Our studies now reveal TBK1 as another kinase that phosphorylates NuMA and that is required for its association with dynein and for localization of NuMA to the centrosomes in mitotic cells.	SIGNOR-278432
P45985	Q9H3Y6	phosphorylation	down-regulates activity	0.2	SRMS directly phosphorylates MKK4 and inhibits MKK4-JNK-c-Jun activation upon platinum treatment. Platinum treatment-induced ROS activates SRMS, which inhibits MKK4 kinase activity by directly phosphorylating MKK4 at Y269 and Y307, and consequently attenuates MKK4-JNK activation.	SIGNOR-277902
P31321	O43164	polyubiquitination	down-regulates quantity by destabilization	0.2	Praja2 controls the stability of PKA regulatory subunits. Praja2 ubiquitylates RIIα/β subunits. Subunits	SIGNOR-271857
P42081	Q8TCQ1	ubiquitination	down-regulates quantity by destabilization	0.2	Among nine family members examined, forced expression of MARCH1, -2, and -8 induced a significant reduction of surface CD86 in several cell lines.\|CD86 is ubiquitinated by MARCH1.	SIGNOR-278628
Q8N884	P43405	phosphorylation	up-regulates activity	0.2	Mechanistically, viral infection or foreign DNA transfection triggers recruitment of the spleen tyrosine kinase (SYK) and cGAS to the endosomal vacuolar H+ pump (V-ATPase), where SYK is activated and then phosphorylates human cGASY214/215 (mouse cGasY200/201) to prime its activation.	SIGNOR-277844
O95379	P08754	binding	up-regulates activity	0.2	TNFAIP8: a new effector for Galpha(i) coupling to reduce cell death and induce cell transformation	SIGNOR-256490
Q9NZJ5	Q15382	binding	down-regulates activity	0.2	Rheb GTPase directly binds and activates PERK in vitro	SIGNOR-260873
P19174	P63215	binding	up-regulates	0.2	Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance.	SIGNOR-199141
Q9Y5H1	Q9Y5H9	binding	up-regulates activity	0.2	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265691
O60741	Q13127	transcriptional regulation	down-regulates quantity by repression	0.2	Levels of NRSF and its physical binding to the Hcn1 gene were augmented after SE, resulting in repression of HCN1 expression and HCN1-mediated currents (I(h) ), and reduced I(h) -dependent resonance in hippocampal CA1 pyramidal cell dendrites.	SIGNOR-268970
Q9P0L0	Q92953	relocalization	up-regulates quantity	0.2	Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays.\|As Kv2.1 accumulates on the surface it begins to bind ER VAPs and form the large and stable membrane junctions.	SIGNOR-262124
P35575	P04150	transcriptional regulation	up-regulates quantity	0.2	Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB	SIGNOR-256104
Q9BVV6	Q86YT6	ubiquitination	down-regulates quantity by destabilization	0.2	Conversely, expression of active, but not inactive, Mib1 likewise drastically reduced the levels of centriolar Talpid3 (XREF_FIG).\|Mib1 promotes the poly-ubiquitylation of Talpid3, Cep131, and PCM1.	SIGNOR-278829
O95837	Q9BPV8	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-257027
P69905	P15289	acetylation	up-regulates activity	0.2	ASA acetylates hemoglobin. Purified acetylated hemoglobin had a slightly increased oxygen affinity and decreased heme-heme interaction.	SIGNOR-251773
P55040	P0DP25	binding	up-regulates activity	0.2	Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells.	SIGNOR-266342
P32245	P01189-PRO_0000024969	binding	up-regulates activity	0.2	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268711
Q12809	P29350	dephosphorylation	down-regulates	0.2	Our results show that erg-1 is a shp-1 substrate constituting the first report that an ion current is regulated by shp-1.	SIGNOR-94007
Q9Y5F8	Q9Y5I2	binding	up-regulates activity	0.2	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265711
P10636	O95155	ubiquitination	down-regulates quantity by destabilization	0.2	Ubiquitination and degradation of Tau by UBE4B and STUB1 in mammalian neuroblastoma cells.	SIGNOR-278682
P49411	Q9BXM7	phosphorylation	down-regulates activity	0.2	PINK1 interacts with the autophagy effector TUFm and phosphorylates TUFm at Ser222. These results indicated that p222-hTUFm sequestered more monomer Atg5 and reduced the conjugated Atg5-Atg12 complex to subdue mitophagy.	SIGNOR-266382
Q8N695	P17676	transcriptional regulation	up-regulates quantity by expression	0.2	Luciferase reporter assays of deletion mutants of SLC5A8 promoter demonstrated that a 295-bp region is essential for the basal promoter activity of the SLC5A8 gene. Further analysis indicated that the CCAAT boxes and GC boxes were involved in positive regulation of SLC5A8 promoter. Overexpression of two transcription factors, CCAAT/enhancer binding protein beta (C/EBPbeta) and specific transcription factor 1 (Sp1), upregulated the activities of the human SLC5A8 promoter and protein expression, suggesting that both C/EBPbeta and Sp1 transcription factors might have functions in SLC5A8 transcription.	SIGNOR-254054
O95837	Q96LB1	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-257434
Q96NY9	P68400	phosphorylation	up-regulates activity	0.2	Here, we show that the CK2 kinase phosphorylates MUS81 at Serine 87 in late-G2/mitosis, and upon mild replication stress. Phosphorylated MUS81 interacts with SLX4, and this association promotes the function of the MUS81 complex.	SIGNOR-273626
P13056	P28482	phosphorylation	down-regulates activity	0.2	We also reported that ERK2-phosphorylated TR2 is recruited to PML nuclear bodies (PML NBs) for its subsequent small ubiquitin-like modification (SUMOylation) and function as a potent transcriptional repressor xref , xref .	SIGNOR-278957
Q9NYU1	O60613	binding	up-regulates activity	0.2	The enzymatic activity of UGGT2 is enhanced by complex formation with Sep15	SIGNOR-261373
Q68D86	P51955	phosphorylation	down-regulates activity	0.2	CCDC102B is recruited to the centrosome by C-Nap1 (also known as CEP250) and interacts with the centrosome linker components rootletin and LRRC45. CCDC102B decorates and facilitates the formation of rootletin filaments. Furthermore, CCDC102B is phosphorylated by Nek2A (an isoform encoded by NEK2) and is disassociated from the centrosome at the onset of mitosis.	SIGNOR-275626
O00763	Q8NHY2	ubiquitination	down-regulates quantity by destabilization	0.2	TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1. Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D).	SIGNOR-271599
P16104	P78527	phosphorylation	up-regulates	0.2	Dna-dependentprotein_ kinase_ (dna-pk) that phosphorylate h2ax at dsbs	SIGNOR-192443
P13051	P49841	phosphorylation	down-regulates quantity by destabilization	0.2	Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.\|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation	SIGNOR-264885
