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
Q96T49	P17252	phosphorylation	down-regulates activity	0.2	PKCα phosphorylated the full length recombinant TIMAP in in vitro kinase assay and Ser331 of TIMAP was shown to be phosphorylated by PKC. Phosphorylation of TIMAP upon PKC activation in endothelial cells results in enrichment of TIMAP in the membrane, but no such change can be observed in PKC depleted cells. Phosphorylation state of TIMAP, through affecting PP1 activity, has a remarkable effect on endothelial barrier function.	SIGNOR-273802
P09471	Q9H1C0	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-256997
Q07812	Q05513	phosphorylation	down-regulates activity	0.2	Protein kinase czeta abrogates the proapoptotic function of bax through phosphorylation. Overexpression of wild type or the constitutively active a119d but not the dominant negative k281w pkczeta mutant results in bax phosphorylation at serine 184.	SIGNOR-155111
Q92886	Q9HCK8	transcriptional regulation	down-regulates quantity	0.2	Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells	SIGNOR-268919
P01019-PRO_0000032458	P12821	cleavage	up-regulates quantity	0.2	Ang I is subsequently converted into the major RAS effector peptide Ang II or Ang (1–8), through activity of the zinc-dependent protease ACE, which hydrolyzes two amino acids from the carboxy terminus of Ang I	SIGNOR-260236
O15169	P62140	dephosphorylation	down-regulates activity	0.2	The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin\| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity\| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated	SIGNOR-248567
O96004	Q99717	transcriptional regulation	up-regulates quantity	0.2	Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation	SIGNOR-268941
Q96BR9	Q8TBB1	polyubiquitination	down-regulates quantity by destabilization	0.2	LNX (ligand of Numb protein-X) is a RING finger and four PDZ domain-containing E3 ubiquitin ligase. Lnx-l induced K48-linked polyubiquitylation of Boz, leading to its proteasomal degradation in human 293T cells and in zebrafish embryos.	SIGNOR-272777
Q16695	Q92831	acetylation	down-regulates activity	0.2	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269621
P38405	P35367	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-256921
C9JLW8	P28482	phosphorylation	down-regulates activity	0.2	When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.\| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation	SIGNOR-264774
Q07820	P28062	null	down-regulates quantity by destabilization	0.2	Surprisingly, siRNA knockdown of PSMB8 (LMP7), an ‘immunoproteasome’ component, reversed IFNγ-induced sensitivity to Fas ligation and prevented Fas/IFNγ-induced degradation of Mcl-1, but did not protect p-Bcl-2 or p-Bcl-XL. Proteasome inhibition markedly increased Mcl-1, p-Bcl-2, and p-Bcl-XL levels after IFNγ treatment	SIGNOR-261974
Q07817	P59635	binding	down-regulates activity	0.2	In this study, we show that the overexpression of Bcl-XL, a prosurvival member of the Bcl-2 family, blocks 7a-induced apoptosis, suggesting that the mechanism for apoptosis induction by 7a is at the level of or upstream from the Bcl-2 family.	SIGNOR-261075
P52757	P06239	phosphorylation	down-regulates activity	0.2	We now demonstrate Lck-dependent phosphorylation of beta2-chimaerin in response to TCR triggering. We identify Tyr-153 as the Lck-dependent phosphorylation residue and show that its phosphorylation negatively regulates membrane stabilization of beta2-chimaerin, decreasing its GAP activity to Rac.	SIGNOR-276240
P21333	P48454	dephosphorylation	down-regulates quantity by destabilization	0.2	Filamin is a phosphoprotein that organizes actin filaments into networks. We report that a purified C-terminal recombinant region of filamin is a suitable substrate for calcineurin \|Mutagenesis analysis showed that a dephosphorylation step occurred in Ser 2152, which was previously shown to provide resistance to calpain cleavage when endogenous PKA is activated. In contrast, phosphorylation of Ser 2152 was recently reported to be necessary for membrane dynamic changes. In this regard, we found that CsA protects filamin in platelets from calpain degradation.	SIGNOR-248507
Q2M385	O96017	phosphorylation	up-regulates activity	0.2	Chk2 phosphorylates Mps1-T288 after DNA damage.\|In the present study, we show that Chk2 stabilizes Mps1 protein and phosphorylates Aurora B-B-serine 331 to prevent mitotic exit in vertebrate cells when the majority of kinetochores are unattached.	SIGNOR-279160
Q6NXT2	Q9Y4C1	demethylation	up-regulates activity	0.2	Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.	SIGNOR-276847
P68431	Q92830	acetylation	down-regulates activity	0.2	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269602
Q96NG3	Q96M91	binding	up-regulates activity	0.2	CFAP53 likely facilitates the transport of TTC25 and the dyneins into cilia. CFAP53 at the centriolar satellites may form a complex with TTC25 and ODAs, including DNAH5 and DNAH11, and regulate their trafficking into the cilium (Fig 10B).	SIGNOR-265543
P42336	Q5VWQ8	binding	down-regulates activity	0.2	DAB2IP inhibits the PI3K–AKT axis by directly interacting with both proteins, reducing phosphorylation and activation of AKT. The GAP activity of DAB2IP can further enforce inhibition of the PI3K–AKT axis by reducing Ras-dependent activation of PI3K p110α subunit.	SIGNOR-254750
O00429	O60260	ubiquitination	down-regulates quantity	0.2	Parkin interacts with and subsequently ubiquitinates Drp1, thus promoting its proteasome dependent degradation .\|We have demonstrated that parkin promotes Drp1 degradation after OGDR insult.	SIGNOR-278589
Q9NP31	O60469	binding	up-regulates activity	0.2	Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels.	SIGNOR-264279
Q8IUX7	P28482	phosphorylation	up-regulates activity	0.2	We show that DNA binding by AEBP1 requires both the N- and C-terminal domains of AEBP1, and MAPK interaction with AEBP1 (through its N terminus) results in enhanced DNA binding. A threonine at position 623 within the C-terminal domain of AEBP1 plays an important role in DNA binding by AEBP1, because the mutation results in decreased DNA binding by AEBP1, which leads to a decrease in the transcriptional repression ability of AEBP1. We also show that in vitro phosphorylation of AEBP1 by MAPK is greatly reduced upon mutation of T623. These results suggest that MAPK regulates the transcriptional activity of AEBP1 by a novel dual mechanism, in which MAPK interaction enhances and subsequent phosphorylation decreases the DNA-binding ability of AEBP1.	SIGNOR-262897
P02818	P07711	cleavage	down-regulates quantity by destabilization	0.2	This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42.	SIGNOR-256322
P05787	P18031	dephosphorylation	down-regulates activity	0.2	Keratin 8 phospho-Tyr-267 is dephosphorylated by PTP1B and promotes insolubility and filament organization, as does the paralogous GFAP tyrosine.	SIGNOR-265495
P10275	O75592	ubiquitination	down-regulates quantity by destabilization	0.2	We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop.	SIGNOR-267149
