GleghornLab/Signor_3class · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels int64 0 2	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
O95486	Q9NR31	2	binding	up-regulates quantity	0.756	Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer.	SIGNOR-265303
Q86YT6	Q00535	0	phosphorylation	up-regulates activity	0.325	Similar to the mechanism of PAR-1 regulation of Mib in neurogenesis, CDK5 phosphorylation is proposed to enhance Mib1 ligase activity leading to destabilization.\|The cyclin dependent kinase 5 (CDK5) enriched in neurons phosphorylates Mib1 and suppresses the inhibitory effects of Mib1 on neurite morphology.	SIGNOR-280217
P17252	P08581	1	phosphorylation	down-regulates	0.256	These data show that phosphorylation of ser985 is a key mechanism for the negative regulation of hgf/sf receptor.	SIGNOR-37718
P60484	O15327	0	dephosphorylation	down-regulates activity	0.632	In support, the increase in PTEN caused by INPP4B knockdown was associated with increased phosphorylation of the Ser380, Thr382, Thr383 and Ser385 cluster of the protein (XREF_FIG), which is known to increase PTEN half-life, in colon cancer cells.\|Exogenous INPP4B could pull down and dephosphorylate endogenous PTEN, suggesting that effect of INPP4B on PTEN in colon cancer cells is not due to cell-type-specific characteristics of INPP4B per se.\|INPP4B downregulates PTEN in colon cancer cells.	SIGNOR-277018
P21802	P05230	2	binding	up-regulates	0.909	We have crystallized a complex between human FGF1 and a two-domain extracellular fragment of human FGFR2.	SIGNOR-73811
Q9Y3M8	P61586	1	gtpase-activating protein	down-regulates activity	0.645	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260521
P19784	P42768	1	phosphorylation	up-regulates activity	0.347	We identify two phosphorylation sites in the VCA domain of WASP at serines 483 and 484. S483 and S484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the VCA domain for the Arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length WASP molecule.	SIGNOR-251048
Q13131	Q8N5S9	0	phosphorylation	up-regulates	0.462	Ampka1 activators increased phosphorylation level and cytoplasmic localization (reduced nuclear/cytoplasmic ratio). Ampka1 activators reduced rna synthesis in the nucleoli.	SIGNOR-176598
Q96EQ8	Q9BYX4	1	polyubiquitination	down-regulates quantity by destabilization	0.657	Here, we found that RIG-I undergoes proteasomal degradation after conjugation to ubiquitin by RNF125. Further, RNF125 conjugates ubiquitin to MDA5, a family protein of RIG-I as well as IPS-1, which is also a downstream protein of RIG-I signaling that results in suppressing the functions of these proteins. Because RNF125 is enhanced by IFN, these functions constitute a negative regulatory loop circuit for IFN production.	SIGNOR-271646
O96013	P17676	1	phosphorylation	up-regulates activity	0.2	Importantly, we found that PAK4 enhanced CEBPB phosphorylation on Thr 235.\|In summary, we showed that PAK4 mediated CEBPB activation upregulated CLDN4 expression to promote breast cancer cell migration and invasion.	SIGNOR-280055
Q9HBW0	P19086	2	binding	up-regulates activity	0.25	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257324
P63096	Q8TDV5	2	binding	up-regulates activity	0.278	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-257040
P27707	P67775	0	dephosphorylation	down-regulates activity	0.2	Protein phosphatase 2A regulates deoxycytidine kinase activity via Ser-74 dephosphorylation\|Deoxycytidine kinase (dCK) is a critical enzyme for activation of anticancer nucleoside analogs. Its activity is controlled via Ser-74 phosphorylation. Here, we investigated which Ser/Thr phosphatase dephosphorylates Ser-74. In cells, the PP1/PP2A inhibitor okadaic acid increased both dCK activity and Ser-74 phosphorylation	SIGNOR-275803
P17252	Q9UJY1	1	phosphorylation	up-regulates activity	0.307	Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation	SIGNOR-107688
P10275	Q13772	2	binding	up-regulates	0.86	We demonstrated that ara70 and ar physically interact and that ara70 can function as an androgen-dependent coactivator for ar.	SIGNOR-67684
Q92934	P04637	2	binding	up-regulates activity	0.328	We also demonstrate that bad physically interacts with cytoplasmic p53. bad is able to direct p53 to the mitochondria and forms a p53/bad complex at the mitochondria. the mitochondrial p53/bad complex promotes apoptosis	SIGNOR-149815
O43918	Q05084	1	transcriptional regulation	down-regulates quantity by repression	0.362	Sequence variation in promoter of Ica1 gene, which encodes protein implicated in type 1 diabetes, causes transcription factor autoimmune regulator (AIRE) to increase its binding and down-regulate expression.	SIGNOR-268973
Q05086	O94788	1	ubiquitination	down-regulates quantity by destabilization	0.2	Hyperactivity of E3 ubiquitin (Ub) ligase UBE3A, stemming from 15q11-q13 copy number variations, accounts for 1%-3% of ASD cases worldwide, but the underlying mechanisms remain incompletely characterized. Here we report that the functionality of ALDH1A2, the rate-limiting enzyme of retinoic acid (RA) synthesis, is negatively regulated by UBE3A in a ubiquitylation-dependent manner.	SIGNOR-265135
Q05086	P49815	1	ubiquitination	down-regulates quantity by destabilization	0.629	An in vivo ubiquitination assay was done to reveal that E6AP promoted the ubiquitination of TSC2 independent of HPV16 E6. We further found that TSC2 bound E6AP in the presence as well as in the absence of HPV16 E6. The binding regions on E6AP and TSC2 have been identified as amino acid (aa) 260-316, aa 428-500 and aa 1-175, aa 1251-1807, respectively. Taken together, degradation of TSC2 is mediated by E6AP ubiquitin ligase.	SIGNOR-271396
Q8IXJ6	P15259	1	deacetylation	up-regulates activity	0.2	Here we report that PGAM is acetylated at lysine 100 (K100), an active site residue that is invariably conserved from bacteria, to yeast, plant, and mammals. K100 acetylation is detected in fly, mouse, and human cells and in multiple tissues and decreases PGAM2 activity. The cytosolic protein deacetylase sirtuin 2 (SIRT2) deacetylates and activates PGAM2.	SIGNOR-266518
O14737	P68400	0	phosphorylation	up-regulates	0.2	Programmed cell death 5 (pdcd5), a protein involved in cell death and down-regulated in different forms of human tumors. Pdcd5 is phosphorylated in vitro by both ck2alpha subunit and by the ck2 holoenzyme at a residue, s118, which is found phosphorylated in vivo. Transfection of the non-phosphorylatable mutant (s118a) impairs the pdcd5 acceleration of either doxorubimicin- or uv-induced apoptosis in u2os cells	SIGNOR-187106
P06239	Q9UJZ1	2	binding	up-regulates activity	0.2	In these studies, we also found that SLP-2 interacted with Lck, ZAP70, LAT, and PLC-gamma1 during the 30-min period following stimulation in vitro\|The SLP-2-associated pool of these molecules became phosphorylated/activated in a sequential manner, a profile compatible with their temporal involvement in early TCR signalling.	SIGNOR-260376
P30307	P43405	0	phosphorylation	down-regulates activity	0.36	SYK Phosphorylates CDC25C on Serine 216.\|We now provide new genetic and biochemical evidence that SYK is an inhibitor of CDC25C in B-lineage lymphoid cells as well as non lymphohematopoietic cells, that prevents premature entry into mitosis by phosphorylating CDC25C at S216 when G 2 checkpoint responses are activated.	SIGNOR-278328
Q70Z35	P60953	1	guanine nucleotide exchange factor	up-regulates activity	0.423	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260572