P47869	Q8TAB3	binding	up-regulates quantity by stabilization	0.2	Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.	SIGNOR-267218
P36897	Q9UI12	binding	up-regulates activity	0.2	ATP6V1H interacts with TGF-β receptor I and AP-2 complex to regulate the proliferation and differentiation of BMSCs.	SIGNOR-266886
O60716	P17612	phosphorylation	down-regulates	0.2	We showed that pkc_ phosphorylation of p120 at serine (s)879 in response to thrombin or lipopolysaccharide challenge reduced p120 binding affinity for ve-cadherin and mediated aj disassembly secondary to ve-cadherin internalization	SIGNOR-198288
P11137	Q9BPU6	binding	down-regulates activity	0.2	The studies on CRMP5 function show that, by interacting with tubulin and MAP2, this protein inhibits neurite growth especially at the dendritic level and restricts the promotional effect of CRMP2 on axon and dendrite growth	SIGNOR-264836
P68431	Q7LBC6	demethylation	down-regulates activity	0.2	We have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. JHDM2A exhibits hormone-dependent recruitment to androgen-receptor target genes, resulting in H3K9 demethylation and transcriptional activation. Thus, our work identifies a histone demethylase and links its function to hormone-dependent transcriptional activation.	SIGNOR-266634
P48436	O76039	phosphorylation	down-regulates activity	0.2	Based on these studies, we hypothesized that Cdkl5 dependent phosphorylation at Ser 199 suppresses Sox9 function during AKI.\|We also found that Cdkl5 phosphorylates Sox9 at Ser 199 residue during kidney injury in vivo.	SIGNOR-279457
P31323	O43164	polyubiquitination	down-regulates quantity by destabilization	0.2	Praja2 controls the stability of PKA regulatory subunits. Praja2 ubiquitylates RIIα/β subunits. Subunits	SIGNOR-271858
O75385	Q9Y2H1	phosphorylation	down-regulates quantity	0.2	STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination	SIGNOR-270348
O60928	P17612	phosphorylation	up-regulates	0.2	Pka activation induced an increase of kir7.1 currents. This effect was absent in mutant kir7.1 channels lacking pka consensus site (287)s	SIGNOR-181859
Q9UQD0	P49841	phosphorylation	up-regulates activity	0.2	In vivo genetic manipulations demonstrate that GSK3β and Nav1.6 are molecular determinants of MSN excitability and that silencing of GSK3β prevents maladaptive plasticity of IC MSNs. In vitro studies reveal direct interaction of GSK3β with Nav1.6 and phosphorylation at Nav1.6T1936 by GSK3β. A GSK3β-Nav1.6T1936 competing peptide reduces MSNs excitability in IC, but not EC rats. These results identify GSK3β regulation of Nav1.6 as a biosignature of MSNs maladaptive plasticity.	SIGNOR-275763
O75496	O43791	ubiquitination	down-regulates activity	0.2	SPOP promotes K27-linked non-degradative poly-ubiquitination of Geminin at lysine residues 100 and 127. This poly-ubiquitination of Geminin prevents DNA replication over-firing by indirectly blocking the association of Cdt1 with the MCM protein complex, an interaction required for DNA unwinding and replication.	SIGNOR-268926
Q86U44	Q9UHD2	phosphorylation	up-regulates activity	0.2	TBK1 also promotes METTL3 activation and m 6 A modification to stabilize IRF3 mRNA .\|We here find TBK1, a key kinase of antiviral pathways, phosphorylates the core m 6 A methyltransferase METTL3 at serine 67.	SIGNOR-279299
P34972	Q8NB16	phosphorylation	down-regulates quantity by destabilization	0.2	Under hyperglycemic conditions, high glucose induced CB2R internalization in a β-arrestin 2-dependent manner; thereafter, MLKL (mixed lineage kinase domain-like), but not receptor-interacting protein kinase 1 or 3, phosphorylated CB2R at serine 352 and promoted CB2R degradation by ubiquitin modification. CB2R transcriptionally repressed necroptosis through interaction with BACH2; in turn, MLKL formed a negative feedback to phosphorylate CB2R.	SIGNOR-274121
Q99466	Q15369	ubiquitination	down-regulates	0.2	Using proteomic techniques, several components of the elongin c complex were identified as candidate notch4(icd) interactors. Elongin c complexes can function as ubiquitin ligases capable of regulating proteasomal degradation of specific protein substrates. Our studies indicate that ectopic elongin c expression stimulates notch4(icd) degradation and inhibits its transcriptional activity in human kidney tubule hk11 cells.	SIGNOR-176779
Q9H2G9	Q9H2K2	ADP-ribosylation	down-regulates quantity by destabilization	0.2	Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation.	SIGNOR-263384
P00450	Q15465	binding	down-regulates	0.2	Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. Ptch exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms.	SIGNOR-132672
Q96J02	P41240	phosphorylation	down-regulates activity	0.2	CISK strongly interacts and colocalizes with the E3 ubiquitin ligase AIP4, which is important for the ubiquitin-dependent lysosomal degradation of CXCR4. Moreover, the observed inhibition is both dependent on the interaction between CISK and AIP4 and on the activation status of CISK. Consistent with this, an activated form of CISK but not of the related kinase SGK1 phosphorylates specific sites of AIP4 in vitro.	SIGNOR-245327
P42345	Q92544	binding	down-regulates activity	0.2	TM9SF4 inhibited mTOR activity in HEK293 cells. Under nutrient starvation, TM9SF4 functions to facilitate mTOR inactivation, resulting in an enhanced autophagic flux, which serves to protect cells from apoptotic cell death.	SIGNOR-266703
Q92837	P17612	phosphorylation	down-regulates	0.2	Phosphorylation of ser188 by pka inhibited the ability of frat1 to activate beta-catenin-dependent transcription.	SIGNOR-149689
Q86WV6	Q99942	ubiquitination	down-regulates quantity by destabilization	0.2	The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA. RNF5 targeted MITA at Lys150 for ubiquitination and degradation after viral infection.	SIGNOR-271484
P84243	Q15418	phosphorylation	down-regulates activity	0.2	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-70428
P15336	Q9Y297	ubiquitination	down-regulates quantity by destabilization	0.2	Our data suggest that mTORC1 promotes the binding of the E3 ligase, βTrCP, to CREB2 (Figure 4D), promoting CREB2 degradation by the proteasome (Figure 4E). Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2).	SIGNOR-267830
P06737	O15294	glycosylation	up-regulates activity	0.2	O-GlcNAcylation at Ser-430 promotes PYGL activity	SIGNOR-267988
O75306	P06493	phosphorylation	up-regulates activity	0.2	Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.\|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation	SIGNOR-275592
P56181	P06493	phosphorylation	up-regulates activity	0.2	Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.\|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation	SIGNOR-275593