P35244	Q96AP0	binding	down-regulates activity	0.2	The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA	SIGNOR-263329
Q9Y4D1	P54792	binding	up-regulates	0.2	Importantly, daam1 binds to disheveled (dvl) and thus functions downstream of the frizzled receptors. Little is known of how daam1 is localized and functions in mammalian cells.	SIGNOR-199451
Q9H9R9	Q13049	ubiquitination	down-regulates quantity by destabilization	0.2	TRIM32 is an E3 ubiquitin ligase for dysbindin. TRIM32 targets dysbindin for degradation.	SIGNOR-271422
P05198	Q86TM6	ubiquitination	down-regulates quantity by destabilization	0.2	HRD1 overexpression also decreased the expression of eIF2alpha and p-eIF2alpha in HKC-8 cells.\|HRD1 promoted eIF2alpha ubiquitylation and degradation, thereby providing a protective mechanism that suppressed tubular epithelial cell apoptosis.	SIGNOR-278671
A0A0B4J2F0	Q96S66	binding	up-regulates activity	0.2	The PIGBOS microprotein interacts with the ER protein CLCC1. PIGBOS localizes to the mitochondrial outer membrane where itinteracts with the ER protein CLCC1 at ER–mitochondria contact sites. PIGBOS-CLCC1 interaction is necessary for PIGBOS function	SIGNOR-261040
Q12888	O15264	phosphorylation	down-regulates activity	0.2	Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.\|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks \|phosphorylation of T1609 is likely to be mediated by p38 MAPK	SIGNOR-264449
Q9BZI1	P28482	phosphorylation	up-regulates activity	0.2	We tested the transcriptional properties of Irx2 by dividing it into amino- and carboxy terminal parts and found that Mek1-mediated phosphorylation activates and derepresses the amino and carboxyl parts, respectively. When Ser46 and Ser65 were mutated to alanine (S46A and S65A), phosphorylation was reduced, whereas substitution of Ser83 and Ser103 (S83A and S103A) did not affect phosphorylation.	SIGNOR-263052
Q16695	Q15652	demethylation	down-regulates activity	0.2	We now determine that JMJD1C is recruited by USF-1 to various lipogenic genes for H3K9 demethylation to enhance chromatin accessibility in the fed state.	SIGNOR-265170
Q9UI09	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-275587
P06702	P17676	transcriptional regulation	up-regulates quantity by expression	0.2	Among several known transcription factor binding motifs, nuclear protein(s) of VD3-treated HL-60 cells and THP-1 cells bound to the CCAAT/enhancer binding protein (C/EBP)-binding motif that was located in the upstream region of the MRP14 gene (-81), as evidenced by the competitive gel mobility-shift assay.\|Thus, it was concluded that C/EBP alpha and -beta were able to bind to the C/EBP motif, and that C/EBP alpha bound to the motif in THP-1 cells and C/EBP beta bound to that in the VD3-treated HL-60 cells.	SIGNOR-254044
P25054	P04264	phosphorylation	up-regulates activity	0.2	Phosphorylation of this central repeat region of APC significantly enhances its affinity for β-catenin. When the repeats are phosphorylated by the cooperative action of CK1 and GSK3β, the binding interaction is significantly altered and enhanced.	SIGNOR-251879
P11308	P48729	phosphorylation	down-regulates quantity by destabilization	0.2	Using in vitro kinase assays, we further demonstrated that deletion of degron 1 largely abolished CKI-mediated phosphorylation of ERG (Figure S5B), indicating that serine residues within degron 1 are the major CKI phosphorylation sites.	SIGNOR-276935
P63092	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 ‚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-256787
P37231	Q8IXJ9	binding	down-regulates activity	0.2	Our genome-wide analysis confirmed the physiological roles of ASXL1 and ASXL2 in adipogenesis at the molecular level, supporting the hypothesis that ASXL1 is an authentic corepressor of PPARγ, whereas ASXL2 is a PPARγ coactivator, and that together ASXL1 and ASXL2 fine-tune adipogenesis via differential regulation of PPARγ.	SIGNOR-260064
Q96E09	O14757	phosphorylation	down-regulates activity	0.2	Knockout of FAM122A results in activation of PP2A-B55α, a phosphatase that dephosphorylates the WEE1 protein and rescues WEE1 from ubiquitin-mediated degradation. in tumor cells with oncogene-driven replication stress, CHK1 can directly phosphorylate FAM122A, leading to activation of the PP2A-B55α phosphatase and increased WEE1 expression.	SIGNOR-266380
Q13371	P25098	phosphorylation	down-regulates activity	0.2	The phosphorylation of purified phosducin and PhLP by recombinant GRK2 proceeds rapidly and stoichiometrically (0.82 +/- 0.1 and 0.83 +/- 0.09 mol of P (i)/mol of protein, respectively).	SIGNOR-279178
Q16891	P17612	phosphorylation	down-regulates activity	0.2	PKA directly phosphorylated the Ser528 residue of MIC60. Phosphorylation of MIC60 Interrupts Parkin Recruitment and Formation of the MICOS Complex	SIGNOR-266302
P55089	P10275	transcriptional regulation	down-regulates quantity by repression	0.2	When cells were treated with DHT alone, AR was upregulated and translocated into the nuclei, which might repress UCN1 expression via a potential androgen-responsive element found in human CRF family promoter\|These data suggest that DHT differentially influences UCN1 levels under normal and inflammatory conditions in human umbilical vein endothelial cells, which involves AR-dependent and -independent mechanisms respectively.	SIGNOR-253688
P08670	Q05513	phosphorylation	up-regulates activity	0.2	Results suggest that aPKCs target multiple activation sites (Ser33/39/56) on Vimentin and therefore is essential for VIF dynamics regulation during the metastasis of prostate cancer cells.	SIGNOR-277622
Q9UKX7	P27361	phosphorylation	down-regulates activity	0.2	Erk phosphorylates nup50 at ser221 and ser315 phosphorylation of nup50 reduces affinity for importin-beta	SIGNOR-187378
Q9HD90	Q12857	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-268891
Q86T82	Q01094	transcriptional regulation	up-regulates quantity by expression	0.2	USP37 was induced by E2F transcription factors in G1\|Ectopic E2F1 activated the wild-type promoter, but not the mutant promoter, 3-fold over basal levels in 293T cells (Figure 4F), confirming the functionality of the E2F binding sites in the USP37 promoter.	SIGNOR-265047
P30622	P17252	phosphorylation	down-regulates	0.2	Furthermore, by using phosphoproteomic analysis, we determined that s309 and s311 of clip-170 are phosphorylated in cells and mapped s311 as a protein kinase a (pka) phosphorylation site.phosphorylation of s311 may be critical for establishing the ?folded Back? Conformation of clip-170clip-170 open and folded back conformations represent active and inactive modes of the protein, respectively	SIGNOR-165857
Q96AC1	Q8IWT3	ubiquitination	down-regulates quantity by destabilization	0.2	M-phase-specific CDK1–cyclin B1 complex directly binds KIND1 and KIND2 and phosphorylates a conserved proline-directed CDK1 consensus motif in the flexible and intrinsically disordered loop of the F1 domain. This then results in the recruitment of the CUL9–FBXL10 complex, modification with K48-linked polyubiquitin chains and proteasomal degradation of KIND1 and KIND2.	SIGNOR-276717
