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
Q12857	P41221	1	transcriptional regulation	down-regulates quantity	0.2	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268877
P00519	O75122	1	phosphorylation	up-regulates quantity	0.502	We find that Abl binds to and phosphorylates CLASP2 in response to extracellular signals such as serum or PDGF.	SIGNOR-279580
P50391	P01303	2	binding	up-regulates	0.692	Human y4 bound human pp family members in i-pyy membrane binding assays with a distinctive rank order (table 1): pp > pyy > npy > npy free acid.	SIGNOR-29633
P55211	P62136	0	dephosphorylation	up-regulates	0.2	Pp1 dephosphorylated thr125 site of caspase-9 and activated caspase-9 to mediate il-2 deprivation-induced apoptosis.	SIGNOR-195992
P31749	P49841	1	phosphorylation	down-regulates activity	0.792	Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3beta (GSK3B). The AKT-mediated phosphorylation of glycogen synthase kinase 3b on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1	SIGNOR-245416
P32121	Q00987	2	binding	up-regulates quantity by stabilization	0.434	Our current results demonstrated that the binding of Mdm2 to beta-arrestin 2 was significantly enhanced by stimulation of GPCRs. Activation of GPCRs led to formation of a ternary complex of Mdm2, beta-arrestin 2, and GPCRs and thus recruited Mdm2 to GPCRs at plasma membrane. Moreover, the binding of beta-arrestin 2 to Mdm2 suppressed the self-ubiquitination of Mdm2 and consequently reduced the Mdm2-mediated p53 degradation and ubiquitination.	SIGNOR-272592
P24928	Q8IXW5	0	dephosphorylation	up-regulates activity	0.738	In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.\|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator	SIGNOR-248748
O95136	Q14344	2	binding	up-regulates activity	0.59	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-257401
P68400	Q14761	1	phosphorylation	up-regulates quantity by stabilization	0.2	We demonstrated for the first time that LPAP is a substrate for protein kinase CK2 that phosphorylates it at Ser153, presumably ensuring LPAP resistance to degradation.	SIGNOR-273629
P45984	P55957	1	phosphorylation	up-regulates activity	0.406	(c) The phosphorylation of recombinant Bid by JNK2 (in vitro kinase assay) prevents its cleavage by caspase-8	SIGNOR-279220
P12931	P13688	1	phosphorylation	up-regulates activity	0.426	Recent reports have also suggested that Bgp1 behaves as a signal transduction molecule. Several physiological events promote the Tyr phosphorylation of Bgp1 on one or two Tyr residues within its cytoplasmic domain (Tyr-488 and Tyr-515). BGP becomes Tyr-phosphorylated by Src-like Tyr kinases in activated neutrophils (24) and in human colon carcinoma cellsWe have recently shown that Tyr phosphorylation of the mouse Bgp1 cytoplasmic domain in CT51 mouse colonic carcinoma cells led to its binding to the protein-Tyr phosphatase SHP-1 and that this event required the presence of both Tyr-488 and Tyr-515	SIGNOR-246471
O15146	O15146	2	phosphorylation	up-regulates activity	0.2	AGRN is released by the nerve and binds to LRP4, which then binds to MuSK. This interaction leads to MuSK autophosphorylation and activation of its kinase function, leading to anterograde signalling by subsequent phosphorylation of DOK7 (not shown), which binds MuSK as a dimer.	SIGNOR-273851
P11474	Q9H0X6	1	transcriptional regulation	up-regulates quantity by expression	0.2	Furthermore, RNF208 was induced by 17β-estradiol (E2) treatment in an estrogen receptor alpha (ΕRα)-dependent manner	SIGNOR-269052
Q99835	Q13009	2	binding	up-regulates	0.267	This latter work suggested that inactive smo prevents rac1 activation by interacting with the rac guanine nucleotide exchange factor (gef) t-lymphoma invasion and metastasis 1 (tiam1). This smo-tiam1 complex dissociates upon shh-mediated activation of smo, thus allowing tiam1 to activate rac1	SIGNOR-199192
P42680	P12931	0	phosphorylation	up-regulates activity	0.32	The proximal event following T cell-APC synapse formation is immediate activation of several signaling molecules: The Src kinase phosphorylates and activates Tec tyrosine kinases, which then activate PLC-\u03b3 that is required for IP 3 generation to sustain intracellular calcium flux.	SIGNOR-280135
P49366	P63241	1	post translational modification	up-regulates activity	0.933	Deoxyhypusine synthase (DHPS) utilizes spermidine and NAD as cofactors to incorporate a hypusine modification into the eukaryotic translation initiation factor 5A (eIF5A). Hypusine is essential for eIF5A activation, which, in turn, plays a key role in regulating protein translation of selected mRNA that are associated with the synthesis of oncoproteins, thereby enhancing tumor cell proliferation.	SIGNOR-266374
Q00535	Q8IXJ6	1	phosphorylation	up-regulates activity	0.397	Cdk5 phosphorylation-induced SIRT2 nuclear translocation promotes the death of dopaminergic neurons in Parkinson's disease.\|Moreover, the cyclin-dependent kinase 5 (Cdk5)-mediated phosphorylation of SIRT2 at the Ser331 and Ser335 sites appears to be necessary for such nuclear translocation.	SIGNOR-279684
P12931	Q9UGK3	1	phosphorylation	up-regulates activity	0.406	To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase Tyr-22 and Tyr-322 are the major tyrosine phosphorylation sites by v-Src.	SIGNOR-247337
P49715	P06702	1	transcriptional regulation	up-regulates quantity by expression	0.227	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-254041
P68400	P49716	1	phosphorylation	up-regulates activity	0.2	Here, we have identified the CCAAT/enhancer binding protein δ (C/EBPδ) as a new substrate for CK2. Using point mutants of C/EBPδ the major phosphorylation site for CK2 was mapped to serine 57, which is located within the transactivation domain of C/EBPδ. For proper functioning as a transcription factor C/EBPδ has to be translocated into the nucleus where it forms heterodimers with other members of the C/EBP family of proteins and ATF4. Here, we found that CK2 phosphorylation does neither influence the subcellular localization of C/EBPδ nor its interaction with C/EBPβ, but rather does CK2 phosphorylation modulate the transcriptional activity of C/EBPδ.	SIGNOR-276886
P0DP25	P55040	2	binding	up-regulates activity	0.2	Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells.	SIGNOR-266342
Q16566	Q92793	1	phosphorylation	up-regulates activity	0.635	Ser301 of CBP was identified as a major target of CaMKIV phosphorylation in vitro and in vivo. CaM kinase inhibitors attenuated phosphorylation at Ser301 and blocked CBP-dependent transcription. Additionally, mutation of Ser301 impaired NMDA- and CaMKIV-stimulated transcription. These findings demonstrate that activity-induced CaMKIV signaling contributes to CREB/CBP-dependent transcription by phosphorylating CBP at Ser301.	SIGNOR-250710