O60486	O75326	2	binding	up-regulates	0.913	Plexin-c1 is a receptor for the gpi-anchored semaphorin sema7a. The cytoplasmic domain of plexins associates with a tyrosine kinase activity. Plexins may also act as ligands mediating repulsion in epithelial cells in vitro.	SIGNOR-71260
Q9NRM7	Q4VCS5	1	phosphorylation	up-regulates quantity by stabilization	0.516	Here low serum and high LATS1 activity are found to enhance the levels of the 130-kDa isoform of angiomotin (Amot130) through phosphorylation by LATS1/2 at serine 175, which then forms a binding site for 14-3-3. Such phosphorylation, in turn, enables the ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiquitinate, and stabilize Amot130	SIGNOR-275846
P15391	P07948	2	binding	up-regulates activity	0.772	CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades.	SIGNOR-242894
Q86YT6	Q86YT6	2	polyubiquitination	down-regulates quantity by destabilization	0.2	The RING finger motifs of DIP-1 have E3 ligase activity that can auto-ubiquitinate DIP-1 in vitro. In vivo, DIP-1 is detected as a polyubiquitinated protein, suggesting that the intracellular levels of DIP-1 are regulated by the ubiquitin-proteasome system.	SIGNOR-272603
P04150	Q16649	1	transcriptional regulation	up-regulates quantity by expression	0.296	GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription	SIGNOR-268051
O75385	Q15437	1	phosphorylation	up-regulates quantity by stabilization	0.2	Here, we show that the F-box protein FBXW5 targets SEC23B, a component of COPII, for proteasomal degradation and that this event limits the autophagic flux in the presence of nutrients. In response to starvation, ULK1 phosphorylates SEC23B on Serine 186, preventing the interaction of SEC23B with FBXW5 and, therefore, inhibiting SEC23B degradation.	SIGNOR-265285
P84243	Q09472	0	acetylation	down-regulates activity	0.2	These results highlight the substrate and site specificities of hats in cells, demonstrate the distinct roles of gcn5/pcaf- and cbp/p300-mediated histone acetylations in gene activation, and suggest an important role of cbp/p300-mediated h3k18/27ac in nr-dependent transcription.	SIGNOR-170266
P49137	P28482	0	phosphorylation	up-regulates	0.507	Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation of any two of the three residues thr222, ser272 and thr334. gst-mapkap kinase-2 lacking the n-terminal domain was inactive, but activated fully when phosphorylated at thr222, ser272 and thr334 by p42 mapk or rk.	SIGNOR-44343
P05412	Q969H0	2	binding	down-regulates quantity by destabilization	0.495	We report that in neurons the stability of c-Jun is regulated by the E3 ligase SCF(Fbw7), which ubiquitinates phosphorylated c-Jun and facilitates c-Jun degradation.	SIGNOR-272950
Q5VWQ8	P27986	2	binding	down-regulates activity	0.283	DAB2IP binds the p85 subunit of PI3K through its PR domain and prevents PI3K-p85 relocation from the cytoplasm to the membrane, a necessary step for PI3K activation and signaling to AKT. Notably, DAB2IP reinforces this inhibitory effect by directly binding AKT.2	SIGNOR-254757
P26992	Q9UBD9	2	binding	up-regulates	0.702	Striking phenotypic differences between cntf- and cntfr-deficient mice suggest that cntfr serves as a receptor for a second, developmentally important ligand. We have identified this factor as a stable secreted complex of cardiotrophin-like cytokine (clc) and the soluble receptor cytokine-like factor-1 (clf).	SIGNOR-81376
Q09472	P15172	1	acetylation	up-regulates	0.681	Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo.	SIGNOR-81053
Q92886	Q13164	0	phosphorylation	up-regulates activity	0.35	Activation of ERK5 potentiates while inhibition of ERK5 attenuates Neurog1 stimulated neurogenesis.\|ERK5 directly phosphorylated Neurog1 in vitro and modulated the transcriptional and pro-neural activity of Neurog1 in cortical progenitors.	SIGNOR-278364
P06213	Q12923	0	dephosphorylation	down-regulates	0.26	We demonstrate that ptpl1, like ptp1b, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that ptpl1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines.	SIGNOR-132555
O60260	Q9NX09	1	ubiquitination	down-regulates quantity by destabilization	0.2	In conclusion, our work in cellular and animal models and in human samples strongly indicates that RTP801 is a substrate of parkin and that RTP801 elevation due to parkin loss of function in both AR-JP and sporadic Parkinson's disease may contribute to neurodegeneration.\|We showed that parkin poly-ubiquitinates RTP801, both in vitro and in vivo.	SIGNOR-278560
P08254	Q9ULU4	0	transcriptional regulation	down-regulates quantity by repression	0.2	Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported	SIGNOR-262043
O76064	P0C0S8	1	ubiquitination	up-regulates	0.2	Rnf8 and ubc13 ubiquitylate h2a and h2ax, but other substrates probably exist.	SIGNOR-166174
Q05397	O75962	1	phosphorylation	up-regulates activity	0.509	A FAK phosphorylation site, tyrosine residue 2737, was identified in subdomain I of the Trio kinase domain. Additionally, in vitro phosphorylation assays and in vivo co-expression studies indicated that Trio enhances FAK kinase activity.	SIGNOR-249188
P63000	Q7Z6I6	0	gtpase-activating protein	down-regulates activity	0.403	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260486
P20042	P49770	0	guanine nucleotide exchange factor	up-regulates activity	0.751	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.	SIGNOR-269130
P00747	P02749	1	cleavage	down-regulates activity	0.458	Plasmin can reduce the function of human beta2 glycoprotein I by cleaving domain V into a nicked form\| The cleavage site of r-Domain V and beta2GPI by plasmin was proved to be Lys 317-Thr 318 by amino acid sequence analysis of the digest and of the C-terminal peptide isolated by high-performance liquid chromatography. The cleavage was completely inhibited by plasmin inhibitor (alpha2PI). The nicked form was demonstrated to show reduced affinity for CL with a dissociation constant of one order of magnitude larger than that of the intact beta2GPI.	SIGNOR-266996
P00533	Q05397	1	phosphorylation	up-regulates	0.595	In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases.	SIGNOR-167646
P49841	Q13237	0	phosphorylation	down-regulates activity	0.258	These data indicate that hypertrophic differentiation of growth plate chondrocytes during skeletal growth is promoted by phosphorylation and inactivation of GSK-3beta by cGKII.	SIGNOR-280095
Q96KN7	Q92834	2	binding	down-regulates activity	0.714	The RPGR H98Q and F130C mutants exhibit compromised interaction with RPGRIP1, suggesting that RPGR–RPGRIP1 interaction may be an important determinant of RPGR activity. As RPGRIP1 appears to link RPGR to the cilium, it is possible that RPGR's effect on RAB8A function may occur in distinct subcellular compartments of photoreceptors and that RPGRIP1 and other interacting proteins may modulate targeting of RPGR to such compartments.	SIGNOR-253031
Q15398	Q9Y3I1	2	binding	down-regulates quantity by destabilization	0.45	We show here that Fbx7, an F-box protein without WD repeats and leucine-rich repeats, is required for the proteasome-mediated proteolysis of the hepatoma up-regulated protein (HURP).Thus, Fbx7 is a functional adaptor of the SCF complex with a proline-rich region as the substrate-binding module. Depletion of Fbx7 by small interfering RNA leads to depression of HURP ubiquitination and accumulation of HURP abundance. In the SCFFbx7 complex, Fbx7 recruits HURP through its C-terminal proline-rich region in a Cdk1-cyclin B-phosphorylation dependent manner.	SIGNOR-271506