P04908

Q9H3R0

0

demethylation

down-regulates activity

0.2

As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation

SIGNOR-263862

O95863

Q8NEZ5

0

ubiquitination

down-regulates quantity by destabilization

0.2

FBXO22 elicits its antimetastatic effects by targeting SNAIL, a master regulator of EMT and breast cancer metastasis, for ubiquitin-mediated proteasomal degradation in a glycogen synthase kinase 3β phosphorylation-dependent manner.

SIGNOR-273446

Q9H0X6

P11474

0

transcriptional regulation

up-regulates quantity by expression

0.2

Furthermore, RNF208 was induced by 17β-estradiol (E2) treatment in an estrogen receptor alpha (ΕRα)-dependent manner

SIGNOR-269052

P51532

P48730

0

phosphorylation

down-regulates quantity by destabilization

0.2

We reveal that CK1δ phosphorylates Brg1 at Ser31/Ser35 residues to facilitate the binding of Brg1 to FBW7, leading to ubiquitination-mediated degradation.

SIGNOR-277407

P35575

Q53ET0

0

transcriptional regulation

up-regulates quantity

0.2

Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB

SIGNOR-256103

P08754

Q99677

0

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-257170

Q99574

Q86TM6

0

polyubiquitination

down-regulates quantity by destabilization

0.2

In this study, we demonstrate that two ER-associated E3 ligases, Hrd1 and gp78, are involved in the ubiquitination and degradation of mutant neuroserpin.

SIGNOR-272757

P32314

P51812

0

phosphorylation

down-regulates quantity by destabilization

0.2

Importantly, we identified RSK2 kinase as the upstream kinase for the FOXN2 phosphodegron. The Ser365 and Ser369 sites in a conserved DSGYAS motif are responsible for the ubiquitination of FOXN2 by β-Trcp.