P00441	P14174	0	relocalization	down-regulates quantity by destabilization	0.307	Here, we show that MIF inhibits mutant SOD1 nuclear clearance when overexpressed in motor neuron-like NSC-34 cells\|SOD1WT is evenly distributed between the cytoplasm and the nucleus while mutant SOD1G93A shows predominantly cytoplasmic distribution (Fig. 1a, b). Expression of MIF in cells expressing SOD1WT had no effect on the distribution of the SOD1WT–EGFP protein. However, expression of MIF together with the mutant SOD1G93A–EGFP, inhibited the nuclear clearance of misfolded SOD1 resulting in a more wild-type-like distribution of the mutant SOD1 protein	SIGNOR-262797
P12643	Q13873	2	binding	up-regulates	0.8	Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor.	SIGNOR-33425
Q99986	P16104	1	phosphorylation	up-regulates activity	0.2	In response to DNA damage induced by ionizing radiation, histone H2AX is phosphorylated in Ser139 by VRK1.	SIGNOR-278370
P05556	Q9Y5I1	2	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-265670
P32245	P25098	0	phosphorylation	down-regulates activity	0.2	Mutagenesis studies revealed that Thr312 and Ser329/330 in the C-terminal tail are potential sites for PKA and GRK phosphorylation and may play an essential role in the recruitment of beta-arrestin to the activated receptor.	SIGNOR-247770
Q13188	Q6ZTQ3	2	binding	down-regulates	0.658	When rassf 6 is bound to mst2, rassf 6 inhibits mst2 activity, thus, inhibiting its role in the hippo pathway.	SIGNOR-198463
P12931	Q06124	0	dephosphorylation	up-regulates activity	0.653	Several protein tyrosine phosphatases are capable of activating Src by dephosphorylating Y530 (reviewed in ref. 9). These include PTP-α, PTP-λ, SHP-1, SHP-2, and PTP1B	SIGNOR-248671
P15692	Q16665	0	transcriptional regulation	up-regulates quantity	0.773	Transcription of the human erythropoietin (EPO) gene is activated in Hep3B cells exposed to hypoxia. Hypoxia-inducible factor 1 (HIF-1) is a nuclear factor whose DNA binding activity is induced by hypoxia in Hep3B cells, and HIF-1 binds at a site in the EPO gene enhancer that is required for hypoxic activation of transcription.	SIGNOR-256592
O14757	P30304	1	phosphorylation	down-regulates	0.857	The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216).	SIGNOR-163134
Q14247	Q14289	0	phosphorylation	up-regulates activity	0.365	In conclusion, these data suggest that Pyk2 phosphorylates cortactin on tyrosine residues Y421, Y466, and Y482.\|To confirm the direct and indirect effects of Pyk2 on cortactin phosphorylation, we used cells overexpressing Arg YFP and treated with Pyk2 siRNA or a nonsilencing siRNA.	SIGNOR-278344
Q92793	Q9UBR4	2	binding	up-regulates activity	0.2	Transcription of pituitary alpha-glycoprotein hormone subunit (alpha-GSU) and thyrotropin beta subunit (TSH-beta) genes is stimulated by thyrotropin-releasing hormone (TRH). P-Lim and CBP Act Synergistically in TRH Stimulation of the Human α-GSU Promoter.	SIGNOR-267206
P12931	P60484	2	phosphorylation	down-regulates	0.536	Activated src reduces the ability of pten to dephosphorylate phosphatidylinositols in micelles and promotes akt translocation to cellular plasma membranes but does not alter pten activity toward water-soluble phosphatidylinositols.	SIGNOR-103721
P20226	P62258	2	binding	up-regulates activity	0.347	The in vitro binding with general transcription factors TBP and TFIIB together with its nuclear location provide evidence supporting a role for 14-3-3 proteins as transcriptional activators or coactivators when part of a DNA binding complex.	SIGNOR-262834
O43791	Q9NZQ7	1	ubiquitination	down-regulates quantity	0.325	Loss-of-function mutations in SPOP compromise ubiquitination-mediated PD-L1 degradation, leading to increased PD-L1 levels and reduced numbers of tumor-infiltrating lymphocytes (TILs) in mouse tumors and in primary human prostate cancer specimens.	SIGNOR-274978
O95198	Q9HA47	1	ubiquitination	down-regulates quantity by destabilization	0.346	We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation. We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1.	SIGNOR-275962
Q86VP3	Q13489	0	polyubiquitination	down-regulates quantity by destabilization	0.286	Under basal conditions, PACS-2 underwent K48-linked poly-ubiquitination, resulting in PACS-2 proteasomal degradation. Biochemical assays showed cIAP-1 and cIAP-2 interacted with PACS-2 in vitro and co-immunoprecipitation studies demonstrated that the two cIAPs bound PACS-2 in vivo. More importantly, both cIAP-1 and cIAP-2 directly mediated PACS-2 ubiquitination in a cell-free assay.	SIGNOR-272852
P50148	P43119	2	binding	up-regulates activity	0.4	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-257078
P31749	Q04912	1	phosphorylation	up-regulates	0.559	Akt/pkb phosphorylates ron ser-1394, thus providing a docking site for 14-3-3based on these results, we propose a mechanism based on msp-ron-dependent phosphorylation and 14-3-3 association, whereby the function of alpha6beta4 switches from a mechanical adhesive device into a signaling component, and might be critically involved in human epidermal wound healing	SIGNOR-252471
P46695	P28482	0	phosphorylation	up-regulates	0.552	Upon phosphorylation by erks, iex-1 acquires the ability to inhibit cell death induced by various stimuli. In turn, iex-1 potentiates erk activation in response to various growth factors.	SIGNOR-93740
Q99527	P62873	2	binding	up-regulates activity	0.385	GPCRs transduce their signal via G-protein heterotrimers (αβγ) that dissociate in free Gα-subunit protein and Gβγ-subunit protein complexes following ligand stimulation; GNB1 stands for the subunit β, which dissociates from the receptor after the binding of GTP on α-subunit.	SIGNOR-251103
Q00653	P49841	0	phosphorylation	down-regulates activity	0.271	More recently, phosphorylation of S707 and S711 by GSK3beta has been shown to promote complete proteasomal degradation of p100 involving the E3 ligase Fbw7 .\|These studies suggest that a pool of p100 is constitutively phosphorylated by GSK3beta at S707 and S711, triggering the Fbw7 mediated ubiquitination and proteasomal degradation of p100 which controls the levels of p100 available for the non canonical pathway.	SIGNOR-279186
Q13794	Q9UBF6	0	ubiquitination	down-regulates activity	0.39	SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase. by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes.	SIGNOR-271446
Q9Y243	P99999	1	phosphorylation	down-regulates activity	0.265	Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain.	SIGNOR-277235
P63096	O14843	2	binding	up-regulates activity	0.2	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256678
P09471	P32239	2	binding	up-regulates activity	0.255	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-257238
P68104	P08047	2	binding	up-regulates activity	0.2	Subsequently, the elevated expression of eEF1A1 resulted in its binding to SP1, which in turn drove the binding of SP1 to its target HGF gene promoter to increase its transcription	SIGNOR-278105