P31749	P62714	0	dephosphorylation	down-regulates	0.508	These results confirm that the activity changes observed are achieved by a reversible phosphorylation mechanism, and also argue that pp2a may negatively regulate rac-pk activity in vivo. Dephosphorylation of the activated rac-pk in itro by pp2ac resulted in an 87% reduction of kinase activity	SIGNOR-252636
Q9H4P4	O60260	1	polyubiquitination	down-regulates quantity by destabilization	0.2	Here we further demonstrated that overexpression of Nrdp1 significantly reduced the endogenous Parkin level in an Nrdp1 dosage-dependent and proteasome-dependent manner. More importantly, Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells, indicating Parkin is an Nrdp1 substrate.	SIGNOR-272639
P07437	P84022	2	binding	down-regulates activity	0.2	Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin.	SIGNOR-232113
P22888	P10589	0	transcriptional regulation	down-regulates quantity by repression	0.275	Functional analysis showed that EAR2 and EAR3/COUP-TFI repressed the hLHR promoter activity, whereas TR4 activated hLHR gene transcription.	SIGNOR-266218
Q99500	O95837	2	binding	up-regulates activity	0.385	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-257437
P78504	O76050	0	ubiquitination	down-regulates quantity by destabilization	0.707	We find that NEDD4 targets an RNA-binding protein, NANOS2, in spermatogonia to destabilize it, leading to cell differentiation.\|Jagged1 is also regulated by the E3 ligase Neuralized-like1 (Neurl1), which induces the monoubiquitination of membrane tethered Jagged1 in the C-terminal region.	SIGNOR-278772
P10275	P11309	0	phosphorylation	up-regulates activity	0.381	PIM1 phosphorylates the AR and 14-3-3 ζ and coordinates their interaction. PIM1 phosphorylation of the AR and 14-3-3 ζ enhances their interaction and shifts their occupancy on chromatin, resulting in 14-3-3 ζ co-regulation of AR, likely by recruiting other AR co-regulators such as hnRNPK and TRIM28.	SIGNOR-277575
P16949	Q13554	0	phosphorylation	down-regulates	0.515	Stimulation via cd2 activated multiple signal transduction pathways, resulting in phosphorylation of distinct sites of stathmin. Ser16 of recombinant human stathmin was phosphorylated also by purified cam kinase ii, and in vivo, cam kinase ii activity was indeed stimulated in cd2-triggered jurkat cells.	SIGNOR-59358
Q01860	P26358	1	transcriptional regulation	up-regulates quantity by expression	0.437	Oct4 and Nanog upregulate Dnmt1 through direct binding to its promoter, thereby leading to the repressed expression of p16 and p21 and genes associated with development and lineage differentiation	SIGNOR-253158
P12259	P08246	0	cleavage	up-regulates activity	0.366	Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V\|NH2-terminal sequence analysis of F.V treated with HNE indicated cleavage at Ile819 and Ile1484 under conditions during which the procofactor expressed enhanced cofactor activity in the prothrombinase complex.	SIGNOR-263637
Q15418	P49841	1	phosphorylation	down-regulates	0.359	S6k then phosphorylates the same serine residue on gsk3 that is targeted by pkb/akt (fig. 1), thereby inhibiting its activity.	SIGNOR-110917
P29350	Q8NER1	1	dephosphorylation	down-regulates activity	0.2	Shp-1 dephosphorylates TRPV1 in dorsal root ganglion neurons and alleviates CFA-induced inflammatory pain in rats.\|These results suggested that Shp-1 dephosphorylated and inhibited TRPV1 in DRG neurons, contributing to maintain thermal nociceptive thresholds in normal rats, and as a compensatory mechanism, Shp-1 increased in DRGs of rats with CFA-induced inflammatory pain, which was involved in protecting against excessive thermal hyperalgesia.	SIGNOR-277129
P15259	Q8IXJ6	0	deacetylation	up-regulates activity	0.2	Here we report that PGAM is acetylated at lysine 100 (K100), an active site residue that is invariably conserved from bacteria, to yeast, plant, and mammals. K100 acetylation is detected in fly, mouse, and human cells and in multiple tissues and decreases PGAM2 activity. The cytosolic protein deacetylase sirtuin 2 (SIRT2) deacetylates and activates PGAM2.	SIGNOR-266518
P12272	P07288	0	cleavage	down-regulates activity	0.422	Our study demonstrates that PTHrP is a substrate for PSA. The cleavage of the amino-terminal portion of PTHrP completely disrupts its ability to interact with the PTH/PTHrP receptor and thus inhibits its PTH-like activity. \| Our data show that PSA proteolytically cleaves PTHrP (1-34) after either residue 22 or 23, generating three peptide fragments.	SIGNOR-270547
P21462	P04083	2	binding	up-regulates activity	0.743	We show that the mimetic N-terminal annexin 1 peptide Ac1-25 is able to activate and desensitize not only FPR but also FPRL1 and FPRL2.	SIGNOR-259439
Q92934	P27361	0	phosphorylation	down-regulates	0.483	Erk-1 map kinase prevents tnf-induced apoptosis through bad phosphorylation and inhibition of bax translocation in hela cells.	SIGNOR-188172
O15117	P06241	0	phosphorylation	up-regulates activity	0.2	two tyrosines, Tyr595 and Tyr651, of FYB are major sites of phosphorylation by FYN-T and mediate binding to SLP-76 in Jurkat T cells. We further demonstrate that the loss of SLP-76 binding by mutation of these sites markedly reduced the ability of FYN-T-FYB-SLP-76 to up-regulate IL-2 transcription.	SIGNOR-251163
P27448	P30307	1	phosphorylation	down-regulates activity	0.485	C-TAK1 protein kinase phosphorylates human Cdc25C on serine 216 and promotes 14-3-3 protein binding. Phosphorylation of serine 21 6 promotes 1 4-3-3 binding to Cdc25C and is inhibitory to Cdc25C function.	SIGNOR-250176
P04637	P02511	1	transcriptional regulation	up-regulates quantity by expression	0.47	Aberrant expression of CRYAB has been shown to be associated with several neurological diseases and malignant neoplasms. To identify transcriptional regulators of CRYAB expression, we examined its promoter for binding sites of transcription factors and identified four potential AP-2 binding sites in addition to a p53 binding site reported previously\|Taken together, our results indicate that AP-2_ up-regulates the transcription of the CRYAB gene through stabilizing p53	SIGNOR-253638
Q9NZ94	Q9Y4C0	2	binding	up-regulates activity	0.825	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.\|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264162
Q9UHC7	P38936	1	polyubiquitination	down-regulates quantity by destabilization	0.313	Makorin Ring Finger Protein 1 (MKRN1) is a transcriptional co-regulator and an E3 ligase. Here, we show that MKRN1 simultaneously functions as a differentially negative regulator of p53 and p21. In normal conditions, MKRN1 could destabilize both p53 and p21 through ubiquitination and proteasome-dependent degradation. As a result, depletion of MKRN1 induced growth arrest through activation of p53 and p21.	SIGNOR-271845
P15173	P15172	0	transcriptional regulation	up-regulates quantity by expression	0.46	We conclude that MyoD is the major MRF that binds to the E-box from the myogenin promoter during differentiation.	SIGNOR-255640
P63096	P21728	2	binding	up-regulates activity	0.284	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-257068
P62834	Q8WZA2	2	binding	up-regulates quantity	0.794	The SUR1 subunit of KATP channels recruits Epac2 to the plasma membrane where a signaling complex comprised of Epac2, Rap1 and PLC-ε is formed. Rap1 is activated by Epac2, and the activated form of Rap1 binds to and activates PLC-ε.	SIGNOR-278143