Q2Q1W2	P17612	phosphorylation	up-regulates quantity by stabilization	0.2	These observations suggested that LINK-A expression potentially inhibits PKA phosphorylation/activity and PKA-mediated phosphorylation of TRIM71 at Ser3.	SIGNOR-277454
O60885	Q9C0F0	binding	up-regulates activity	0.2	We report a critical link between BAP1 complex and BRD4, which is bridged by the physical interaction between ASXL3 and BRD4 in an SCLC subtype (SCLC-A), which expresses a high level of ASCL1. We further showed that ASXL3 functions as an adaptor protein, which directly interacts with BRD4's extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), and maintains chromatin occupancy of BRD4 to active enhancers.	SIGNOR-266762
P37231	P11274	phosphorylation	down-regulates activity	0.2	Overexpression of Bcr WT inhibited PPARgamma transcriptional activity (XREF_FIG).\|Point-mutation and in vitro kinase analysis showed that PPAR\u03b3 was phosphorylated by Bcr at serine 82.	SIGNOR-279441
Q15910	Q9P275	deubiquitination	up-regulates quantity by stabilization	0.2	We observed a MELK-mediated increase of EZH2 S220 phosphorylation along with a concomitant loss of EZH2 K222 ubiquitination, suggesting a phosphorylation-dependent regulation of EZH2 ubiquitination. Furthermore, we identify USP36 as the deubiquitinating enzyme that deubiquitinates EZH2 at K222.	SIGNOR-277481
P17661	Q14814	transcriptional regulation	up-regulates quantity by expression	0.2	Ectopic expression of myogenin and a specific Mef2 isoform induced myogenic differentiation without activating endogenous MyoD expression. Under these conditions, the regulatory sequences of late gene loci were not in close proximity, and these genes were prematurely activated.	SIGNOR-241504
O95140	Q9NX47	ubiquitination	up-regulates activity	0.2	Taken together, these results suggested that MITOL regulates endoplasmic reticulum tethering to mitochondria by activating Mfn2 via K192 ubiquitination.\|Therefore, MITOL specifically ubiquitinates mitochondrial Mfn2.	SIGNOR-278553
Q5TEC6	Q9Y4C1	demethylation	up-regulates activity	0.2	Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.	SIGNOR-276843
Q96P70	Q13315	phosphorylation	up-regulates activity	0.2	In line with our previous results, IR exposure induced the nuclear accumulation of RanBP9, which was prevented by ATM inhibition using KU-55933.\|Taken together these data indicate that RanBP9 is a novel target of ATM and that ATM phosphorylates at least two different residues (S181 and S603) of RanBP9 following IR exposure.	SIGNOR-278910
P30566	Q96KS0	hydroxylation	up-regulates activity	0.2	ADSL is hydroxylated by EglN2 on Proline 24. An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. ADSL regulates cMYC protein level through adenosine levels	SIGNOR-266613
P23786	Q86TM6	ubiquitination	down-regulates quantity	0.2	Taken together, these data suggest that HRD1 selectively and specifically downregulates intracellular CPT2 levels.\|These results demonstrate that HRD1 ubiquitinates CPT2, which is processed through Lys-48-linked ubiquitin chains.	SIGNOR-278723
P01024	Q96PZ7	binding	down-regulates quantity	0.2	CUB and sushi multiple domains 1 (CSMD1) is a relatively poorly studied large transmembrane protein of 390 kDa composed of 14 N-terminal CUB domains interspersed with complement control protein (CCP) domains followed by 15 consecutive CCP domains. The active domains of CSMD1 were then identified in CCP17-21, which were shown to interact with C4b and C3b and present these complement proteins for degradation by factor	SIGNOR-265148
Q9BZX2	Q86U44	post transcriptional regulation	up-regulates quantity by stabilization	0.2	Furthermore, the m6A modification regulated by METTL3 led to UCK2 increased messenger RNA (mRNA) stability in melanoma cancer. Functional and mechanistic experiments indicated that UCK2 enhanced the metastasis of melanoma cancer cells through the WNT/β-catenin pathway.	SIGNOR-275862
P25098	P12931	phosphorylation	up-regulates activity	0.2	Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq.	SIGNOR-266305
Q12933	P62714	dephosphorylation	down-regulates activity	0.2	We show that the Thr117 residue in TRAF2 is phosphorylated following TNFalpha stimulation. This phosphorylation process is modulated by PP2A and is required for TRAF2 functional activity.	SIGNOR-248597
P10275	Q8WY64	ubiquitination	down-regulates quantity	0.2	MYLIP knockdown increased AR protein levels whereas CNPY2 knockdown increased MYLIP and reduced AR protein expression levels.\|These results showed that the E3 ligase MYLIP could ubiquitinate lysine 845 and 847 residues of AR.	SIGNOR-278766
P37231	P36406	ubiquitination	up-regulates quantity by stabilization	0.2	In this study, we showed that TRIM23 mediates atypical polyubiquitin conjugation including M1- and K27 linked ubiquitin chains to PPARgamma and that ubiquitination of PPARgamma by TRIM23 causes reduced recognition of PPARgamma by 26S proteasome.	SIGNOR-278577
Q9UQ88	O75293	binding	down-regulates activity	0.2	Western blot analysis for SPDEF revealed that overexpression of GADD45α, β and γ prevents SPDEF degradation mediated by CDK11p58 \|We identified CDK11p58 as an interaction partner of GADD45α by co-immunoprecipitation analysis. We corroborated these data by co-immunoprecipitation in vitro translation assays, showing that all three members of the GADD45 family interact with CDK11p58.	SIGNOR-273024
Q06830	Q13043	phosphorylation	down-regulates activity	0.2	Mst1 inactivates Prdx1 by phosphorylating it at Thr-90 and Thr-183, leading to accumulation of hydrogen peroxide in cells.Prdx1 is phosphorylated by Mst1 predominantly at Thr-18, Thr-90, and Thr-183.	SIGNOR-276486
P19086	Q96G91	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-257328
O15259	P68400	phosphorylation	up-regulates	0.2	Casein kinase 2 (ck2)-mediated phosphorylation of three critical serine residues within a cluster of acidic amino acids in nephrocystin mediates pacs-1 binding, and is essential for colocalization of nephrocystin with pacs-1 at the base of cilia. Inhibition of ck2 activity abrogates this interaction and results in the loss of correct nephrocystin targeting.	SIGNOR-142343
P15976	Q9NQU5	phosphorylation	up-regulates activity	0.2	In addition, PAK5 knockdown also markedly reduced the association of GATA1 with HDAC3/4.\|PAK5 phosphorylates the transcription factor GATA1 mainly at Ser161 and Ser 187, phosphorylated GATA1 recruits more HDAC3/4 to the promoter of E-cadherin and consequently suppresses the transcription of E-cadherin gene and promotes the EMT of breast cancer cells.	SIGNOR-278415
O00303	Q7Z6M2	polyubiquitination	down-regulates quantity by destabilization	0.2	Mediation of eIF3-f polyubiquitination by the SCFMAFbx. The association of MAFbx with the essential Skp1, Roc 1 and Cul1 proteins, specific components of an E3 ubiquitin–protein ligase (SCFMAFbx), was previously described. Here, we present evidence that during muscle atrophy MAFbx targets the eukaryotic initiation factor 3 subunit 5 (eIF3-f) for ubiquitination and degradation by the proteasome.	SIGNOR-271768