O43318	P46734	1	phosphorylation	up-regulates activity	0.505	Taken together, our data indicate that TAK1 and TAB1 play a pivotal role as upstream signal transducers activating the MKK3-p38 MAPK signaling cascade that leads to the induction of type I collagen expression by TGF-beta(1). In addition, our findings also suggest that TAK1 has a novel function in regulation of the steady-state protein levels of MKK3 and p38 MAPK.	SIGNOR-42402
P41968	Q5JWF2	1	null	up-regulates activity	0.547	We hypothesize that XLŒ±s may be involved in this regulatory loop by coupling to melanocortin receptors 3 and 4 in the hypothalamus.	SIGNOR-253068
Q13153	P15153	2	binding	up-regulates	0.778	This report shows that rac1 binds to and stimulates the kinase activity of pak1 approximately 2- and 4-5-fold, respectively, better than rac2.	SIGNOR-59546
O75449	Q92630	0	phosphorylation	down-regulates quantity by destabilization	0.509	DYRK2 mediated phosphorylation is required for Katanin p60 degradation. Serine 42, serine 109 and threonine 133 are likely to be the major DYRK2 phosphorylation sites as single mutations for these sites showed reduced phosphorylation by DYRK2 and the triple mutant showed almost no DYRK2 mediated phosphorylation (Fig. 5d).	SIGNOR-262847
P84243	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-264304
P14778	P01584	2	binding	up-regulates activity	0.906	Pro-IL-1beta, mIL-1beta and mIL-beta all bind to IL-1RI, which recruits the IL-1 receptor accessory protein (IL-1RAcP) as a co-receptor.	SIGNOR-249511
P56279	Q9Y243	2	binding	up-regulates	0.503	Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation	SIGNOR-81434
P53805	Q99759	0	phosphorylation	up-regulates	0.448	Essential role of mekk3 signaling in angiotensin ii-induced calcineurin/nuclear factor of activated t-cells activation	SIGNOR-102294
Q08828	P08754	2	binding	down-regulates	0.595	Concentration-dependent inhibition of adenylyl cyclases by purified Gi alpha subunits is described. Activated Gi alpha but not G(o) alpha was effective, and myristoylation of Gi alpha was required	SIGNOR-38029
Q9BXM7	O43464	1	phosphorylation	up-regulates	0.607	Htra2 is phosphorylated on activation of the p38 pathway, occurring in a pink1-dependent mannerwe suggest that pink1-dependent phosphorylation of htra2 might modulate its proteolytic activity, thereby contributing to an increased resistance of cells to mitochondrial stress.	SIGNOR-158052
P27816	P33981	0	phosphorylation	down-regulates quantity by destabilization	0.2	We further uncovered that Mps1 is a kinase of MAP4, and E7-MAP4 binding blocks Mps1 phosphorylation of MAP4, thereby interrupting phosphorylation-dependent MAP4 degradation.	SIGNOR-277458
Q12852	P45985	1	phosphorylation	up-regulates activity	0.572	As expected, DLK significantly increased MKK4 phosphorylation on Ser257 / Thr261, and myrAKT1 enhanced MKK4 phosphorylation on Ser78 (XREF_FIG).\|While MKK4 activated by DLK had strong activity in phosphorylating JNK3, MKK4 expressed with DLK and AKT1 together exhibited little activity, even though the two samples had similar levels of Ser257 / Thr261 phosphorylation (XREF_FIG).	SIGNOR-279629
Q9Y2T1	Q9NTX7	0	ubiquitination	down-regulates quantity by destabilization	0.671	Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation.	SIGNOR-263336
P27986	Q5VWQ8	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
P23025	O95714	0	ubiquitination	down-regulates	0.385	Herc2 may ubiquitinate xpa and thus target it for proteolytic degradation	SIGNOR-164595
Q00839	P78527	0	phosphorylation	up-regulates	0.375	We identify heterogeneous nuclear ribonucleoprotein u (hnrnp-u), also termed scaffold attachment factor a (saf-a), as a specific substrate for dna-pk. We show that hnrnp-u is phosphorylated at ser59 by dna-pk in vitro and in cells in response to dna double-strand breaks	SIGNOR-185058
P43378	P06213	1	dephosphorylation	down-regulates	0.26	Ectopic expression of ptp-meg2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while rnai-mediated reduction of ptp-meg2 transcript levels enhanced insulin action	SIGNOR-146676
Q8IYT8	P08237	1	phosphorylation	down-regulates activity	0.2	Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).	SIGNOR-274044
P35222	Q9ULB4	2	binding	up-regulates activity	0.586	At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin	SIGNOR-265871
P00748	P45452	0	cleavage	down-regulates quantity by destabilization	0.313	The data presented in this study show for the first time the degradation of Factor XII of the blood clotting system by matrix metalloproteinases. MMP-12, MMP-13, and MMP-14 cleave at Gly376Leu377\|However, no activity of Factor XII can be observed after MMPinduced cleavage.	SIGNOR-263609
P43146	O75962	2	binding	up-regulates quantity	0.606	TrioY2622 is required for both netrin-1-induced activation of Rac1 and enhanced association with DCC. Phosphorylation of Trio at Tyr2622 participates in maintaining the level of surface DCC at the growth cone plasma membrane leading to axon outgrowth. Therefore, we propose that TrioY2622 is essential for the proper assembly and stability of the DCC/Trio signaling complex at the cell surface of growth cones in order to mediate netrin-1-induced cortical axon outgrowth.	SIGNOR-273856
Q9Y6Q9	Q16877	0	phosphorylation	up-regulates activity	0.326	PFKFB4, a regulatory enzyme that synthesizes an allosteric stimulator of glycolysis2, was found to be a robust stimulator of SRC-3 that co-activates estrogen receptor (ER). PFKFB4 phosphorylates SRC-3 at serine 857 (S857) enhancing its transcriptional activity, whereas either suppression of PFKFB4 or ectopic expression of a phosphorylation-deficient SRC-3 mutant S857A (SRC-3S857A) significantly abolishes SRC-3-mediated transcriptional output	SIGNOR-267269
P19447	P68400	0	phosphorylation	down-regulates activity	0.2	Phosphorylation of S751 by CKII inhibits 5′ incision.	SIGNOR-276013
P40818	P08581	1	destabilization	down-regulates quantity	0.456	Degradation of acutely stimulated receptor tyrosine kinases, epidermal growth factor receptor and Met, is strongly inhibited in UBPY knockdown cells suggesting that UBPY function is essential for growth factor receptor down-regulation.	SIGNOR-266903
P27361	P01100	1	phosphorylation	up-regulates activity	0.717	In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity.	SIGNOR-118023
Q12913	P09619	1	dephosphorylation	down-regulates activity	0.582	Primary sequence determinants responsible for site-selective dephosphorylation of the PDGF beta-receptor by the receptor-like protein tyrosine phosphatase DEP-1\|DEP-1 dephosphorylation of original and chimeric phospho-peptides spanning the preferred pY1021	SIGNOR-248704
Q99835	P63096	2	binding	up-regulates	0.516	Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling.	SIGNOR-199159