Q07954	P17252	0	phosphorylation	up-regulates	0.2	Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase calpha regulates endocytosis and association with adaptor moleculesthese results indicate that elimination of serine and threonine phosphorylation sites in the lrp cytoplasmic domain reduces the extent of tyr63 phosphorylation and leads to impaired association with the adaptor protein shc.	SIGNOR-127215
P12830	Q5XUX0	2	binding	down-regulates quantity by destabilization	0.2	Here we show that the low levels of FBXO31 are maintained through proteasomal degradation by anaphase-promoting complex/cyclosome (APC/C). We find that the APC/C coactivators CDH1 and CDC20 bind to a destruction-box (D-box) motif present in FBXO31 to promote its polyubiquitination and degradation in a cell-cycle-regulated manner, which requires phosphorylation of FBXO31 on serine-33 by the prosurvival kinase AKT.	SIGNOR-277377
P06493	Q03060	1	phosphorylation	down-regulates quantity by destabilization	0.296	The MAPKs extracellular signal-regulated kinases 1 and 2 physically interact with ICER and mediated the phosphorylation of ICER on a critical serine residue (Ser-41). A mutant form of ICER in which Ser-41 was substituted by alanine had a half-life 4-5 h longer than its wild-type counterpart. This alteration in stability was due to the inability of the Ser-41-mutant ICER to be efficiently ubiquitinated and degraded via the ubiquitin-proteasome pathway.	SIGNOR-275979
P35869	Q16678	1	transcriptional regulation	up-regulates quantity by expression	0.489	The formation of the AHR/ARNT dimerization complex converts the AHR into a high affinity DNA-binding form that recognizes specific DNA recognition sites termed DREs. In this manner, the agonist activated AHR upregulates a battery of target genes, including those involved in the metabolism of chemical carcinogens, such as CYP1A1 and CYP1B1 .	SIGNOR-253642
P49841	Q13485	1	phosphorylation	down-regulates quantity by destabilization	0.398	In the presence of FGF, Wnt potentiates TGF-β signaling by preventing Smad4 GSK3 phosphorylations that inhibit a transcriptional activation domain located in the linker region.	SIGNOR-276440
P22736	Q15349	0	phosphorylation	down-regulates activity	0.367	Phosphorylation of a residue in the DNA-binding region (Ser-350 of NGFI-B and 354 of Nur77) has been described in detail to have effect on the transcriptional function of the protein [11, 24]. Growth-related kinase pp90rsk, but not ERK1 (pp44mapk), was shown to phosphorylate recombinant Nur77 in vitro in the DNA binding domain, but not the amino-terminus, using an immune complex kinase as- say [11].	SIGNOR-249429
P46531	Q9ULJ6	2	binding	up-regulates activity	0.452	The N-terminal domain (NTD) is critical for Zmiz1 to function as a Notch collaborator. Zmiz1 and Notch1 cooperatively recruit each other to chromatin through the TPR domain. The N-terminal domain (NTD) of Zmiz1 is important for enhancing Notch reporter activity and contains tetratricopeptide repeats (TPR) that mediate protein-protein interactions	SIGNOR-263937
O15297	Q07812	1	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
Q8IWW6	P63000	1	gtpase-activating protein	down-regulates activity	0.546	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260469
O60674	P10912	1	phosphorylation	up-regulates activity	0.766	Jak2 is then phosphorylated and, in turn, phosphorylates the GHR and the signal transducers and activators of transcription (STAT) protein.	SIGNOR-279198
Q12778	Q13237	0	phosphorylation	up-regulates activity	0.356	Biochemical assays using mammalian cGKII and FoxO1 reveal that cGKII enhances the transcriptional activity of FoxO1 through phosphorylation of the FoxO1 S319 site in the same manner as LRRK2.	SIGNOR-279564
O95837	P08908	2	binding	up-regulates activity	0.25	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257197
Q9UMX1	P10070	1	relocalization	down-regulates activity	0.909	We demonstrate here that Su(fu) prevents the nuclear accumulation of Gli1 and Gli2 through multiple mechanisms	SIGNOR-129065
O96013	Q15796	1	phosphorylation	down-regulates quantity by destabilization	0.339	In addition, PAK4 phosphorylates Smad2 on Ser465, leading to the degradation of Smad2 through ubiquitin-proteasome-dependent pathway under hepatocyte growth factor (HGF) stimulation.	SIGNOR-279084
O60674	P00519	0	phosphorylation	up-regulates activity	0.41	Jak2 peptide substrate studies indicated that the Bcr-Abl and Abl tyrosine kinases specifically phosphorylated Y1007 of Jak2 but only poorly phosphorylated Y1008. Phosphorylation of Y1007 of Jak2 is known to be critical for its tyrosine kinase activation.	SIGNOR-245365
P04637	Q9HCM9	0	ubiquitination	down-regulates quantity by destabilization	0.351	Furthermore, we show here that the Trim39 can directly bind and ubiquitylate p53 in vitro and in vivo, leading to p53 degradation.	SIGNOR-272020
P08069	Q9Y4H2	1	phosphorylation	up-regulates	0.802	Our results reveal that igf-1 receptors promote beta-cell development and survival through the irs-2 signalling pathway.	SIGNOR-70477
P49715	P35247	1	transcriptional regulation	up-regulates quantity by expression	0.259	Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells\| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D.	SIGNOR-254042
P00519	P22681	0	ubiquitination	down-regulates quantity by destabilization	0.614	We found that while c-cbl e3 ligase induced ubiquitin-dependent degradation of mature and phosphorylated bcr-abl proteins	SIGNOR-167194
Q16816	P46020	2	binding	down-regulates activity	0.691	Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit.	SIGNOR-267405
P07339	P02818	1	cleavage	down-regulates quantity by destabilization	0.314	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-256319
O95863	Q16512	0	phosphorylation	up-regulates	0.2	Pak1 phosphorylation of snail, a master regulator of epithelial-to-mesenchyme transition, modulates snail's subcellular localization and functionswe found for the first time that pak1 promotes transcription repression activity of snail from e-cadherin, occludin, and aromatase promoters. Pak1 regulates the repressor activity of snail by phosphorylating on ser(246). Pak1 phosphorylation of snail supports snail's accumulation in the nucleus as well as its repressor functions.	SIGNOR-135609
O14920	Q9Y5X2	2	binding	up-regulates activity	0.2	IFNγ induced JAK1-mediated phosphorylation of SNX8 at Tyr95 and Tyr126, which promoted the recruitment of IKKβ to the JAK1 complex.	SIGNOR-273646
O14974	O60285	0	phosphorylation	down-regulates	0.507	Phosphorylation of ser(445), ser(472), and ser(910) of mypt1 by nuak1 promoted the interaction of mypt1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity.	SIGNOR-164747
P00519	P15056	0	phosphorylation	up-regulates activity	0.275	BRAF V600E activates Abl and Arg.\|Rather, BRAF V600E, a serine threonine kinase, induced Abl threonine phosphorylation (XREF_FIG), and tyrosine phosphorylation of kinase-inactive Abl or Arg, which lack the ability to autophosphorylate (XREF_FIG).	SIGNOR-278914
Q16659	Q9Y6Q9	1	phosphorylation	up-regulates	0.481	Here, we report that erk3 interacted with and phosphorylated steroid receptor coactivator 3 (src-3), an oncogenic protein overexpressed in multiple human cancers at serine 857 (s857)	SIGNOR-196957
P63092	P29274	2	binding	up-regulates activity	0.3	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-256766