P05556	Q9Y5H6	binding	up-regulates activity	0.2	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion.	SIGNOR-265671
Q13546	Q8TE49	deubiquitination	down-regulates activity	0.2	NF-kappaB Suppression by the Deubiquitinating Enzyme Cezanne\|Our study provides several lines of evidence to suggest that Cezanne suppresses TNFR signaling to NF-κB by targeting RIP1 for deubiquitination.	SIGNOR-268410
P08754	P43657	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-256868
Q13177	Q9NYV4	phosphorylation	up-regulates activity	0.2	Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway	SIGNOR-273110
Q15746	Q9C009	transcriptional regulation	down-regulates quantity by repression	0.2	Results from this analysis revealed that the inhibitory activity of HFH-1 was contained within the forkhead DNA-binding domain. Truncated HFH-1 proteins that lack the entire forkhead domain were unable to repress telokin promoter activity, in contrast expression of the forkhead domain alone was able to repress promoter activity	SIGNOR-261609
Q9UBI6	Q99835	binding	up-regulates	0.2	As pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp.	SIGNOR-152817
O43776	P18848	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-269422
Q9NRM7	Q9Y4B6	binding	down-regulates quantity by destabilization	0.2	CRL4 DCAF1 ubiquitylates and inhibits Lats.	SIGNOR-272227
P18848	P68400	phosphorylation	down-regulates quantity by destabilization	0.2	By using mutants of ATF4 we identified serine 215 as the main CK2 phosphorylation site. The ATF4 S215A mutant turned out to be more stable than the wild-type form.	SIGNOR-276425
Q86WV6	O75385	phosphorylation	down-regulates activity	0.2	Collectively, our data indicates that cGAS is essential for the activation of AMPK and ULK1 suppression of STING (XREF_FIG) and that cGAMPs are responsible for triggering the dephosphorylation of AMPK T172 and activation of ULK1 which phosphorylates STING on S366 to impede its activity (XREF_FIG).\|Collectively, our data indicates that cGAS is essential for the activation of AMPK/ULK1 suppression of STING ( xref ) and that cGAMPs are responsible for triggering the dephosphorylation of AMPK T172 and activation of ULK1 which phosphorylates STING on S366 to impede its activity ( xref ).	SIGNOR-279316
Q5FBB7	O14965	phosphorylation	up-regulates activity	0.2	Loss of INCENP/Aurora B in Mitosis Correlates with Delocalization of MEI-S332\|MEI-S332 Is Phosphorylated by Aurora B In Vitro\|Of these, MEI-S332S124,125,126A was a poor substrate for Aurora B kinase in vitro	SIGNOR-252046
Q16695	Q9UGL1	demethylation	up-regulates activity	0.2	KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.	SIGNOR-264303
Q06330	Q9UQF2	binding	down-regulates	0.2	Here, we show that jip1 suppresses notch1 activity. Jip1 was found to physically associate with either intracellular domain of notch1 or rbp-jk and interfere with the interaction between them.	SIGNOR-165713
P08754	P35367	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-257163
Q86UX7	P17252	phosphorylation	up-regulates activity	0.2	PKC-induced phosphorylation events, as we have shown kindlin-3 to be a PKC phosphorylation target (Fig. 6C), are often followed by rapid activation of phosphatases (38).	SIGNOR-266415
Q13085	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-271598
P11362	Q02156	phosphorylation	up-regulates	0.2	Phosphorylation of serine 779 in fibroblast growth factor receptor 1 and 2 by protein kinase c(epsilon) regulates ras/mitogen-activated protein kinase signaling and neuronal differentiationour findings show that in addition to fgfr tyrosine phosphorylation, the phosphorylation of a conserved serine residue, ser(779), can quantitatively control ras/mapk signaling to promote specific cellular responses.	SIGNOR-201671
Q9GZQ8	Q8TD19	phosphorylation	down-regulates activity	0.2	LC3B is phosphorylated at Thr-50 within the LDS by serine/threonine kinase (STK) 3 and STK4. Here, we identified LIR motifs in STK3 and atypical protein kinase Cζ (PKCζ) and never in mitosis A (NIMA)-related kinase 9 (NEK9). All three kinases phosphorylated LC3B Thr-50 in vitro A phospho-mimicking substitution of Thr-50 impaired binding of several LIR-containing proteins, such as ATG4B, FYVE, and coiled-coil domain-containing 1 (FYCO1), and autophagy cargo receptors p62/sequestosome 1 (SQSTM1) and neighbor of BRCA1 gene (NBR1).	SIGNOR-273904
Q07820	Q9NX47	ubiquitination	down-regulates quantity by destabilization	0.2	MARCH5 promotes ubiquitination of MCL1 and NOXA.\|Together, this suggests that degradation of MCL1 by MARCH5 depends on binding to NOXA, but degradation of NOXA may be promoted by additional E3-ligases if MCL1 levels become limited, or can simply no longer be degraded.	SIGNOR-278700
Q9UPP1	P28482	phosphorylation	down-regulates activity	0.2	Upon IFNgamma treatment, PHF8 is phosphorylated by ERK2 and evicted from the promoters, which correlates with an increase in H4K20me1 and H3K4me3 levels.	SIGNOR-279745
P16144	Q99704	binding	down-regulates activity	0.2	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257689
P09471	P32249	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-256994
P35611	Q05513	phosphorylation	up-regulates	0.2	These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc.	SIGNOR-43834
Q07820	Q13627	phosphorylation	up-regulates quantity	0.2	Furthermore, DYRK1A likely directly bound and phosphorylated Mcl-1, thereby enhancing Mcl-1 protein stability and contributing to the development of acquired resistance to Bcl-2 inhibitors.\|DYRK1A upregulates Mcl-1 expression in NSCLC cells.\|We demonstrated that DYRK1A suppression by siRNA or harmine decreased the phosphorylation of Mcl-1 at Ser159/Thr163.	SIGNOR-279704
P32121	Q495A1	binding	up-regulates activity	0.2	With TIGIT/PVR engagement, cytoplasmic TIGIT was phosphorylated at Tyr-225 and Tyr-231 residues. Phosphorylated Tyr-225 recruits adaptor protein beta arrestin 2\|TIGIT/PVR signaling mediates suppression of IFN- gamma production via the NF-kappaB pathway. We identified a new adaptor β-arrestin 2 that associates with phosphorylated TIGIT and mediates recruitment of inositol phosphatase SHIP1 through the ITT-like motif (Fig. 7). Finally, SHIP1 impairs TRAF6 autoubiquitination to abolish NF-kappaB activation, leading to inhibition of IFN- gamma production in NK cells.	SIGNOR-261482
Q9Y5Y9	Q92913	binding	down-regulates activity	0.2	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253439
Q9Y5G5	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-265680
Q9UQ88	O95257	binding	down-regulates activity	0.2	Western blot analysis for SPDEF revealed that overexpression of GADD45α, β and γ prevents SPDEF degradation mediated by CDK11p58 \|We identified CDK11p58 as an interaction partner of GADD45α by co-immunoprecipitation analysis. We corroborated these data by co-immunoprecipitation in vitro translation assays, showing that all three members of the GADD45 family interact with CDK11p58.	SIGNOR-273025