O43318	Q86WV6	1	phosphorylation	up-regulates activity	0.2	Activated TAK1 directly mediates STING phosphorylation on serine 355, which facilitates its interaction with STING ER exit protein (STEEP) and thereby promotes its oligomerization and translocation to the ERGIC for subsequent activation	SIGNOR-277887
O43474	P11831	2	binding	down-regulates	0.368	Klf4 antagonizes contractile gene expression through diverse mechanisms including (i) inhibiting the binding of srf-myocd or srf-mrtfs to the carg box by direct association with srf.	SIGNOR-174258
Q00987	Q13547	1	ubiquitination	down-regulates quantity by destabilization	0.468	MDM2 induces ubiquitination of HDAC1 in VSMCs.\|Under calcification inducing conditions, proteasomal degradation of HDAC1 precedes VC and it is mediated by MDM2 E3 ubiquitin ligase that initiates HDAC1 K74 ubiquitination.	SIGNOR-278761
P08069	Q9UNH7	2	binding	down-regulates quantity	0.2	Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures.	SIGNOR-269445
Q9NYA1	P19525	0	phosphorylation	up-regulates activity	0.2	This suggests that PKR is critical in the phosphorylation of SPHK1 at Ser225.\|We confirmed that phosphorylated PKR activates SPHK1 kinase activity, but it remained necessary to determine whether there has mutual correlation or any reciprocal effect between these two kinases in stressed cells.	SIGNOR-278514
Q15437	O75385	0	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
Q13002	O60260	0	ubiquitination	down-regulates quantity by destabilization	0.2	Parkin interacts with and ubiquitinates the GluK2 KAR subunit and regulates GluK2 levels and KAR currents.\|The loss of parkin function increases surface and total GluK2 levels, and consistently increases KAR currents.	SIGNOR-278541
P25963	P19525	0	phosphorylation	down-regulates quantity by destabilization	0.532	As described for other stimuli, following pIC treatment, PKR phosphorylates the NF-kappa B inhibitor I kappa B alpha at serine 32 before degradation.	SIGNOR-249335
P17252	Q13976	1	phosphorylation	up-regulates	0.344	Antibodies generated against phosphorylated threonine 58 were used to demonstrate phosphorylation in response to pma treatment of the cells with kinetics similar to vasodilator-stimulated phosphoprotein phosphorylation. A phospho-mimetic mutation at this site (t58e) generated a partially activated pkg that was more sensitive to cgmp levels. A phospho- mutation (t58a) revealed that this residue is important but not sufficient for pkg activation by pkc.	SIGNOR-98803
Q92769	P00519	0	phosphorylation	up-regulates quantity by stabilization	0.285	C-Abl stabilizes HDAC2 levels by tyrosine phosphorylation repressing neuronal gene expression in Alzheimer's disease.	SIGNOR-260928
P50542	P28328	0	ubiquitination	down-regulates quantity by destabilization	0.579	Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle.	SIGNOR-253021
P42345	Q96B36	1	phosphorylation	down-regulates activity	0.904	We propose that after mtorc1 kinase activation by upstream regulators, pras40 is phosphorylated directly by mtor, thus contributing to the relief of pras40-mediated substrate competitionwe also find that mutation of ser-221 to ala increases the inhibitory activity of pras40 toward mtorc1.	SIGNOR-178128
Q9H0A0	Q9Y6X9	2	binding	up-regulates activity	0.2	MORC2 directly interacts with PARP1. MORC2 mediates the interaction between PARP1 and NAT10 and thereby promotes NAT10-mediated PARP1 acetylation at K949, which blocks CHFR-mediated ubiquitination and degradation of PARP1.	SIGNOR-273716
Q9NYA4	Q15796	1	dephosphorylation	down-regulates	0.53	Here we demonstrate that myotubularin-related protein 4 (mtmr4), a fyve domain-containing dual-specificity protein phosphatase (dsp), attenuates tgfbeta signaling by reducing the phosphorylation level of r-smads in early endosomes.	SIGNOR-163031
Q13131	P36956	1	phosphorylation	down-regulates activity	0.36	Ampk was recently found to phosphorylate a conserved serine near the cleavage site within srebp1, suppressing its activation	SIGNOR-176497
Q13315	Q96J02	1	phosphorylation	up-regulates activity	0.264	Here we uncover ATM as a novel positive modulator of ITCH E3-ubiquitin ligase activity. A single residue on ITCH protein, S161, which is part of an ATM SQ consensus motif, is required for ATM-dependent activation of ITCH.	SIGNOR-276488
Q8NFU7	O15294	0	glycosylation	up-regulates activity	0.44	The DNA demethylation enzyme Tet1 interacts with Ogt and is O-GlcNAcylated. Tet1 protein stability is positively regulated by O-GlcNAcylation, and its repression function on targeting genes is dependent on Ogt.	SIGNOR-259184
Q01970	P17612	0	phosphorylation	down-regulates	0.26	These data indicate that pkc and pka act similarly in that they inhibit galpha(q)-stimulated plcbeta(3) as a result of phosphorylation of ser(1105).	SIGNOR-79148
Q99717	Q13485	1	phosphorylation	up-regulates	0.675	Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus.	SIGNOR-168737
Q92519	P23443	0	phosphorylation	down-regulates quantity by destabilization	0.356	Furthermore, Smurf1-mediated ubiquitination required phosphorylation of TRIB2 by p70 S6 kinase (p70S6K) via another domain (amino acids 69-85) that is also essential for correct TRIB2 subcellular localization. Mutation of Ser-83 diminished p70S6K-induced phosphorylation of TRIB2.	SIGNOR-275433
Q16539	P25098	0	phosphorylation	down-regulates	0.2	Phosphorylation of p38 by grk2 at the docking groove unveils a novel mechanism for inactivating p38mapk p38 associates with grk2 endogenously and is phosphorylated by grk2 at thr-123, a residue located at its docking groove. Mimicking phosphorylation at this site impairs the binding and activation of p38 by mkk6 and diminishes the capacity of p38 to bind and phosphorylate its substrates	SIGNOR-150152
Q9NR48	P68431	1	trimethylation	up-regulates activity	0.2	We show that human ASH1L specifically methylates histone H3 Lys-36. Our data implicate that there may be a regulatory mechanism of ASH1L histone methyltransferases	SIGNOR-269055
Q9HBW0	P38405	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-256927
Q99835	O00141	2	binding	down-regulates	0.2	SGK1 is known to inhibit another intrinsic pathway, the Hedgehog pathway, through downregulation of SMO and the GLI transcription factor family	SIGNOR-251673
Q92934	Q15818	0	relocalization	up-regulates activity	0.2	Immunofluorescence staining and subcellular fractionation analyses revealed increased mitochondrial translocation of Bad and Bax proteins from cytoplasm following OGD (4 h) and simultaneously increased release of Cyt C from mitochondria followed by activation of caspase-3. NP1 protein was immunoprecipitated with Bad and Bax proteins; OGD caused increased interactions of NP1 with Bad and Bax, thereby, facilitating their mitochondrial translocation and dissipation of mitochondrial membrane potential	SIGNOR-261483