SIGNOR-273841

O60260

P68036

0

ubiquitination

up-regulates activity

0.2

Only UbcH5 and Related Class I E2s Support Ubiquitination of S5a—UbcH5 belongs to the Class I family of E2s which contains a catalytic core (UBC domain) without a distinct Ub binding domain (38). To test whether other Class I E2s can also support ubiquitination of S5a, we assayed the ubiquitination of S5a with UbcH7 and the E3s, Nedd4, or Parkin. With either of these E3s, UbcH7 supported ubiquitination of S5a (Fig. 8, A and B). In addition, another Class I E2, Ubc4, a close homolog of UbcH5, supported ubiquitination of S5a by the APC, a multimeric Ring finger E3 responsible for cell cycle progression through mitosis (39) (Fig. 8C). Thus, multiple Class I E2s can support ubiquitination of S5a by various types of E3s (Table 1).

SIGNOR-272734

Q6NUN9

O60260

0

polyubiquitination

down-regulates quantity by destabilization

0.2

. Parkin ubiquitinates and regulates the ubiquitin proteasomal degradation of PARIS

SIGNOR-272758

Q04206

P11309

0

phosphorylation

up-regulates

0.2

In this study we show that phosphorylation of rela/p65 at ser276 prevents its degradation by ubiquitin-mediated proteolysis. importantly, we identify pim-1 as a further kinase responsible for the phosphorylation of rela/p65 at ser276.

SIGNOR-189125

Q9H267

P18433

0

dephosphorylation

down-regulates activity

0.2

Here, we report that VPS33B, a host protein involved in vesicle trafficking, is dephosphorylated by PtpA leading to a block of phagosome maturation by M. tuberculosis.|These data suggest that M. tuberculosis PtpA inhibits phagosome maturation.To assess the role of VPS33B in phagosome maturation, we attenuated the expression of endogenous VPS33B expression in THP-1 cells using a siRNA based approach.

SIGNOR-277015

P11940

Q13064

0

ubiquitination

down-regulates activity

0.2

MKRN3-mediated ubiquitination was found to attenuate the binding of PABPs to the poly(A) tails of mRNA|Altogether, it is thus clear that the ubiquitination of PABPC1 or PABPC4 by MKRN3 negatively regulates the formation of translation initiation complex (TIC), attenuates their binding to poly (A)-tail contained mRNAs, and leads to the shortened poly (A) tail-length of GNRH1 mRNA.

SIGNOR-278764

Q99708

P14618

0

phosphorylation

up-regulates activity

0.2

Here, we uncover an unexpected mechanism through which pyruvate kinase M2 (PKM2), the highly expressed PK isoform in cancer cells and a master regulator of cancer metabolic reprogramming, integrates with the DDR to directly promote DNA double-strand break (DSB) repair. In response to ionizing radiation and oxidative stress, ATM phosphorylates PKM2 at T328 resulting in its nuclear accumulation.

SIGNOR-277413

Q8NHM5

Q99814

0

transcriptional regulation

up-regulates quantity by expression

0.2

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-271582

P19544

Q93008

0

deubiquitination

up-regulates quantity by stabilization

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-275614

P48058

Q9BYB0

0

binding

up-regulates quantity

0.2

SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).

SIGNOR-264604

Q9Y653

P02461

0

binding

up-regulates activity

0.2

Using the N-terminal fragment of GPR56 (GPR56(N)) as a probe, we have recently demonstrated that collagen III is the ligand of GPR56 in the developing brain. In this report, we discover a new functional domain in GPR56(N), the ligand binding domain.

SIGNOR-253979

O75015

Q05481

0

transcriptional regulation

down-regulates quantity by repression

0.2

Thus, these results indicate that these cloned ZNF140 and ZNF91 proteins function as repressors for the human Fc gamma RIIB transcription.

SIGNOR-266215

Q99714

O60260

0

ubiquitination

down-regulates quantity by destabilization

0.2

This study identifies the multifunctional PD-related mitochondrial matrix enzyme 17-β hydroxysteroid dehydrogenase type 10 (HSD17B10) as a new Parkin substrate.

SIGNOR-272823

Q96J84

P06241

0

phosphorylation

up-regulates activity

0.2

Here we have characterized Neph1, another SD component, as a novel substrate of SFK. Fyn interacts with and phosphorylates the cytoplasmic domain of Neph1 in vitro and in intact cells. Both tyrosine 637 and 638 of Neph1 are crucial for Neph1-Grb2 binding.

SIGNOR-262746

Q99501

P51955

0

phosphorylation

up-regulates activity

0.2

Nek2A mediates G2/M phosphorylation of GAS2L1. GAS2L1 and its Ser352 phosphorylation are required for proper spindle organization and chromosome segregation.

SIGNOR-273683

O60610

O14757

0

phosphorylation

down-regulates activity

0.2

Chk1 Phosphorylates Drf1 for beta-Trcp-Dependent Degradation.|From this we conclude that Chk1 inhibits Drf1, but not the other three limiting factors at the MBT.