Q96T49

P17252

0

phosphorylation

down-regulates activity

0.2

PKCα phosphorylated the full length recombinant TIMAP in in vitro kinase assay and Ser331 of TIMAP was shown to be phosphorylated by PKC. Phosphorylation of TIMAP upon PKC activation in endothelial cells results in enrichment of TIMAP in the membrane, but no such change can be observed in PKC depleted cells. Phosphorylation state of TIMAP, through affecting PP1 activity, has a remarkable effect on endothelial barrier function.

SIGNOR-273802

P09471

Q9H1C0

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-256997

Q07812

Q05513

0

phosphorylation

down-regulates activity

0.2

Protein kinase czeta abrogates the proapoptotic function of bax through phosphorylation. Overexpression of wild type or the constitutively active a119d but not the dominant negative k281w pkczeta mutant results in bax phosphorylation at serine 184.

SIGNOR-155111

Q92886

Q9HCK8

0

transcriptional regulation

down-regulates quantity

0.2

Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells

SIGNOR-268919

P01019-PRO_0000032458

P12821

0

cleavage

up-regulates quantity

0.2

Ang I is subsequently converted into the major RAS effector peptide Ang II or Ang (1–8), through activity of the zinc-dependent protease ACE, which hydrolyzes two amino acids from the carboxy terminus of Ang I

SIGNOR-260236

O15169

P62140

0

dephosphorylation

down-regulates activity

0.2

The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated

SIGNOR-248567

O96004

Q99717

0

transcriptional regulation

up-regulates quantity

0.2

Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation

SIGNOR-268941

Q96BR9

Q8TBB1

0

polyubiquitination

down-regulates quantity by destabilization

0.2

LNX (ligand of Numb protein-X) is a RING finger and four PDZ domain-containing E3 ubiquitin ligase. Lnx-l induced K48-linked polyubiquitylation of Boz, leading to its proteasomal degradation in human 293T cells and in zebrafish embryos.

SIGNOR-272777

Q16695

Q92831

0

acetylation

down-regulates activity

0.2

The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.

SIGNOR-269621

P38405

P35367

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-256921

C9JLW8

P28482

0

phosphorylation

down-regulates activity

0.2

When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation

SIGNOR-264774

Q07820

P28062

0

null

down-regulates quantity by destabilization

0.2

Surprisingly, siRNA knockdown of PSMB8 (LMP7), an ‘immunoproteasome’ component, reversed IFNγ-induced sensitivity to Fas ligation and prevented Fas/IFNγ-induced degradation of Mcl-1, but did not protect p-Bcl-2 or p-Bcl-XL. Proteasome inhibition markedly increased Mcl-1, p-Bcl-2, and p-Bcl-XL levels after IFNγ treatment

SIGNOR-261974

Q07817

P59635

0

binding

down-regulates activity

0.2

In this study, we show that the overexpression of Bcl-XL, a prosurvival member of the Bcl-2 family, blocks 7a-induced apoptosis, suggesting that the mechanism for apoptosis induction by 7a is at the level of or upstream from the Bcl-2 family.

SIGNOR-261075

P52757

P06239

0

phosphorylation

down-regulates activity

0.2

We now demonstrate Lck-dependent phosphorylation of beta2-chimaerin in response to TCR triggering. We identify Tyr-153 as the Lck-dependent phosphorylation residue and show that its phosphorylation negatively regulates membrane stabilization of beta2-chimaerin, decreasing its GAP activity to Rac.

SIGNOR-276240

P21333

P48454

0

dephosphorylation

down-regulates quantity by destabilization

0.2

Filamin is a phosphoprotein that organizes actin filaments into networks. We report that a purified C-terminal recombinant region of filamin is a suitable substrate for calcineurin |Mutagenesis analysis showed that a dephosphorylation step occurred in Ser 2152, which was previously shown to provide resistance to calpain cleavage when endogenous PKA is activated. In contrast, phosphorylation of Ser 2152 was recently reported to be necessary for membrane dynamic changes. In this regard, we found that CsA protects filamin in platelets from calpain degradation.

SIGNOR-248507

Q2M385

O96017

0

phosphorylation

up-regulates activity

0.2

Chk2 phosphorylates Mps1-T288 after DNA damage.|In the present study, we show that Chk2 stabilizes Mps1 protein and phosphorylates Aurora B-B-serine 331 to prevent mitotic exit in vertebrate cells when the majority of kinetochores are unattached.

SIGNOR-279160

Q6NXT2

Q9Y4C1

0

demethylation

up-regulates activity

0.2

Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.

SIGNOR-276847

P68431

Q92830

0

acetylation

down-regulates activity

0.2

The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.

SIGNOR-269602

Q96NG3

Q96M91

0

binding

up-regulates activity

0.2

CFAP53 likely facilitates the transport of TTC25 and the dyneins into cilia. CFAP53 at the centriolar satellites may form a complex with TTC25 and ODAs, including DNAH5 and DNAH11, and regulate their trafficking into the cilium (Fig 10B).

SIGNOR-265543

P42336

Q5VWQ8

0

binding

down-regulates activity

0.2

DAB2IP inhibits the PI3K–AKT axis by directly interacting with both proteins, reducing phosphorylation and activation of AKT. The GAP activity of DAB2IP can further enforce inhibition of the PI3K–AKT axis by reducing Ras-dependent activation of PI3K p110α subunit.

SIGNOR-254750

O00429

O60260

0

ubiquitination

down-regulates quantity

0.2

Parkin interacts with and subsequently ubiquitinates Drp1, thus promoting its proteasome dependent degradation .|We have demonstrated that parkin promotes Drp1 degradation after OGDR insult.

SIGNOR-278589

Q9NP31

O60469

0

binding

up-regulates activity

0.2

Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels.

SIGNOR-264279

Q8IUX7

P28482

0

phosphorylation

up-regulates activity

0.2

We show that DNA binding by AEBP1 requires both the N- and C-terminal domains of AEBP1, and MAPK interaction with AEBP1 (through its N terminus) results in enhanced DNA binding. A threonine at position 623 within the C-terminal domain of AEBP1 plays an important role in DNA binding by AEBP1, because the mutation results in decreased DNA binding by AEBP1, which leads to a decrease in the transcriptional repression ability of AEBP1. We also show that in vitro phosphorylation of AEBP1 by MAPK is greatly reduced upon mutation of T623. These results suggest that MAPK regulates the transcriptional activity of AEBP1 by a novel dual mechanism, in which MAPK interaction enhances and subsequent phosphorylation decreases the DNA-binding ability of AEBP1.

SIGNOR-262897

P02818

P07711

0

cleavage

down-regulates quantity by destabilization

0.2

This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42.

SIGNOR-256322

P05787

P18031

0

dephosphorylation

down-regulates activity

0.2

Keratin 8 phospho-Tyr-267 is dephosphorylated by PTP1B and promotes insolubility and filament organization, as does the paralogous GFAP tyrosine.

SIGNOR-265495

P10275

O75592

0

ubiquitination

down-regulates quantity by destabilization

0.2

We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop.

SIGNOR-267149

P35244

Q96AP0

0

binding

down-regulates activity

0.2

The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA

SIGNOR-263329

Q9Y4D1

P54792

0

binding

up-regulates

0.2

Importantly, daam1 binds to disheveled (dvl) and thus functions downstream of the frizzled receptors. Little is known of how daam1 is localized and functions in mammalian cells.