O95486

Q9NR31

2

binding

up-regulates quantity

0.756

Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer.

SIGNOR-265303

Q86YT6

Q00535

0

phosphorylation

up-regulates activity

0.325

Similar to the mechanism of PAR-1 regulation of Mib in neurogenesis, CDK5 phosphorylation is proposed to enhance Mib1 ligase activity leading to destabilization.|The cyclin dependent kinase 5 (CDK5) enriched in neurons phosphorylates Mib1 and suppresses the inhibitory effects of Mib1 on neurite morphology.

SIGNOR-280217

P17252

P08581

1

phosphorylation

down-regulates

0.256

These data show that phosphorylation of ser985 is a key mechanism for the negative regulation of hgf/sf receptor.

SIGNOR-37718

P60484

O15327

0

dephosphorylation

down-regulates activity

0.632

In support, the increase in PTEN caused by INPP4B knockdown was associated with increased phosphorylation of the Ser380, Thr382, Thr383 and Ser385 cluster of the protein (XREF_FIG), which is known to increase PTEN half-life, in colon cancer cells.|Exogenous INPP4B could pull down and dephosphorylate endogenous PTEN, suggesting that effect of INPP4B on PTEN in colon cancer cells is not due to cell-type-specific characteristics of INPP4B per se.|INPP4B downregulates PTEN in colon cancer cells.

SIGNOR-277018

P21802

P05230

2

binding

up-regulates

0.909

We have crystallized a complex between human FGF1 and a two-domain extracellular fragment of human FGFR2.

SIGNOR-73811

Q9Y3M8

P61586

1

gtpase-activating protein

down-regulates activity

0.645

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260521

P19784

P42768

1

phosphorylation

up-regulates activity

0.347

We identify two phosphorylation sites in the VCA domain of WASP at serines 483 and 484. S483 and S484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the VCA domain for the Arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length WASP molecule.

SIGNOR-251048

Q13131

Q8N5S9

0

phosphorylation

up-regulates

0.462

Ampka1 activators increased phosphorylation level and cytoplasmic localization (reduced nuclear/cytoplasmic ratio). Ampka1 activators reduced rna synthesis in the nucleoli.

SIGNOR-176598

Q96EQ8

Q9BYX4

1

polyubiquitination

down-regulates quantity by destabilization

0.657

Here, we found that RIG-I undergoes proteasomal degradation after conjugation to ubiquitin by RNF125. Further, RNF125 conjugates ubiquitin to MDA5, a family protein of RIG-I as well as IPS-1, which is also a downstream protein of RIG-I signaling that results in suppressing the functions of these proteins. Because RNF125 is enhanced by IFN, these functions constitute a negative regulatory loop circuit for IFN production.

SIGNOR-271646

O96013

P17676

1

phosphorylation

up-regulates activity

0.2

Importantly, we found that PAK4 enhanced CEBPB phosphorylation on Thr 235.|In summary, we showed that PAK4 mediated CEBPB activation upregulated CLDN4 expression to promote breast cancer cell migration and invasion.

SIGNOR-280055

Q9HBW0

P19086

2

binding

up-regulates activity

0.25

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

SIGNOR-257324

P63096

Q8TDV5

2

binding

up-regulates activity

0.278

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-257040

P27707

P67775

0

dephosphorylation

down-regulates activity

0.2

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

SIGNOR-275803

P17252

Q9UJY1

1

phosphorylation

up-regulates activity

0.307

Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation

SIGNOR-107688

P10275

Q13772

2

binding

up-regulates

0.86

We demonstrated that ara70 and ar physically interact and that ara70 can function as an androgen-dependent coactivator for ar.

SIGNOR-67684

Q92934

P04637

2

binding

up-regulates activity

0.328

We also demonstrate that bad physically interacts with cytoplasmic p53. bad is able to direct p53 to the mitochondria and forms a p53/bad complex at the mitochondria. the mitochondrial p53/bad complex promotes apoptosis

SIGNOR-149815

O43918

Q05084

1

transcriptional regulation

down-regulates quantity by repression

0.362

Sequence variation in promoter of Ica1 gene, which encodes protein implicated in type 1 diabetes, causes transcription factor autoimmune regulator (AIRE) to increase its binding and down-regulate expression.

SIGNOR-268973

Q05086

O94788

1

ubiquitination

down-regulates quantity by destabilization

0.2

Hyperactivity of E3 ubiquitin (Ub) ligase UBE3A, stemming from 15q11-q13 copy number variations, accounts for 1%-3% of ASD cases worldwide, but the underlying mechanisms remain incompletely characterized. Here we report that the functionality of ALDH1A2, the rate-limiting enzyme of retinoic acid (RA) synthesis, is negatively regulated by UBE3A in a ubiquitylation-dependent manner.

SIGNOR-265135

Q05086

P49815

1

ubiquitination

down-regulates quantity by destabilization

0.629

An in vivo ubiquitination assay was done to reveal that E6AP promoted the ubiquitination of TSC2 independent of HPV16 E6. We further found that TSC2 bound E6AP in the presence as well as in the absence of HPV16 E6. The binding regions on E6AP and TSC2 have been identified as amino acid (aa) 260-316, aa 428-500 and aa 1-175, aa 1251-1807, respectively. Taken together, degradation of TSC2 is mediated by E6AP ubiquitin ligase.

SIGNOR-271396

Q8IXJ6

P15259

1

deacetylation

up-regulates activity

0.2

Here we report that PGAM is acetylated at lysine 100 (K100), an active site residue that is invariably conserved from bacteria, to yeast, plant, and mammals. K100 acetylation is detected in fly, mouse, and human cells and in multiple tissues and decreases PGAM2 activity. The cytosolic protein deacetylase sirtuin 2 (SIRT2) deacetylates and activates PGAM2.

SIGNOR-266518

O14737

P68400

0

phosphorylation

up-regulates

0.2

Programmed cell death 5 (pdcd5), a protein involved in cell death and down-regulated in different forms of human tumors. Pdcd5 is phosphorylated in vitro by both ck2alpha subunit and by the ck2 holoenzyme at a residue, s118, which is found phosphorylated in vivo. Transfection of the non-phosphorylatable mutant (s118a) impairs the pdcd5 acceleration of either doxorubimicin- or uv-induced apoptosis in u2os cells

SIGNOR-187106

P06239

Q9UJZ1

2

binding

up-regulates activity

0.2

In these studies, we also found that SLP-2 interacted with Lck, ZAP70, LAT, and PLC-gamma1 during the 30-min period following stimulation in vitro|The SLP-2-associated pool of these molecules became phosphorylated/activated in a sequential manner, a profile compatible with their temporal involvement in early TCR signalling.

SIGNOR-260376

P30307

P43405

0

phosphorylation

down-regulates activity

0.36

SYK Phosphorylates CDC25C on Serine 216.|We now provide new genetic and biochemical evidence that SYK is an inhibitor of CDC25C in B-lineage lymphoid cells as well as non lymphohematopoietic cells, that prevents premature entry into mitosis by phosphorylating CDC25C at S216 when G 2 checkpoint responses are activated.