SIGNOR-279026

Q9NZQ7

Q9UNE7

0

destabilization

down-regulates quantity by destabilization

0.2

Deletion of STUB1 resulted in a more profound increase in PD-L1 levels in CMTM6 deficient than in CMTM6 proficient cells, identifying STUB1 as an E3 ligase that causes destabilization of PD-L1 (Fig. 4f,g), either by direct modification of one of the lysines in the PD-L1 cytoplasmic domain or indirectly

SIGNOR-274979

Q9UPS8

Q01196

0

transcriptional regulation

down-regulates quantity by repression

0.2

In healthy individual, RUNX1/FLI1 complex negatively regulates ANKRD26 gene expression in MKs.

SIGNOR-266069

P30559

O15530

0

phosphorylation

up-regulates activity

0.2

We found that Ser261 in OXTR was phosphorylated by protein kinase D1 (PKD1).|In HEK293A cells, the PKD1-mediated phosphorylation of OXTR promoted its binding to Gq protein and, in turn, OXTR-mediated phosphorylation of PKD1, indicating a positive feedback loop.

SIGNOR-268577

P09211

P05771

0

phosphorylation

up-regulates activity

0.2

Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently

SIGNOR-276023

Q5JPH6

Q2TAL8

0

transcriptional regulation

up-regulates quantity by expression

0.2

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

SIGNOR-269402

P49674

Q2M2I3

0

binding

up-regulates quantity

0.2

We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates.

SIGNOR-273763

Q07812

O15297

0

dephosphorylation

down-regulates activity

0.2

34 In this study, a novel function of Wip1 was identified, that is, its ability to dephosphorylate directly and thus inactivate apoptotic BAX protein in response to gamma irradiation.|To ascertain whether Wip1 dephosphorylates BAX, recombinant Wip1 was incubated with previously reported BAX-derived phosphopeptides containing Ser87, Ser163, Thr167, and Ser184 in an in vitro phosphatase assay. xref , xref Peptides containing phospho-Thr180 from p38 MAPK and phospho-Thr31 from UNG2 were used as a positive and negative control, respectively. xref As shown in xref , purified Wip1 did not dephosphorylate the four BAX-derived phosphopeptides.

SIGNOR-276993

Q8NFG4

P0DMV8

0

binding

up-regulates quantity by stabilization

0.2

These data suggest that inhibition of Hsp70 does not lead to an increase in misfolded FLCN but instead to its degradation.

SIGNOR-256506

P50148

Q99527

0

binding

up-regulates

0.2

However, grpr preferentially couples to galfaq proteins.

SIGNOR-195320

P19086

Q13153

0

phosphorylation

up-regulates

0.2

Phosphorylation of either ser(16) by pak1 or ser(27) by pkc decreased the affinity of galpha(z) for gbetagamma;phosphorylation of both residues by pkc caused no further effect. Pak1 thus regulates galpha(z) function by attenuating the inhibitory effects of both gaps and gbetagamma.

SIGNOR-48673

Q01860

P49137

0

phosphorylation

up-regulates activity

0.2

MK2 mediated OCT4 transcriptional activation is a novel mechanism for activating the MYC oncogene in progressive disease neuroblastoma that provides a therapeutic target.|OCT4 phosphorylation at the S111 residue by MK2 was upstream of MYC transcriptional activation.

SIGNOR-279542

P16615

P45984

0

phosphorylation

up-regulates activity

0.2

JNK2 Enhances SERCA2 Function in a CaMKII-Independent Manner..|We found that JNK2 and SERCA2 proteins are physically associated with each other, and that JNK2 directly elevates the maximal rate of the SERCA2 activity by phosphorylating SERCA2.

SIGNOR-279540

P54756

O00712

0

transcriptional regulation

up-regulates quantity

0.2

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

SIGNOR-268902

Q14164

Q9HCE1

0

binding

up-regulates activity

0.2

MOV10 enhances IRF3 activation and IRF3-mediated gene induction. This indicated that MOV10-mediated antiviral activity is most likely mediated through IKKε and not through TBK1. Involvement of IKKε was further established by examining the physical interaction of MOV10 and IKKε.

SIGNOR-261138

P78352

Q96NR3

0

binding

up-regulates quantity

0.2

Using Western blotting, we validated our MS approach confirming the binding of Dgl4 (also known as PSD95) and VPS35 to the recombinant Ptchd1 C terminus. Endogenous DLG4 and VPS35 from membrane and soluble mouse brain fractions were recovered specifically on the GST fusion proteins containing the cytoplasmic but not the extracellular, negative control sequences of Ptchd1 (Fig. 5E). Binding of DLG4 was dependent on the PDZ-binding motif in Ptchd1, whereas VPS35 binding was not (Fig. 5E). These results demonstrate a biochemical interaction of Ptchd1 with postsynaptic trafficking proteins in the mouse brain. Together, these data suggest that loss of Ptchd1 results in severe alterations in synaptic function in the dentate gyrus

SIGNOR-266652

P49585

Q02447

0

transcriptional regulation

up-regulates quantity by expression

0.2

Sp1 and Sp3 function as transcriptional activators of the Ctpct promoter

SIGNOR-266232

Q8N884

Q8WV44

0

ubiquitination

up-regulates activity

0.2

Our finding that RINCK positively regulates cGAS activation by mediating the monoubiquitination of cGAS uncovers the function of RINCK in cGAS mediated innate immunity.|Together, these data suggest that RINCK mediates cGAS monoubiquitination.