SIGNOR-199451

Q9H9R9

Q13049

0

ubiquitination

down-regulates quantity by destabilization

0.2

TRIM32 is an E3 ubiquitin ligase for dysbindin. TRIM32 targets dysbindin for degradation.

SIGNOR-271422

P05198

Q86TM6

0

ubiquitination

down-regulates quantity by destabilization

0.2

HRD1 overexpression also decreased the expression of eIF2alpha and p-eIF2alpha in HKC-8 cells.|HRD1 promoted eIF2alpha ubiquitylation and degradation, thereby providing a protective mechanism that suppressed tubular epithelial cell apoptosis.

SIGNOR-278671

A0A0B4J2F0

Q96S66

0

binding

up-regulates activity

0.2

The PIGBOS microprotein interacts with the ER protein CLCC1. PIGBOS localizes to the mitochondrial outer membrane where itinteracts with the ER protein CLCC1 at ER–mitochondria contact sites. PIGBOS-CLCC1 interaction is necessary for PIGBOS function

SIGNOR-261040

Q12888

O15264

0

phosphorylation

down-regulates activity

0.2

Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK

SIGNOR-264449

Q9BZI1

P28482

0

phosphorylation

up-regulates activity

0.2

We tested the transcriptional properties of Irx2 by dividing it into amino- and carboxy terminal parts and found that Mek1-mediated phosphorylation activates and derepresses the amino and carboxyl parts, respectively. When Ser46 and Ser65 were mutated to alanine (S46A and S65A), phosphorylation was reduced, whereas substitution of Ser83 and Ser103 (S83A and S103A) did not affect phosphorylation.

SIGNOR-263052

Q16695

Q15652

0

demethylation

down-regulates activity

0.2

We now determine that JMJD1C is recruited by USF-1 to various lipogenic genes for H3K9 demethylation to enhance chromatin accessibility in the fed state.

SIGNOR-265170

Q9UI09

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-275587

P06702

P17676

0

transcriptional regulation

up-regulates quantity by expression

0.2

Among several known transcription factor binding motifs, nuclear protein(s) of VD3-treated HL-60 cells and THP-1 cells bound to the CCAAT/enhancer binding protein (C/EBP)-binding motif that was located in the upstream region of the MRP14 gene (-81), as evidenced by the competitive gel mobility-shift assay.|Thus, it was concluded that C/EBP alpha and -beta were able to bind to the C/EBP motif, and that C/EBP alpha bound to the motif in THP-1 cells and C/EBP beta bound to that in the VD3-treated HL-60 cells.

SIGNOR-254044

P25054

P04264

0

phosphorylation

up-regulates activity

0.2

Phosphorylation of this central repeat region of APC significantly enhances its affinity for β-catenin. When the repeats are phosphorylated by the cooperative action of CK1 and GSK3β, the binding interaction is significantly altered and enhanced.

SIGNOR-251879

P11308

P48729

0

phosphorylation

down-regulates quantity by destabilization

0.2

Using in vitro kinase assays, we further demonstrated that deletion of degron 1 largely abolished CKI-mediated phosphorylation of ERG (Figure S5B), indicating that serine residues within degron 1 are the major CKI phosphorylation sites.

SIGNOR-276935

P63092

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 ‚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-256787

P37231

Q8IXJ9

0

binding

down-regulates activity

0.2

Our genome-wide analysis confirmed the physiological roles of ASXL1 and ASXL2 in adipogenesis at the molecular level, supporting the hypothesis that ASXL1 is an authentic corepressor of PPARγ, whereas ASXL2 is a PPARγ coactivator, and that together ASXL1 and ASXL2 fine-tune adipogenesis via differential regulation of PPARγ.

SIGNOR-260064

Q96E09

O14757

0

phosphorylation

down-regulates activity

0.2

Knockout of FAM122A results in activation of PP2A-B55α, a phosphatase that dephosphorylates the WEE1 protein and rescues WEE1 from ubiquitin-mediated degradation. in tumor cells with oncogene-driven replication stress, CHK1 can directly phosphorylate FAM122A, leading to activation of the PP2A-B55α phosphatase and increased WEE1 expression.

SIGNOR-266380

Q13371

P25098

0

phosphorylation

down-regulates activity

0.2

The phosphorylation of purified phosducin and PhLP by recombinant GRK2 proceeds rapidly and stoichiometrically (0.82 +/- 0.1 and 0.83 +/- 0.09 mol of P (i)/mol of protein, respectively).

SIGNOR-279178

Q16891

P17612

0

phosphorylation

down-regulates activity

0.2

PKA directly phosphorylated the Ser528 residue of MIC60. Phosphorylation of MIC60 Interrupts Parkin Recruitment and Formation of the MICOS Complex

SIGNOR-266302

P55089

P10275

0

transcriptional regulation

down-regulates quantity by repression

0.2

When cells were treated with DHT alone, AR was upregulated and translocated into the nuclei, which might repress UCN1 expression via a potential androgen-responsive element found in human CRF family promoter|These data suggest that DHT differentially influences UCN1 levels under normal and inflammatory conditions in human umbilical vein endothelial cells, which involves AR-dependent and -independent mechanisms respectively.

SIGNOR-253688

P08670

Q05513

0

phosphorylation

up-regulates activity

0.2

Results suggest that aPKCs target multiple activation sites (Ser33/39/56) on Vimentin and therefore is essential for VIF dynamics regulation during the metastasis of prostate cancer cells.

SIGNOR-277622

Q9UKX7

P27361

0

phosphorylation

down-regulates activity

0.2

Erk phosphorylates nup50 at ser221 and ser315 phosphorylation of nup50 reduces affinity for importin-beta

SIGNOR-187378

Q9HD90

Q12857

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-268891

Q86T82

Q01094

0

transcriptional regulation

up-regulates quantity by expression

0.2

USP37 was induced by E2F transcription factors in G1|Ectopic E2F1 activated the wild-type promoter, but not the mutant promoter, 3-fold over basal levels in 293T cells (Figure 4F), confirming the functionality of the E2F binding sites in the USP37 promoter.

SIGNOR-265047

P30622

P17252

0

phosphorylation

down-regulates

0.2

Furthermore, by using phosphoproteomic analysis, we determined that s309 and s311 of clip-170 are phosphorylated in cells and mapped s311 as a protein kinase a (pka) phosphorylation site.phosphorylation of s311 may be critical for establishing the ?folded Back? Conformation of clip-170clip-170 open and folded back conformations represent active and inactive modes of the protein, respectively

SIGNOR-165857

Q96AC1

Q8IWT3

0

ubiquitination

down-regulates quantity by destabilization

0.2

M-phase-specific CDK1–cyclin B1 complex directly binds KIND1 and KIND2 and phosphorylates a conserved proline-directed CDK1 consensus motif in the flexible and intrinsically disordered loop of the F1 domain. This then results in the recruitment of the CUL9–FBXL10 complex, modification with K48-linked polyubiquitin chains and proteasomal degradation of KIND1 and KIND2.

SIGNOR-276717

Q2Q1W2

P17612

0

phosphorylation

up-regulates quantity by stabilization

0.2

These observations suggested that LINK-A expression potentially inhibits PKA phosphorylation/activity and PKA-mediated phosphorylation of TRIM71 at Ser3.