SIGNOR-278328

Q70Z35

P60953

1

guanine nucleotide exchange factor

up-regulates activity

0.423

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260572

O60486

O75326

2

binding

up-regulates

0.913

Plexin-c1 is a receptor for the gpi-anchored semaphorin sema7a. The cytoplasmic domain of plexins associates with a tyrosine kinase activity. Plexins may also act as ligands mediating repulsion in epithelial cells in vitro.

SIGNOR-71260

Q9NRM7

Q4VCS5

1

phosphorylation

up-regulates quantity by stabilization

0.516

Here low serum and high LATS1 activity are found to enhance the levels of the 130-kDa isoform of angiomotin (Amot130) through phosphorylation by LATS1/2 at serine 175, which then forms a binding site for 14-3-3. Such phosphorylation, in turn, enables the ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiquitinate, and stabilize Amot130

SIGNOR-275846

P15391

P07948

2

binding

up-regulates activity

0.772

CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades.

SIGNOR-242894

Q86YT6

2

polyubiquitination

down-regulates quantity by destabilization

0.2

The RING finger motifs of DIP-1 have E3 ligase activity that can auto-ubiquitinate DIP-1 in vitro. In vivo, DIP-1 is detected as a polyubiquitinated protein, suggesting that the intracellular levels of DIP-1 are regulated by the ubiquitin-proteasome system.

SIGNOR-272603

P04150

Q16649

1

transcriptional regulation

up-regulates quantity by expression

0.296

GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription

SIGNOR-268051

O75385

Q15437

1

phosphorylation

up-regulates quantity by stabilization

0.2

Here, we show that the F-box protein FBXW5 targets SEC23B, a component of COPII, for proteasomal degradation and that this event limits the autophagic flux in the presence of nutrients. In response to starvation, ULK1 phosphorylates SEC23B on Serine 186, preventing the interaction of SEC23B with FBXW5 and, therefore, inhibiting SEC23B degradation.

SIGNOR-265285

P84243

Q09472

0

acetylation

down-regulates activity

0.2

These results highlight the substrate and site specificities of hats in cells, demonstrate the distinct roles of gcn5/pcaf- and cbp/p300-mediated histone acetylations in gene activation, and suggest an important role of cbp/p300-mediated h3k18/27ac in nr-dependent transcription.

SIGNOR-170266

P49137

P28482

0

phosphorylation

up-regulates

0.507

Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation of any two of the three residues thr222, ser272 and thr334. gst-mapkap kinase-2 lacking the n-terminal domain was inactive, but activated fully when phosphorylated at thr222, ser272 and thr334 by p42 mapk or rk.

SIGNOR-44343

P05412

Q969H0

2

binding

down-regulates quantity by destabilization

0.495

We report that in neurons the stability of c-Jun is regulated by the E3 ligase SCF(Fbw7), which ubiquitinates phosphorylated c-Jun and facilitates c-Jun degradation.

SIGNOR-272950

Q5VWQ8

P27986

2

binding

down-regulates activity

0.283

DAB2IP binds the p85 subunit of PI3K through its PR domain and prevents PI3K-p85 relocation from the cytoplasm to the membrane, a necessary step for PI3K activation and signaling to AKT. Notably, DAB2IP reinforces this inhibitory effect by directly binding AKT.2

SIGNOR-254757

P26992

Q9UBD9

2

binding

up-regulates

0.702

Striking phenotypic differences between cntf- and cntfr-deficient mice suggest that cntfr serves as a receptor for a second, developmentally important ligand. We have identified this factor as a stable secreted complex of cardiotrophin-like cytokine (clc) and the soluble receptor cytokine-like factor-1 (clf).

SIGNOR-81376

Q09472

P15172

1

acetylation

up-regulates

0.681

Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo.

SIGNOR-81053

Q92886

Q13164

0

phosphorylation

up-regulates activity

0.35

Activation of ERK5 potentiates while inhibition of ERK5 attenuates Neurog1 stimulated neurogenesis.|ERK5 directly phosphorylated Neurog1 in vitro and modulated the transcriptional and pro-neural activity of Neurog1 in cortical progenitors.

SIGNOR-278364

P06213

Q12923

0

dephosphorylation

down-regulates

0.26

We demonstrate that ptpl1, like ptp1b, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that ptpl1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines.

SIGNOR-132555

O60260

Q9NX09

1

ubiquitination

down-regulates quantity by destabilization

0.2

In conclusion, our work in cellular and animal models and in human samples strongly indicates that RTP801 is a substrate of parkin and that RTP801 elevation due to parkin loss of function in both AR-JP and sporadic Parkinson's disease may contribute to neurodegeneration.|We showed that parkin poly-ubiquitinates RTP801, both in vitro and in vivo.

SIGNOR-278560

P08254

Q9ULU4

0

transcriptional regulation

down-regulates quantity by repression

0.2

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

SIGNOR-262043

O76064

P0C0S8

1

ubiquitination

up-regulates

0.2

Rnf8 and ubc13 ubiquitylate h2a and h2ax, but other substrates probably exist.

SIGNOR-166174

Q05397

O75962

1

phosphorylation

up-regulates activity

0.509

A FAK phosphorylation site, tyrosine residue 2737, was identified in subdomain I of the Trio kinase domain. Additionally, in vitro phosphorylation assays and in vivo co-expression studies indicated that Trio enhances FAK kinase activity.

SIGNOR-249188

P63000

Q7Z6I6

0

gtpase-activating protein

down-regulates activity

0.403

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260486

P20042

P49770

0

guanine nucleotide exchange factor

up-regulates activity

0.751

EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.

SIGNOR-269130

P00747

P02749

1

cleavage

down-regulates activity

0.458

Plasmin can reduce the function of human beta2 glycoprotein I by cleaving domain V into a nicked form| The cleavage site of r-Domain V and beta2GPI by plasmin was proved to be Lys 317-Thr 318 by amino acid sequence analysis of the digest and of the C-terminal peptide isolated by high-performance liquid chromatography. The cleavage was completely inhibited by plasmin inhibitor (alpha2PI). The nicked form was demonstrated to show reduced affinity for CL with a dissociation constant of one order of magnitude larger than that of the intact beta2GPI.

SIGNOR-266996

P00533

Q05397

1

phosphorylation

up-regulates

0.595

In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases.

SIGNOR-167646

P49841

Q13237

0

phosphorylation

down-regulates activity

0.258

These data indicate that hypertrophic differentiation of growth plate chondrocytes during skeletal growth is promoted by phosphorylation and inactivation of GSK-3beta by cGKII.

SIGNOR-280095

Q96KN7

Q92834

2

binding

down-regulates activity

0.714

The RPGR H98Q and F130C mutants exhibit compromised interaction with RPGRIP1, suggesting that RPGR–RPGRIP1 interaction may be an important determinant of RPGR activity. As RPGRIP1 appears to link RPGR to the cilium, it is possible that RPGR's effect on RAB8A function may occur in distinct subcellular compartments of photoreceptors and that RPGRIP1 and other interacting proteins may modulate targeting of RPGR to such compartments.

SIGNOR-253031

Q15398

Q9Y3I1

2

binding

down-regulates quantity by destabilization

0.45

We show here that Fbx7, an F-box protein without WD repeats and leucine-rich repeats, is required for the proteasome-mediated proteolysis of the hepatoma up-regulated protein (HURP).Thus, Fbx7 is a functional adaptor of the SCF complex with a proline-rich region as the substrate-binding module. Depletion of Fbx7 by small interfering RNA leads to depression of HURP ubiquitination and accumulation of HURP abundance. In the SCFFbx7 complex, Fbx7 recruits HURP through its C-terminal proline-rich region in a Cdk1-cyclin B-phosphorylation dependent manner.