SIGNOR-278794

Q92769

Q96KB5

0

phosphorylation

up-regulates activity

0.2

The results of in vitro studies further confirmed the effect of TOPK on HDAC activity by showing that TOPK overexpression significantly up-regulated p-HDAC1 and p-HDAC2, resulting in an increase in the acetylation of histones H3 and H4 in BV2 cells.|These results indicated that TOPK overexpression resulted in the phosphorylation of HDAC1 and HDAC2, which might inactivate them and promote the acetylation of Histone 3 and Histone 4.

SIGNOR-279087

P08754

Q9UNW8

0

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

Q96PH1

Q9UQM7

0

phosphorylation

up-regulates activity

0.2

In vitro phosphorylation assays revealed that CAMKII can directly phosphorylate Nox5 on Thr494 and Ser498 as detected by phosphorylation state-specific antibodies. Mass spectrometry (MS) analysis revealed the phosphorylation of additional, novel sites at Ser475, Ser502, and Ser675. Of these phosphorylation sites, mutation of only Ser475 to alanine prevented CAMKII-induced increases in Nox5 activity. Together, these results suggest that CAMKII can positively regulate Nox5 activity via the phosphorylation of Ser475.

SIGNOR-276329

O43561

Q13043

0

phosphorylation

up-regulates activity

0.2

MST kinase phosphorylates and activates LATS kinase.

SIGNOR-279661

P38405

O00254

0

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-256904

Q14980

Q9UHD2

0

phosphorylation

up-regulates activity

0.2

Our studies now reveal TBK1 as another kinase that phosphorylates NuMA and that is required for its association with dynein and for localization of NuMA to the centrosomes in mitotic cells.

SIGNOR-278432

P45985

Q9H3Y6

0

phosphorylation

down-regulates activity

0.2

SRMS directly phosphorylates MKK4 and inhibits MKK4-JNK-c-Jun activation upon platinum treatment. Platinum treatment-induced ROS activates SRMS, which inhibits MKK4 kinase activity by directly phosphorylating MKK4 at Y269 and Y307, and consequently attenuates MKK4-JNK activation.

SIGNOR-277902

P31321

O43164

0

polyubiquitination

down-regulates quantity by destabilization

0.2

Praja2 controls the stability of PKA regulatory subunits. Praja2 ubiquitylates RIIα/β subunits. Subunits

SIGNOR-271857

P42081

Q8TCQ1

0

ubiquitination

down-regulates quantity by destabilization

0.2

Among nine family members examined, forced expression of MARCH1, -2, and -8 induced a significant reduction of surface CD86 in several cell lines.|CD86 is ubiquitinated by MARCH1.

SIGNOR-278628

Q8N884

P43405

0

phosphorylation

up-regulates activity

0.2

Mechanistically, viral infection or foreign DNA transfection triggers recruitment of the spleen tyrosine kinase (SYK) and cGAS to the endosomal vacuolar H+ pump (V-ATPase), where SYK is activated and then phosphorylates human cGASY214/215 (mouse cGasY200/201) to prime its activation.

SIGNOR-277844

O95379

P08754

0

binding

up-regulates activity

0.2

TNFAIP8: a new effector for Galpha(i) coupling to reduce cell death and induce cell transformation

SIGNOR-256490

Q9NZJ5

Q15382

0

binding

down-regulates activity

0.2

Rheb GTPase directly binds and activates PERK in vitro

SIGNOR-260873

P19174

P63215

0

binding

up-regulates

0.2

Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance.

SIGNOR-199141

Q9Y5H1

Q9Y5H9

0

binding

up-regulates activity

0.2

The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.

SIGNOR-265691

O60741

Q13127

0

transcriptional regulation

down-regulates quantity by repression

0.2

Levels of NRSF and its physical binding to the Hcn1 gene were augmented after SE, resulting in repression of HCN1 expression and HCN1-mediated currents (I(h) ), and reduced I(h) -dependent resonance in hippocampal CA1 pyramidal cell dendrites.

SIGNOR-268970

Q9P0L0

Q92953

0

relocalization

up-regulates quantity

0.2

Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays.|As Kv2.1 accumulates on the surface it begins to bind ER VAPs and form the large and stable membrane junctions.

SIGNOR-262124

P35575

P04150

0

transcriptional regulation

up-regulates quantity

0.2

Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB

SIGNOR-256104

Q9BVV6

Q86YT6

0

ubiquitination

down-regulates quantity by destabilization

0.2

Conversely, expression of active, but not inactive, Mib1 likewise drastically reduced the levels of centriolar Talpid3 (XREF_FIG).|Mib1 promotes the poly-ubiquitylation of Talpid3, Cep131, and PCM1.

SIGNOR-278829

O95837

Q9BPV8

0

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-257027

P69905

P15289

0

acetylation

up-regulates activity

0.2

ASA acetylates hemoglobin. Purified acetylated hemoglobin had a slightly increased oxygen affinity and decreased heme-heme interaction.

SIGNOR-251773

P55040

P0DP25

0

binding

up-regulates activity

0.2

Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells.