Q12857

P41221

1

transcriptional regulation

down-regulates quantity

0.2

By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development

SIGNOR-268877

P00519

O75122

1

phosphorylation

up-regulates quantity

0.502

We find that Abl binds to and phosphorylates CLASP2 in response to extracellular signals such as serum or PDGF.

SIGNOR-279580

P50391

P01303

2

binding

up-regulates

0.692

Human y4 bound human pp family members in i-pyy membrane binding assays with a distinctive rank order (table 1): pp > pyy > npy > npy free acid.

SIGNOR-29633

P55211

P62136

0

dephosphorylation

up-regulates

0.2

Pp1 dephosphorylated thr125 site of caspase-9 and activated caspase-9 to mediate il-2 deprivation-induced apoptosis.

SIGNOR-195992

P31749

P49841

1

phosphorylation

down-regulates activity

0.792

Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3beta (GSK3B). The AKT-mediated phosphorylation of glycogen synthase kinase 3b on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1

SIGNOR-245416

P32121

Q00987

2

binding

up-regulates quantity by stabilization

0.434

Our current results demonstrated that the binding of Mdm2 to beta-arrestin 2 was significantly enhanced by stimulation of GPCRs. Activation of GPCRs led to formation of a ternary complex of Mdm2, beta-arrestin 2, and GPCRs and thus recruited Mdm2 to GPCRs at plasma membrane. Moreover, the binding of beta-arrestin 2 to Mdm2 suppressed the self-ubiquitination of Mdm2 and consequently reduced the Mdm2-mediated p53 degradation and ubiquitination.

SIGNOR-272592

P24928

Q8IXW5

0

dephosphorylation

up-regulates activity

0.738

In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator

SIGNOR-248748

O95136

Q14344

2

binding

up-regulates activity

0.59

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-257401

P68400

Q14761

1

phosphorylation

up-regulates quantity by stabilization

0.2

We demonstrated for the first time that LPAP is a substrate for protein kinase CK2 that phosphorylates it at Ser153, presumably ensuring LPAP resistance to degradation.