SIGNOR-277454

O60885

Q9C0F0

0

binding

up-regulates activity

0.2

We report a critical link between BAP1 complex and BRD4, which is bridged by the physical interaction between ASXL3 and BRD4 in an SCLC subtype (SCLC-A), which expresses a high level of ASCL1. We further showed that ASXL3 functions as an adaptor protein, which directly interacts with BRD4's extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), and maintains chromatin occupancy of BRD4 to active enhancers.

SIGNOR-266762

P37231

P11274

0

phosphorylation

down-regulates activity

0.2

Overexpression of Bcr WT inhibited PPARgamma transcriptional activity (XREF_FIG).|Point-mutation and in vitro kinase analysis showed that PPAR\u03b3 was phosphorylated by Bcr at serine 82.

SIGNOR-279441

Q15910

Q9P275

0

deubiquitination

up-regulates quantity by stabilization

0.2

We observed a MELK-mediated increase of EZH2 S220 phosphorylation along with a concomitant loss of EZH2 K222 ubiquitination, suggesting a phosphorylation-dependent regulation of EZH2 ubiquitination. Furthermore, we identify USP36 as the deubiquitinating enzyme that deubiquitinates EZH2 at K222.

SIGNOR-277481

P17661

Q14814

0

transcriptional regulation

up-regulates quantity by expression

0.2

Ectopic expression of myogenin and a specific Mef2 isoform induced myogenic differentiation without activating endogenous MyoD expression. Under these conditions, the regulatory sequences of late gene loci were not in close proximity, and these genes were prematurely activated.

SIGNOR-241504

O95140

Q9NX47

0

ubiquitination

up-regulates activity

0.2

Taken together, these results suggested that MITOL regulates endoplasmic reticulum tethering to mitochondria by activating Mfn2 via K192 ubiquitination.|Therefore, MITOL specifically ubiquitinates mitochondrial Mfn2.

SIGNOR-278553

Q5TEC6

Q9Y4C1

0

demethylation

up-regulates activity

0.2

Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.

SIGNOR-276843

Q96P70

Q13315

0

phosphorylation

up-regulates activity

0.2

In line with our previous results, IR exposure induced the nuclear accumulation of RanBP9, which was prevented by ATM inhibition using KU-55933.|Taken together these data indicate that RanBP9 is a novel target of ATM and that ATM phosphorylates at least two different residues (S181 and S603) of RanBP9 following IR exposure.

SIGNOR-278910

P30566

Q96KS0

0

hydroxylation

up-regulates activity

0.2

ADSL is hydroxylated by EglN2 on Proline 24. An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. ADSL regulates cMYC protein level through adenosine levels

SIGNOR-266613

P23786

Q86TM6

0

ubiquitination

down-regulates quantity

0.2

Taken together, these data suggest that HRD1 selectively and specifically downregulates intracellular CPT2 levels.|These results demonstrate that HRD1 ubiquitinates CPT2, which is processed through Lys-48-linked ubiquitin chains.

SIGNOR-278723

P01024

Q96PZ7

0

binding

down-regulates quantity

0.2

CUB and sushi multiple domains 1 (CSMD1) is a relatively poorly studied large transmembrane protein of 390 kDa composed of 14 N-terminal CUB domains interspersed with complement control protein (CCP) domains followed by 15 consecutive CCP domains. The active domains of CSMD1 were then identified in CCP17-21, which were shown to interact with C4b and C3b and present these complement proteins for degradation by factor

SIGNOR-265148

Q9BZX2

Q86U44

0

post transcriptional regulation

up-regulates quantity by stabilization

0.2

Furthermore, the m6A modification regulated by METTL3 led to UCK2 increased messenger RNA (mRNA) stability in melanoma cancer. Functional and mechanistic experiments indicated that UCK2 enhanced the metastasis of melanoma cancer cells through the WNT/β-catenin pathway.

SIGNOR-275862

P25098

P12931

0

phosphorylation

up-regulates activity

0.2

Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq.

SIGNOR-266305

Q12933

P62714

0

dephosphorylation

down-regulates activity

0.2

We show that the Thr117 residue in TRAF2 is phosphorylated following TNFalpha stimulation. This phosphorylation process is modulated by PP2A and is required for TRAF2 functional activity.

SIGNOR-248597

P10275

Q8WY64

0

ubiquitination

down-regulates quantity

0.2

MYLIP knockdown increased AR protein levels whereas CNPY2 knockdown increased MYLIP and reduced AR protein expression levels.|These results showed that the E3 ligase MYLIP could ubiquitinate lysine 845 and 847 residues of AR.

SIGNOR-278766

P37231

P36406

0

ubiquitination

up-regulates quantity by stabilization

0.2

In this study, we showed that TRIM23 mediates atypical polyubiquitin conjugation including M1- and K27 linked ubiquitin chains to PPARgamma and that ubiquitination of PPARgamma by TRIM23 causes reduced recognition of PPARgamma by 26S proteasome.

SIGNOR-278577

Q9UQ88

O75293

0

binding

down-regulates activity

0.2

Western blot analysis for SPDEF revealed that overexpression of GADD45α, β and γ prevents SPDEF degradation mediated by CDK11p58 |We identified CDK11p58 as an interaction partner of GADD45α by co-immunoprecipitation analysis. We corroborated these data by co-immunoprecipitation in vitro translation assays, showing that all three members of the GADD45 family interact with CDK11p58.

SIGNOR-273024

Q06830

Q13043

0

phosphorylation

down-regulates activity

0.2

Mst1 inactivates Prdx1 by phosphorylating it at Thr-90 and Thr-183, leading to accumulation of hydrogen peroxide in cells.Prdx1 is phosphorylated by Mst1 predominantly at Thr-18, Thr-90, and Thr-183.

SIGNOR-276486

P19086

Q96G91

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-257328

O15259

P68400

0

phosphorylation

up-regulates

0.2

Casein kinase 2 (ck2)-mediated phosphorylation of three critical serine residues within a cluster of acidic amino acids in nephrocystin mediates pacs-1 binding, and is essential for colocalization of nephrocystin with pacs-1 at the base of cilia. Inhibition of ck2 activity abrogates this interaction and results in the loss of correct nephrocystin targeting.

SIGNOR-142343

P15976

Q9NQU5

0

phosphorylation

up-regulates activity

0.2

In addition, PAK5 knockdown also markedly reduced the association of GATA1 with HDAC3/4.|PAK5 phosphorylates the transcription factor GATA1 mainly at Ser161 and Ser 187, phosphorylated GATA1 recruits more HDAC3/4 to the promoter of E-cadherin and consequently suppresses the transcription of E-cadherin gene and promotes the EMT of breast cancer cells.

SIGNOR-278415

O00303

Q7Z6M2

0

polyubiquitination

down-regulates quantity by destabilization

0.2

Mediation of eIF3-f polyubiquitination by the SCFMAFbx. The association of MAFbx with the essential Skp1, Roc 1 and Cul1 proteins, specific components of an E3 ubiquitin–protein ligase (SCFMAFbx), was previously described. Here, we present evidence that during muscle atrophy MAFbx targets the eukaryotic initiation factor 3 subunit 5 (eIF3-f) for ubiquitination and degradation by the proteasome.

SIGNOR-271768

P05556

Q9Y5H6

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.