SIGNOR-271506

P31749

P62714

0

dephosphorylation

down-regulates

0.508

These results confirm that the activity changes observed are achieved by a reversible phosphorylation mechanism, and also argue that pp2a may negatively regulate rac-pk activity in vivo. Dephosphorylation of the activated rac-pk in itro by pp2ac resulted in an 87% reduction of kinase activity

SIGNOR-252636

Q9H4P4

O60260

1

polyubiquitination

down-regulates quantity by destabilization

0.2

Here we further demonstrated that overexpression of Nrdp1 significantly reduced the endogenous Parkin level in an Nrdp1 dosage-dependent and proteasome-dependent manner. More importantly, Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells, indicating Parkin is an Nrdp1 substrate.

SIGNOR-272639

P07437

P84022

2

binding

down-regulates activity

0.2

Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin.

SIGNOR-232113

P22888

P10589

0

transcriptional regulation

down-regulates quantity by repression

0.275

Functional analysis showed that EAR2 and EAR3/COUP-TFI repressed the hLHR promoter activity, whereas TR4 activated hLHR gene transcription.

SIGNOR-266218

Q99500

O95837

2

binding

up-regulates activity

0.385

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-257437

P78504

O76050

0

ubiquitination

down-regulates quantity by destabilization

0.707

We find that NEDD4 targets an RNA-binding protein, NANOS2, in spermatogonia to destabilize it, leading to cell differentiation.|Jagged1 is also regulated by the E3 ligase Neuralized-like1 (Neurl1), which induces the monoubiquitination of membrane tethered Jagged1 in the C-terminal region.

SIGNOR-278772

P10275

P11309

0

phosphorylation

up-regulates activity

0.381

PIM1 phosphorylates the AR and 14-3-3 ζ and coordinates their interaction. PIM1 phosphorylation of the AR and 14-3-3 ζ enhances their interaction and shifts their occupancy on chromatin, resulting in 14-3-3 ζ co-regulation of AR, likely by recruiting other AR co-regulators such as hnRNPK and TRIM28.

SIGNOR-277575

P16949

Q13554

0

phosphorylation

down-regulates

0.515

Stimulation via cd2 activated multiple signal transduction pathways, resulting in phosphorylation of distinct sites of stathmin. Ser16 of recombinant human stathmin was phosphorylated also by purified cam kinase ii, and in vivo, cam kinase ii activity was indeed stimulated in cd2-triggered jurkat cells.

SIGNOR-59358

Q01860

P26358

1

transcriptional regulation

up-regulates quantity by expression

0.437

Oct4 and Nanog upregulate Dnmt1 through direct binding to its promoter, thereby leading to the repressed expression of p16 and p21 and genes associated with development and lineage differentiation

SIGNOR-253158

P12259

P08246

0

cleavage

up-regulates activity

0.366

Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.V treated with HNE indicated cleavage at Ile819 and Ile1484 under conditions during which the procofactor expressed enhanced cofactor activity in the prothrombinase complex.

SIGNOR-263637

Q15418

P49841

1

phosphorylation

down-regulates

0.359

S6k then phosphorylates the same serine residue on gsk3 that is targeted by pkb/akt (fig. 1), thereby inhibiting its activity.

SIGNOR-110917

P29350

Q8NER1

1

dephosphorylation

down-regulates activity

0.2

Shp-1 dephosphorylates TRPV1 in dorsal root ganglion neurons and alleviates CFA-induced inflammatory pain in rats.|These results suggested that Shp-1 dephosphorylated and inhibited TRPV1 in DRG neurons, contributing to maintain thermal nociceptive thresholds in normal rats, and as a compensatory mechanism, Shp-1 increased in DRGs of rats with CFA-induced inflammatory pain, which was involved in protecting against excessive thermal hyperalgesia.

SIGNOR-277129

P15259

Q8IXJ6

0

deacetylation

up-regulates activity

0.2

Here we report that PGAM is acetylated at lysine 100 (K100), an active site residue that is invariably conserved from bacteria, to yeast, plant, and mammals. K100 acetylation is detected in fly, mouse, and human cells and in multiple tissues and decreases PGAM2 activity. The cytosolic protein deacetylase sirtuin 2 (SIRT2) deacetylates and activates PGAM2.

SIGNOR-266518

P12272

P07288

0

cleavage

down-regulates activity

0.422

Our study demonstrates that PTHrP is a substrate for PSA. The cleavage of the amino-terminal portion of PTHrP completely disrupts its ability to interact with the PTH/PTHrP receptor and thus inhibits its PTH-like activity. | Our data show that PSA proteolytically cleaves PTHrP (1-34) after either residue 22 or 23, generating three peptide fragments.

SIGNOR-270547

P21462

P04083

2

binding

up-regulates activity

0.743

We show that the mimetic N-terminal annexin 1 peptide Ac1-25 is able to activate and desensitize not only FPR but also FPRL1 and FPRL2.

SIGNOR-259439

Q92934

P27361

0

phosphorylation

down-regulates

0.483

Erk-1 map kinase prevents tnf-induced apoptosis through bad phosphorylation and inhibition of bax translocation in hela cells.

SIGNOR-188172

O15117

P06241

0

phosphorylation

up-regulates activity

0.2

two tyrosines, Tyr595 and Tyr651, of FYB are major sites of phosphorylation by FYN-T and mediate binding to SLP-76 in Jurkat T cells. We further demonstrate that the loss of SLP-76 binding by mutation of these sites markedly reduced the ability of FYN-T-FYB-SLP-76 to up-regulate IL-2 transcription.

SIGNOR-251163

P27448

P30307

1

phosphorylation

down-regulates activity

0.485

C-TAK1 protein kinase phosphorylates human Cdc25C on serine 216 and promotes 14-3-3 protein binding. Phosphorylation of serine 21 6 promotes 1 4-3-3 binding to Cdc25C and is inhibitory to Cdc25C function.

SIGNOR-250176

P04637

P02511

1

transcriptional regulation

up-regulates quantity by expression

0.47

Aberrant expression of CRYAB has been shown to be associated with several neurological diseases and malignant neoplasms. To identify transcriptional regulators of CRYAB expression, we examined its promoter for binding sites of transcription factors and identified four potential AP-2 binding sites in addition to a p53 binding site reported previously|Taken together, our results indicate that AP-2_ up-regulates the transcription of the CRYAB gene through stabilizing p53

SIGNOR-253638

Q9NZ94

Q9Y4C0

2

binding

up-regulates activity

0.825

Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)

SIGNOR-264162

Q9UHC7

P38936

1

polyubiquitination

down-regulates quantity by destabilization

0.313

Makorin Ring Finger Protein 1 (MKRN1) is a transcriptional co-regulator and an E3 ligase. Here, we show that MKRN1 simultaneously functions as a differentially negative regulator of p53 and p21. In normal conditions, MKRN1 could destabilize both p53 and p21 through ubiquitination and proteasome-dependent degradation. As a result, depletion of MKRN1 induced growth arrest through activation of p53 and p21.

SIGNOR-271845

P15173

P15172

0

transcriptional regulation

up-regulates quantity by expression

0.46

We conclude that MyoD is the major MRF that binds to the E-box from the myogenin promoter during differentiation.

SIGNOR-255640

P63096

P21728

2

binding

up-regulates activity

0.284

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-257068

P62834

Q8WZA2

2

binding

up-regulates quantity

0.794

The SUR1 subunit of KATP channels recruits Epac2 to the plasma membrane where a signaling complex comprised of Epac2, Rap1 and PLC-ε is formed. Rap1 is activated by Epac2, and the activated form of Rap1 binds to and activates PLC-ε.