SIGNOR-273629

P45984

P55957

1

phosphorylation

up-regulates activity

0.406

(c) The phosphorylation of recombinant Bid by JNK2 (in vitro kinase assay) prevents its cleavage by caspase-8

SIGNOR-279220

P12931

P13688

1

phosphorylation

up-regulates activity

0.426

Recent reports have also suggested that Bgp1 behaves as a signal transduction molecule. Several physiological events promote the Tyr phosphorylation of Bgp1 on one or two Tyr residues within its cytoplasmic domain (Tyr-488 and Tyr-515). BGP becomes Tyr-phosphorylated by Src-like Tyr kinases in activated neutrophils (24) and in human colon carcinoma cellsWe have recently shown that Tyr phosphorylation of the mouse Bgp1 cytoplasmic domain in CT51 mouse colonic carcinoma cells led to its binding to the protein-Tyr phosphatase SHP-1 and that this event required the presence of both Tyr-488 and Tyr-515

SIGNOR-246471

O15146

2

phosphorylation

up-regulates activity

0.2

AGRN is released by the nerve and binds to LRP4, which then binds to MuSK. This interaction leads to MuSK autophosphorylation and activation of its kinase function, leading to anterograde signalling by subsequent phosphorylation of DOK7 (not shown), which binds MuSK as a dimer.

SIGNOR-273851

P11474

Q9H0X6

1

transcriptional regulation

up-regulates quantity by expression

0.2

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

SIGNOR-269052

Q99835

Q13009

2

binding

up-regulates

0.267

This latter work suggested that inactive smo prevents rac1 activation by interacting with the rac guanine nucleotide exchange factor (gef) t-lymphoma invasion and metastasis 1 (tiam1). This smo-tiam1 complex dissociates upon shh-mediated activation of smo, thus allowing tiam1 to activate rac1

SIGNOR-199192

P42680

P12931

0

phosphorylation

up-regulates activity

0.32

The proximal event following T cell-APC synapse formation is immediate activation of several signaling molecules: The Src kinase phosphorylates and activates Tec tyrosine kinases, which then activate PLC-\u03b3 that is required for IP 3 generation to sustain intracellular calcium flux.

SIGNOR-280135

P49366

P63241

1

post translational modification

up-regulates activity

0.933

Deoxyhypusine synthase (DHPS) utilizes spermidine and NAD as cofactors to incorporate a hypusine modification into the eukaryotic translation initiation factor 5A (eIF5A). Hypusine is essential for eIF5A activation, which, in turn, plays a key role in regulating protein translation of selected mRNA that are associated with the synthesis of oncoproteins, thereby enhancing tumor cell proliferation.

SIGNOR-266374

Q00535

Q8IXJ6

1

phosphorylation

up-regulates activity

0.397

Cdk5 phosphorylation-induced SIRT2 nuclear translocation promotes the death of dopaminergic neurons in Parkinson's disease.|Moreover, the cyclin-dependent kinase 5 (Cdk5)-mediated phosphorylation of SIRT2 at the Ser331 and Ser335 sites appears to be necessary for such nuclear translocation.

SIGNOR-279684

P12931

Q9UGK3

1

phosphorylation

up-regulates activity

0.406

To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase Tyr-22 and Tyr-322 are the major tyrosine phosphorylation sites by v-Src.

SIGNOR-247337

P49715

P06702

1

transcriptional regulation

up-regulates quantity by expression

0.227

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-254041

P68400

P49716

1

phosphorylation

up-regulates activity

0.2

Here, we have identified the CCAAT/enhancer binding protein δ (C/EBPδ) as a new substrate for CK2. Using point mutants of C/EBPδ the major phosphorylation site for CK2 was mapped to serine 57, which is located within the transactivation domain of C/EBPδ. For proper functioning as a transcription factor C/EBPδ has to be translocated into the nucleus where it forms heterodimers with other members of the C/EBP family of proteins and ATF4. Here, we found that CK2 phosphorylation does neither influence the subcellular localization of C/EBPδ nor its interaction with C/EBPβ, but rather does CK2 phosphorylation modulate the transcriptional activity of C/EBPδ.

SIGNOR-276886

P0DP25

P55040

2

binding

up-regulates activity

0.2

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

SIGNOR-266342

Q16566

Q92793

1

phosphorylation

up-regulates activity

0.635

Ser301 of CBP was identified as a major target of CaMKIV phosphorylation in vitro and in vivo. CaM kinase inhibitors attenuated phosphorylation at Ser301 and blocked CBP-dependent transcription. Additionally, mutation of Ser301 impaired NMDA- and CaMKIV-stimulated transcription. These findings demonstrate that activity-induced CaMKIV signaling contributes to CREB/CBP-dependent transcription by phosphorylating CBP at Ser301.

SIGNOR-250710

P00441

P14174

0

relocalization

down-regulates quantity by destabilization

0.307

Here, we show that MIF inhibits mutant SOD1 nuclear clearance when overexpressed in motor neuron-like NSC-34 cells|SOD1WT is evenly distributed between the cytoplasm and the nucleus while mutant SOD1G93A shows predominantly cytoplasmic distribution (Fig. 1a, b). Expression of MIF in cells expressing SOD1WT had no effect on the distribution of the SOD1WT–EGFP protein. However, expression of MIF together with the mutant SOD1G93A–EGFP, inhibited the nuclear clearance of misfolded SOD1 resulting in a more wild-type-like distribution of the mutant SOD1 protein

SIGNOR-262797

P12643

Q13873

2

binding

up-regulates

0.8

Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor.

SIGNOR-33425

Q99986

P16104

1

phosphorylation

up-regulates activity

0.2

In response to DNA damage induced by ionizing radiation, histone H2AX is phosphorylated in Ser139 by VRK1.