SIGNOR-265671

Q13546

Q8TE49

0

deubiquitination

down-regulates activity

0.2

NF-kappaB Suppression by the Deubiquitinating Enzyme Cezanne|Our study provides several lines of evidence to suggest that Cezanne suppresses TNFR signaling to NF-κB by targeting RIP1 for deubiquitination.

SIGNOR-268410

P08754

P43657

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-256868

Q13177

Q9NYV4

0

phosphorylation

up-regulates activity

0.2

Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway

SIGNOR-273110

Q15746

Q9C009

0

transcriptional regulation

down-regulates quantity by repression

0.2

Results from this analysis revealed that the inhibitory activity of HFH-1 was contained within the forkhead DNA-binding domain. Truncated HFH-1 proteins that lack the entire forkhead domain were unable to repress telokin promoter activity, in contrast expression of the forkhead domain alone was able to repress promoter activity

SIGNOR-261609

Q9UBI6

Q99835

0

binding

up-regulates

0.2

As pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp.

SIGNOR-152817

O43776

P18848

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-269422

Q9NRM7

Q9Y4B6

0

binding

down-regulates quantity by destabilization

0.2

CRL4 DCAF1 ubiquitylates and inhibits Lats.

SIGNOR-272227

P18848

P68400

0

phosphorylation

down-regulates quantity by destabilization

0.2

By using mutants of ATF4 we identified serine 215 as the main CK2 phosphorylation site. The ATF4 S215A mutant turned out to be more stable than the wild-type form.

SIGNOR-276425

Q86WV6

O75385

0

phosphorylation

down-regulates activity

0.2

Collectively, our data indicates that cGAS is essential for the activation of AMPK and ULK1 suppression of STING (XREF_FIG) and that cGAMPs are responsible for triggering the dephosphorylation of AMPK T172 and activation of ULK1 which phosphorylates STING on S366 to impede its activity (XREF_FIG).|Collectively, our data indicates that cGAS is essential for the activation of AMPK/ULK1 suppression of STING ( xref ) and that cGAMPs are responsible for triggering the dephosphorylation of AMPK T172 and activation of ULK1 which phosphorylates STING on S366 to impede its activity ( xref ).

SIGNOR-279316

Q5FBB7

O14965

0

phosphorylation

up-regulates activity

0.2

Loss of INCENP/Aurora B in Mitosis Correlates with Delocalization of MEI-S332|MEI-S332 Is Phosphorylated by Aurora B In Vitro|Of these, MEI-S332S124,125,126A was a poor substrate for Aurora B kinase in vitro

SIGNOR-252046

Q16695

Q9UGL1

0

demethylation

up-regulates activity

0.2

KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.

SIGNOR-264303

Q06330

Q9UQF2

0

binding

down-regulates

0.2

Here, we show that jip1 suppresses notch1 activity. Jip1 was found to physically associate with either intracellular domain of notch1 or rbp-jk and interfere with the interaction between them.

SIGNOR-165713

P08754

P35367

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-257163

Q86UX7

P17252

0

phosphorylation

up-regulates activity

0.2

PKC-induced phosphorylation events, as we have shown kindlin-3 to be a PKC phosphorylation target (Fig. 6C), are often followed by rapid activation of phosphatases (38).

SIGNOR-266415

Q13085

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-271598

P11362

Q02156

0

phosphorylation

up-regulates

0.2

Phosphorylation of serine 779 in fibroblast growth factor receptor 1 and 2 by protein kinase c(epsilon) regulates ras/mitogen-activated protein kinase signaling and neuronal differentiationour findings show that in addition to fgfr tyrosine phosphorylation, the phosphorylation of a conserved serine residue, ser(779), can quantitatively control ras/mapk signaling to promote specific cellular responses.

SIGNOR-201671

Q9GZQ8

Q8TD19

0

phosphorylation

down-regulates activity

0.2

LC3B is phosphorylated at Thr-50 within the LDS by serine/threonine kinase (STK) 3 and STK4. Here, we identified LIR motifs in STK3 and atypical protein kinase Cζ (PKCζ) and never in mitosis A (NIMA)-related kinase 9 (NEK9). All three kinases phosphorylated LC3B Thr-50 in vitro A phospho-mimicking substitution of Thr-50 impaired binding of several LIR-containing proteins, such as ATG4B, FYVE, and coiled-coil domain-containing 1 (FYCO1), and autophagy cargo receptors p62/sequestosome 1 (SQSTM1) and neighbor of BRCA1 gene (NBR1).

SIGNOR-273904

Q07820

Q9NX47

0

ubiquitination

down-regulates quantity by destabilization

0.2

MARCH5 promotes ubiquitination of MCL1 and NOXA.|Together, this suggests that degradation of MCL1 by MARCH5 depends on binding to NOXA, but degradation of NOXA may be promoted by additional E3-ligases if MCL1 levels become limited, or can simply no longer be degraded.

SIGNOR-278700

Q9UPP1

P28482

0

phosphorylation

down-regulates activity

0.2

Upon IFNgamma treatment, PHF8 is phosphorylated by ERK2 and evicted from the promoters, which correlates with an increase in H4K20me1 and H3K4me3 levels.

SIGNOR-279745

P16144

Q99704

0

binding

down-regulates activity

0.2

Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation

SIGNOR-257689

P09471

P32249

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-256994

P35611

Q05513

0

phosphorylation

up-regulates

0.2

These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc.

SIGNOR-43834

Q07820

Q13627

0

phosphorylation

up-regulates quantity

0.2

Furthermore, DYRK1A likely directly bound and phosphorylated Mcl-1, thereby enhancing Mcl-1 protein stability and contributing to the development of acquired resistance to Bcl-2 inhibitors.|DYRK1A upregulates Mcl-1 expression in NSCLC cells.|We demonstrated that DYRK1A suppression by siRNA or harmine decreased the phosphorylation of Mcl-1 at Ser159/Thr163.

SIGNOR-279704

P32121

Q495A1

0

binding

up-regulates activity

0.2

With TIGIT/PVR engagement, cytoplasmic TIGIT was phosphorylated at Tyr-225 and Tyr-231 residues. Phosphorylated Tyr-225 recruits adaptor protein beta arrestin 2|TIGIT/PVR signaling mediates suppression of IFN- gamma production via the NF-kappaB pathway. We identified a new adaptor β-arrestin 2 that associates with phosphorylated TIGIT and mediates recruitment of inositol phosphatase SHIP1 through the ITT-like motif (Fig. 7). Finally, SHIP1 impairs TRAF6 autoubiquitination to abolish NF-kappaB activation, leading to inhibition of IFN- gamma production in NK cells.

SIGNOR-261482

Q9Y5Y9

Q92913

0

binding

down-regulates activity

0.2

Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.

SIGNOR-253439

Q9Y5G5

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-265680

Q9UQ88

O95257

0

binding

down-regulates activity

0.2

Western blot analysis for SPDEF revealed that overexpression of GADD45α, β and γ prevents SPDEF degradation mediated by CDK11p58 |We identified CDK11p58 as an interaction partner of GADD45α by co-immunoprecipitation analysis. We corroborated these data by co-immunoprecipitation in vitro translation assays, showing that all three members of the GADD45 family interact with CDK11p58.

SIGNOR-273025