SIGNOR-266342

P32245

P01189-PRO_0000024969

0

binding

up-regulates activity

0.2

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

SIGNOR-268711

Q12809

P29350

0

dephosphorylation

down-regulates

0.2

Our results show that erg-1 is a shp-1 substrate constituting the first report that an ion current is regulated by shp-1.

SIGNOR-94007

Q9Y5F8

Q9Y5I2

0

binding

up-regulates activity

0.2

The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.

SIGNOR-265711

P10636

O95155

0

ubiquitination

down-regulates quantity by destabilization

0.2

Ubiquitination and degradation of Tau by UBE4B and STUB1 in mammalian neuroblastoma cells.

SIGNOR-278682

P49411

Q9BXM7

0

phosphorylation

down-regulates activity

0.2

PINK1 interacts with the autophagy effector TUFm and phosphorylates TUFm at Ser222. These results indicated that p222-hTUFm sequestered more monomer Atg5 and reduced the conjugated Atg5-Atg12 complex to subdue mitophagy.

SIGNOR-266382

Q8N695

P17676

0

transcriptional regulation

up-regulates quantity by expression

0.2

Luciferase reporter assays of deletion mutants of SLC5A8 promoter demonstrated that a 295-bp region is essential for the basal promoter activity of the SLC5A8 gene. Further analysis indicated that the CCAAT boxes and GC boxes were involved in positive regulation of SLC5A8 promoter. Overexpression of two transcription factors, CCAAT/enhancer binding protein beta (C/EBPbeta) and specific transcription factor 1 (Sp1), upregulated the activities of the human SLC5A8 promoter and protein expression, suggesting that both C/EBPbeta and Sp1 transcription factors might have functions in SLC5A8 transcription.

SIGNOR-254054

O95837

Q96LB1

0

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-257434

Q96NY9

P68400

0

phosphorylation

up-regulates activity

0.2

Here, we show that the CK2 kinase phosphorylates MUS81 at Serine 87 in late-G2/mitosis, and upon mild replication stress. Phosphorylated MUS81 interacts with SLX4, and this association promotes the function of the MUS81 complex.

SIGNOR-273626

P13056

P28482

0

phosphorylation

down-regulates activity

0.2

We also reported that ERK2-phosphorylated TR2 is recruited to PML nuclear bodies (PML NBs) for its subsequent small ubiquitin-like modification (SUMOylation) and function as a potent transcriptional repressor xref , xref .

SIGNOR-278957

Q9NYU1

O60613

0

binding

up-regulates activity

0.2

The enzymatic activity of UGGT2 is enhanced by complex formation with Sep15

SIGNOR-261373

Q68D86

P51955

0

phosphorylation

down-regulates activity

0.2

CCDC102B is recruited to the centrosome by C-Nap1 (also known as CEP250) and interacts with the centrosome linker components rootletin and LRRC45. CCDC102B decorates and facilitates the formation of rootletin filaments. Furthermore, CCDC102B is phosphorylated by Nek2A (an isoform encoded by NEK2) and is disassociated from the centrosome at the onset of mitosis.

SIGNOR-275626

O00763

Q8NHY2

0

ubiquitination

down-regulates quantity by destabilization

0.2

TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1. Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D).

SIGNOR-271599

P16104

P78527

0

phosphorylation

up-regulates

0.2

Dna-dependentprotein_ kinase_ (dna-pk) that phosphorylate h2ax at dsbs

SIGNOR-192443

P13051

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.2

Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation

SIGNOR-264885

P47869

Q8TAB3

0

binding

up-regulates quantity by stabilization

0.2

Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.

SIGNOR-267218

P36897

Q9UI12

0

binding

up-regulates activity

0.2

ATP6V1H interacts with TGF-β receptor I and AP-2 complex to regulate the proliferation and differentiation of BMSCs.

SIGNOR-266886

O60716

P17612

0

phosphorylation

down-regulates

0.2

We showed that pkc_ phosphorylation of p120 at serine (s)879 in response to thrombin or lipopolysaccharide challenge reduced p120 binding affinity for ve-cadherin and mediated aj disassembly secondary to ve-cadherin internalization

SIGNOR-198288

P11137

Q9BPU6

0

binding

down-regulates activity

0.2

The studies on CRMP5 function show that, by interacting with tubulin and MAP2, this protein inhibits neurite growth especially at the dendritic level and restricts the promotional effect of CRMP2 on axon and dendrite growth

SIGNOR-264836

P68431

Q7LBC6

0

demethylation

down-regulates activity

0.2

We have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. JHDM2A exhibits hormone-dependent recruitment to androgen-receptor target genes, resulting in H3K9 demethylation and transcriptional activation. Thus, our work identifies a histone demethylase and links its function to hormone-dependent transcriptional activation.

SIGNOR-266634

P48436

O76039

0

phosphorylation

down-regulates activity

0.2

Based on these studies, we hypothesized that Cdkl5 dependent phosphorylation at Ser 199 suppresses Sox9 function during AKI.|We also found that Cdkl5 phosphorylates Sox9 at Ser 199 residue during kidney injury in vivo.