SIGNOR-278143

Q07954

P17252

0

phosphorylation

up-regulates

0.2

Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase calpha regulates endocytosis and association with adaptor moleculesthese results indicate that elimination of serine and threonine phosphorylation sites in the lrp cytoplasmic domain reduces the extent of tyr63 phosphorylation and leads to impaired association with the adaptor protein shc.

SIGNOR-127215

P12830

Q5XUX0

2

binding

down-regulates quantity by destabilization

0.2

Here we show that the low levels of FBXO31 are maintained through proteasomal degradation by anaphase-promoting complex/cyclosome (APC/C). We find that the APC/C coactivators CDH1 and CDC20 bind to a destruction-box (D-box) motif present in FBXO31 to promote its polyubiquitination and degradation in a cell-cycle-regulated manner, which requires phosphorylation of FBXO31 on serine-33 by the prosurvival kinase AKT.

SIGNOR-277377

P06493

Q03060

1

phosphorylation

down-regulates quantity by destabilization

0.296

The MAPKs extracellular signal-regulated kinases 1 and 2 physically interact with ICER and mediated the phosphorylation of ICER on a critical serine residue (Ser-41). A mutant form of ICER in which Ser-41 was substituted by alanine had a half-life 4-5 h longer than its wild-type counterpart. This alteration in stability was due to the inability of the Ser-41-mutant ICER to be efficiently ubiquitinated and degraded via the ubiquitin-proteasome pathway.

SIGNOR-275979

P35869

Q16678

1

transcriptional regulation

up-regulates quantity by expression

0.489

The formation of the AHR/ARNT dimerization complex converts the AHR into a high affinity DNA-binding form that recognizes specific DNA recognition sites termed DREs. In this manner, the agonist activated AHR upregulates a battery of target genes, including those involved in the metabolism of chemical carcinogens, such as CYP1A1 and CYP1B1 .

SIGNOR-253642

P49841

Q13485

1

phosphorylation

down-regulates quantity by destabilization

0.398

In the presence of FGF, Wnt potentiates TGF-β signaling by preventing Smad4 GSK3 phosphorylations that inhibit a transcriptional activation domain located in the linker region.

SIGNOR-276440

P22736

Q15349

0

phosphorylation

down-regulates activity

0.367

Phosphorylation of a residue in the DNA-binding region (Ser-350 of NGFI-B and 354 of Nur77) has been described in detail to have effect on the transcriptional function of the protein [11, 24]. Growth-related kinase pp90rsk, but not ERK1 (pp44mapk), was shown to phosphorylate recombinant Nur77 in vitro in the DNA binding domain, but not the amino-terminus, using an immune complex kinase as- say [11].

SIGNOR-249429

P46531

Q9ULJ6

2

binding

up-regulates activity

0.452

The N-terminal domain (NTD) is critical for Zmiz1 to function as a Notch collaborator. Zmiz1 and Notch1 cooperatively recruit each other to chromatin through the TPR domain. The N-terminal domain (NTD) of Zmiz1 is important for enhancing Notch reporter activity and contains tetratricopeptide repeats (TPR) that mediate protein-protein interactions

SIGNOR-263937

O15297

Q07812

1

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

Q8IWW6

P63000

1

gtpase-activating protein

down-regulates activity

0.546

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260469

O60674

P10912

1

phosphorylation

up-regulates activity

0.766

Jak2 is then phosphorylated and, in turn, phosphorylates the GHR and the signal transducers and activators of transcription (STAT) protein.

SIGNOR-279198

Q12778

Q13237

0

phosphorylation

up-regulates activity

0.356

Biochemical assays using mammalian cGKII and FoxO1 reveal that cGKII enhances the transcriptional activity of FoxO1 through phosphorylation of the FoxO1 S319 site in the same manner as LRRK2.

SIGNOR-279564

O95837

P08908

2

binding

up-regulates activity

0.25

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

SIGNOR-257197

Q9UMX1

P10070

1

relocalization

down-regulates activity

0.909

We demonstrate here that Su(fu) prevents the nuclear accumulation of Gli1 and Gli2 through multiple mechanisms

SIGNOR-129065

O96013

Q15796

1

phosphorylation

down-regulates quantity by destabilization

0.339

In addition, PAK4 phosphorylates Smad2 on Ser465, leading to the degradation of Smad2 through ubiquitin-proteasome-dependent pathway under hepatocyte growth factor (HGF) stimulation.

SIGNOR-279084

O60674

P00519

0

phosphorylation

up-regulates activity

0.41

Jak2 peptide substrate studies indicated that the Bcr-Abl and Abl tyrosine kinases specifically phosphorylated Y1007 of Jak2 but only poorly phosphorylated Y1008. Phosphorylation of Y1007 of Jak2 is known to be critical for its tyrosine kinase activation.

SIGNOR-245365

P04637

Q9HCM9

0

ubiquitination

down-regulates quantity by destabilization

0.351

Furthermore, we show here that the Trim39 can directly bind and ubiquitylate p53 in vitro and in vivo, leading to p53 degradation.

SIGNOR-272020

P08069

Q9Y4H2

1

phosphorylation

up-regulates

0.802

Our results reveal that igf-1 receptors promote beta-cell development and survival through the irs-2 signalling pathway.

SIGNOR-70477

P49715

P35247

1

transcriptional regulation

up-regulates quantity by expression

0.259

Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D.

SIGNOR-254042

P00519

P22681

0

ubiquitination

down-regulates quantity by destabilization

0.614

We found that while c-cbl e3 ligase induced ubiquitin-dependent degradation of mature and phosphorylated bcr-abl proteins

SIGNOR-167194

Q16816

P46020

2

binding

down-regulates activity

0.691

Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit.

SIGNOR-267405

P07339

P02818

1

cleavage

down-regulates quantity by destabilization

0.314

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-256319

O95863

Q16512

0

phosphorylation

up-regulates

0.2

Pak1 phosphorylation of snail, a master regulator of epithelial-to-mesenchyme transition, modulates snail's subcellular localization and functionswe found for the first time that pak1 promotes transcription repression activity of snail from e-cadherin, occludin, and aromatase promoters. Pak1 regulates the repressor activity of snail by phosphorylating on ser(246). Pak1 phosphorylation of snail supports snail's accumulation in the nucleus as well as its repressor functions.

SIGNOR-135609

O14920

Q9Y5X2

2

binding

up-regulates activity

0.2

IFNγ induced JAK1-mediated phosphorylation of SNX8 at Tyr95 and Tyr126, which promoted the recruitment of IKKβ to the JAK1 complex.

SIGNOR-273646

O14974

O60285

0

phosphorylation

down-regulates

0.507

Phosphorylation of ser(445), ser(472), and ser(910) of mypt1 by nuak1 promoted the interaction of mypt1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity.

SIGNOR-164747

P00519

P15056

0

phosphorylation

up-regulates activity

0.275

BRAF V600E activates Abl and Arg.|Rather, BRAF V600E, a serine threonine kinase, induced Abl threonine phosphorylation (XREF_FIG), and tyrosine phosphorylation of kinase-inactive Abl or Arg, which lack the ability to autophosphorylate (XREF_FIG).

SIGNOR-278914

Q16659

Q9Y6Q9

1

phosphorylation

up-regulates

0.481

Here, we report that erk3 interacted with and phosphorylated steroid receptor coactivator 3 (src-3), an oncogenic protein overexpressed in multiple human cancers at serine 857 (s857)

SIGNOR-196957

P63092

P29274

2

binding

up-regulates activity

0.3

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-256766