SIGNOR-278370

P05556

Q9Y5I1

2

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-265670

P32245

P25098

0

phosphorylation

down-regulates activity

0.2

Mutagenesis studies revealed that Thr312 and Ser329/330 in the C-terminal tail are potential sites for PKA and GRK phosphorylation and may play an essential role in the recruitment of beta-arrestin to the activated receptor.

SIGNOR-247770

Q13188

Q6ZTQ3

2

binding

down-regulates

0.658

When rassf 6 is bound to mst2, rassf 6 inhibits mst2 activity, thus, inhibiting its role in the hippo pathway.

SIGNOR-198463

P12931

Q06124

0

dephosphorylation

up-regulates activity

0.653

Several protein tyrosine phosphatases are capable of activating Src by dephosphorylating Y530 (reviewed in ref. 9). These include PTP-α, PTP-λ, SHP-1, SHP-2, and PTP1B

SIGNOR-248671

P15692

Q16665

0

transcriptional regulation

up-regulates quantity

0.773

Transcription of the human erythropoietin (EPO) gene is activated in Hep3B cells exposed to hypoxia. Hypoxia-inducible factor 1 (HIF-1) is a nuclear factor whose DNA binding activity is induced by hypoxia in Hep3B cells, and HIF-1 binds at a site in the EPO gene enhancer that is required for hypoxic activation of transcription.

SIGNOR-256592

O14757

P30304

1

phosphorylation

down-regulates

0.857

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

SIGNOR-163134

Q14247

Q14289

0

phosphorylation

up-regulates activity

0.365

In conclusion, these data suggest that Pyk2 phosphorylates cortactin on tyrosine residues Y421, Y466, and Y482.|To confirm the direct and indirect effects of Pyk2 on cortactin phosphorylation, we used cells overexpressing Arg YFP and treated with Pyk2 siRNA or a nonsilencing siRNA.

SIGNOR-278344

Q92793

Q9UBR4

2

binding

up-regulates activity

0.2

Transcription of pituitary alpha-glycoprotein hormone subunit (alpha-GSU) and thyrotropin beta subunit (TSH-beta) genes is stimulated by thyrotropin-releasing hormone (TRH). P-Lim and CBP Act Synergistically in TRH Stimulation of the Human α-GSU Promoter.

SIGNOR-267206

P12931

P60484

2

phosphorylation

down-regulates

0.536

Activated src reduces the ability of pten to dephosphorylate phosphatidylinositols in micelles and promotes akt translocation to cellular plasma membranes but does not alter pten activity toward water-soluble phosphatidylinositols.

SIGNOR-103721

P20226

P62258

2

binding

up-regulates activity

0.347

The in vitro binding with general transcription factors TBP and TFIIB together with its nuclear location provide evidence supporting a role for 14-3-3 proteins as transcriptional activators or coactivators when part of a DNA binding complex.

SIGNOR-262834

O43791

Q9NZQ7

1

ubiquitination

down-regulates quantity

0.325

Loss-of-function mutations in SPOP compromise ubiquitination-mediated PD-L1 degradation, leading to increased PD-L1 levels and reduced numbers of tumor-infiltrating lymphocytes (TILs) in mouse tumors and in primary human prostate cancer specimens.

SIGNOR-274978

O95198

Q9HA47

1

ubiquitination

down-regulates quantity by destabilization

0.346

We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation. We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1.

SIGNOR-275962

Q86VP3

Q13489

0

polyubiquitination

down-regulates quantity by destabilization

0.286

Under basal conditions, PACS-2 underwent K48-linked poly-ubiquitination, resulting in PACS-2 proteasomal degradation. Biochemical assays showed cIAP-1 and cIAP-2 interacted with PACS-2 in vitro and co-immunoprecipitation studies demonstrated that the two cIAPs bound PACS-2 in vivo. More importantly, both cIAP-1 and cIAP-2 directly mediated PACS-2 ubiquitination in a cell-free assay.

SIGNOR-272852

P50148

P43119

2

binding

up-regulates activity

0.4

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-257078

P31749

Q04912

1

phosphorylation

up-regulates

0.559

Akt/pkb phosphorylates ron ser-1394, thus providing a docking site for 14-3-3based on these results, we propose a mechanism based on msp-ron-dependent phosphorylation and 14-3-3 association, whereby the function of alpha6beta4 switches from a mechanical adhesive device into a signaling component, and might be critically involved in human epidermal wound healing

SIGNOR-252471

P46695

P28482

0

phosphorylation

up-regulates

0.552

Upon phosphorylation by erks, iex-1 acquires the ability to inhibit cell death induced by various stimuli. In turn, iex-1 potentiates erk activation in response to various growth factors.

SIGNOR-93740

Q99527

P62873

2

binding

up-regulates activity

0.385

GPCRs transduce their signal via G-protein heterotrimers (αβγ) that dissociate in free Gα-subunit protein and Gβγ-subunit protein complexes following ligand stimulation; GNB1 stands for the subunit β, which dissociates from the receptor after the binding of GTP on α-subunit.

SIGNOR-251103

Q00653

P49841

0

phosphorylation

down-regulates activity

0.271

More recently, phosphorylation of S707 and S711 by GSK3beta has been shown to promote complete proteasomal degradation of p100 involving the E3 ligase Fbw7 .|These studies suggest that a pool of p100 is constitutively phosphorylated by GSK3beta at S707 and S711, triggering the Fbw7 mediated ubiquitination and proteasomal degradation of p100 which controls the levels of p100 available for the non canonical pathway.

SIGNOR-279186

Q13794

Q9UBF6

0

ubiquitination

down-regulates activity

0.39

SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase. by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes.

SIGNOR-271446

Q9Y243

P99999

1

phosphorylation

down-regulates activity

0.265

Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain.