SIGNOR-279457

P31323

O43164

0

polyubiquitination

down-regulates quantity by destabilization

0.2

Praja2 controls the stability of PKA regulatory subunits. Praja2 ubiquitylates RIIα/β subunits. Subunits

SIGNOR-271858

O75385

Q9Y2H1

0

phosphorylation

down-regulates quantity

0.2

STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination

SIGNOR-270348

O60928

P17612

0

phosphorylation

up-regulates

0.2

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

SIGNOR-181859

Q9UQD0

P49841

0

phosphorylation

up-regulates activity

0.2

In vivo genetic manipulations demonstrate that GSK3β and Nav1.6 are molecular determinants of MSN excitability and that silencing of GSK3β prevents maladaptive plasticity of IC MSNs. In vitro studies reveal direct interaction of GSK3β with Nav1.6 and phosphorylation at Nav1.6T1936 by GSK3β. A GSK3β-Nav1.6T1936 competing peptide reduces MSNs excitability in IC, but not EC rats. These results identify GSK3β regulation of Nav1.6 as a biosignature of MSNs maladaptive plasticity.

SIGNOR-275763

O75496

O43791

0

ubiquitination

down-regulates activity

0.2

SPOP promotes K27-linked non-degradative poly-ubiquitination of Geminin at lysine residues 100 and 127. This poly-ubiquitination of Geminin prevents DNA replication over-firing by indirectly blocking the association of Cdt1 with the MCM protein complex, an interaction required for DNA unwinding and replication.

SIGNOR-268926

Q86U44

Q9UHD2

0

phosphorylation

up-regulates activity

0.2

TBK1 also promotes METTL3 activation and m 6 A modification to stabilize IRF3 mRNA .|We here find TBK1, a key kinase of antiviral pathways, phosphorylates the core m 6 A methyltransferase METTL3 at serine 67.

SIGNOR-279299

P34972

Q8NB16

0

phosphorylation

down-regulates quantity by destabilization

0.2

Under hyperglycemic conditions, high glucose induced CB2R internalization in a β-arrestin 2-dependent manner; thereafter, MLKL (mixed lineage kinase domain-like), but not receptor-interacting protein kinase 1 or 3, phosphorylated CB2R at serine 352 and promoted CB2R degradation by ubiquitin modification. CB2R transcriptionally repressed necroptosis through interaction with BACH2; in turn, MLKL formed a negative feedback to phosphorylate CB2R.

SIGNOR-274121

Q99466

Q15369

0

ubiquitination

down-regulates

0.2

Using proteomic techniques, several components of the elongin c complex were identified as candidate notch4(icd) interactors. Elongin c complexes can function as ubiquitin ligases capable of regulating proteasomal degradation of specific protein substrates. Our studies indicate that ectopic elongin c expression stimulates notch4(icd) degradation and inhibits its transcriptional activity in human kidney tubule hk11 cells.

SIGNOR-176779

Q9H2G9

Q9H2K2

0

ADP-ribosylation

down-regulates quantity by destabilization

0.2

Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation.

SIGNOR-263384

P00450

Q15465

0

binding

down-regulates

0.2

Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. Ptch exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms.

SIGNOR-132672

Q96J02

P41240

0

phosphorylation

down-regulates activity

0.2

CISK strongly interacts and colocalizes with the E3 ubiquitin ligase AIP4, which is important for the ubiquitin-dependent lysosomal degradation of CXCR4. Moreover, the observed inhibition is both dependent on the interaction between CISK and AIP4 and on the activation status of CISK. Consistent with this, an activated form of CISK but not of the related kinase SGK1 phosphorylates specific sites of AIP4 in vitro.

SIGNOR-245327

P42345

Q92544

0

binding

down-regulates activity

0.2

TM9SF4 inhibited mTOR activity in HEK293 cells. Under nutrient starvation, TM9SF4 functions to facilitate mTOR inactivation, resulting in an enhanced autophagic flux, which serves to protect cells from apoptotic cell death.

SIGNOR-266703

Q92837

P17612

0

phosphorylation

down-regulates

0.2

Phosphorylation of ser188 by pka inhibited the ability of frat1 to activate beta-catenin-dependent transcription.

SIGNOR-149689

Q86WV6

Q99942

0

ubiquitination

down-regulates quantity by destabilization

0.2

The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA. RNF5 targeted MITA at Lys150 for ubiquitination and degradation after viral infection.

SIGNOR-271484

P84243

Q15418

0

phosphorylation

down-regulates activity

0.2

Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.

SIGNOR-70428

P15336

Q9Y297

0

ubiquitination

down-regulates quantity by destabilization

0.2

Our data suggest that mTORC1 promotes the binding of the E3 ligase, βTrCP, to CREB2 (Figure 4D), promoting CREB2 degradation by the proteasome (Figure 4E). Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2).

SIGNOR-267830

P06737

O15294

0

glycosylation

up-regulates activity

0.2

O-GlcNAcylation at Ser-430 promotes PYGL activity

SIGNOR-267988

O75306

P06493

0

phosphorylation

up-regulates activity

0.2

Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation

SIGNOR-275592

P56181

P06493

0

phosphorylation

up-regulates activity

0.2

Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation

SIGNOR-275593