SIGNOR-277235

P63096

O14843

2

binding

up-regulates activity

0.2

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

SIGNOR-256678

P09471

P32239

2

binding

up-regulates activity

0.255

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-257238

P68104

P08047

2

binding

up-regulates activity

0.2

Subsequently, the elevated expression of eEF1A1 resulted in its binding to SP1, which in turn drove the binding of SP1 to its target HGF gene promoter to increase its transcription

SIGNOR-278105

O43318

P46734

1

phosphorylation

up-regulates activity

0.505

Taken together, our data indicate that TAK1 and TAB1 play a pivotal role as upstream signal transducers activating the MKK3-p38 MAPK signaling cascade that leads to the induction of type I collagen expression by TGF-beta(1). In addition, our findings also suggest that TAK1 has a novel function in regulation of the steady-state protein levels of MKK3 and p38 MAPK.

SIGNOR-42402

P41968

Q5JWF2

1

null

up-regulates activity

0.547

We hypothesize that XLŒ±s may be involved in this regulatory loop by coupling to melanocortin receptors 3 and 4 in the hypothalamus.

SIGNOR-253068

Q13153

P15153

2

binding

up-regulates

0.778

This report shows that rac1 binds to and stimulates the kinase activity of pak1 approximately 2- and 4-5-fold, respectively, better than rac2.

SIGNOR-59546

O75449

Q92630

0

phosphorylation

down-regulates quantity by destabilization

0.509

DYRK2 mediated phosphorylation is required for Katanin p60 degradation. Serine 42, serine 109 and threonine 133 are likely to be the major DYRK2 phosphorylation sites as single mutations for these sites showed reduced phosphorylation by DYRK2 and the triple mutant showed almost no DYRK2 mediated phosphorylation (Fig. 5d).

SIGNOR-262847

P84243

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-264304

P14778

P01584

2

binding

up-regulates activity

0.906

Pro-IL-1beta, mIL-1beta and mIL-beta all bind to IL-1RI, which recruits the IL-1 receptor accessory protein (IL-1RAcP) as a co-receptor.

SIGNOR-249511

P56279

Q9Y243

2

binding

up-regulates

0.503

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

SIGNOR-81434

P53805

Q99759

0

phosphorylation

up-regulates

0.448

Essential role of mekk3 signaling in angiotensin ii-induced calcineurin/nuclear factor of activated t-cells activation

SIGNOR-102294

Q08828

P08754

2

binding

down-regulates

0.595

Concentration-dependent inhibition of adenylyl cyclases by purified Gi alpha subunits is described. Activated Gi alpha but not G(o) alpha was effective, and myristoylation of Gi alpha was required

SIGNOR-38029

Q9BXM7

O43464

1

phosphorylation

up-regulates

0.607

Htra2 is phosphorylated on activation of the p38 pathway, occurring in a pink1-dependent mannerwe suggest that pink1-dependent phosphorylation of htra2 might modulate its proteolytic activity, thereby contributing to an increased resistance of cells to mitochondrial stress.

SIGNOR-158052

P27816

P33981

0

phosphorylation

down-regulates quantity by destabilization

0.2

We further uncovered that Mps1 is a kinase of MAP4, and E7-MAP4 binding blocks Mps1 phosphorylation of MAP4, thereby interrupting phosphorylation-dependent MAP4 degradation.

SIGNOR-277458

Q12852

P45985

1

phosphorylation

up-regulates activity

0.572

As expected, DLK significantly increased MKK4 phosphorylation on Ser257 / Thr261, and myrAKT1 enhanced MKK4 phosphorylation on Ser78 (XREF_FIG).|While MKK4 activated by DLK had strong activity in phosphorylating JNK3, MKK4 expressed with DLK and AKT1 together exhibited little activity, even though the two samples had similar levels of Ser257 / Thr261 phosphorylation (XREF_FIG).

SIGNOR-279629

Q9Y2T1

Q9NTX7

0

ubiquitination

down-regulates quantity by destabilization

0.671

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

SIGNOR-263336

P27986

Q5VWQ8

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

P23025

O95714

0

ubiquitination

down-regulates

0.385

Herc2 may ubiquitinate xpa and thus target it for proteolytic degradation

SIGNOR-164595

Q00839

P78527

0

phosphorylation

up-regulates

0.375

We identify heterogeneous nuclear ribonucleoprotein u (hnrnp-u), also termed scaffold attachment factor a (saf-a), as a specific substrate for dna-pk. We show that hnrnp-u is phosphorylated at ser59 by dna-pk in vitro and in cells in response to dna double-strand breaks

SIGNOR-185058

P43378

P06213

1

dephosphorylation

down-regulates

0.26

Ectopic expression of ptp-meg2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while rnai-mediated reduction of ptp-meg2 transcript levels enhanced insulin action

SIGNOR-146676

Q8IYT8

P08237

1

phosphorylation

down-regulates activity

0.2

Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).

SIGNOR-274044

P35222

Q9ULB4

2

binding

up-regulates activity

0.586

At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin

SIGNOR-265871

P00748

P45452

0

cleavage

down-regulates quantity by destabilization

0.313

The data presented in this study show for the first time the degradation of Factor XII of the blood clotting system by matrix metalloproteinases. MMP-12, MMP-13, and MMP-14 cleave at Gly376Leu377|However, no activity of Factor XII can be observed after MMPinduced cleavage.

SIGNOR-263609

P43146

O75962

2

binding

up-regulates quantity

0.606

TrioY2622 is required for both netrin-1-induced activation of Rac1 and enhanced association with DCC. Phosphorylation of Trio at Tyr2622 participates in maintaining the level of surface DCC at the growth cone plasma membrane leading to axon outgrowth. Therefore, we propose that TrioY2622 is essential for the proper assembly and stability of the DCC/Trio signaling complex at the cell surface of growth cones in order to mediate netrin-1-induced cortical axon outgrowth.

SIGNOR-273856

Q9Y6Q9

Q16877

0

phosphorylation

up-regulates activity

0.326

PFKFB4, a regulatory enzyme that synthesizes an allosteric stimulator of glycolysis2, was found to be a robust stimulator of SRC-3 that co-activates estrogen receptor (ER). PFKFB4 phosphorylates SRC-3 at serine 857 (S857) enhancing its transcriptional activity, whereas either suppression of PFKFB4 or ectopic expression of a phosphorylation-deficient SRC-3 mutant S857A (SRC-3S857A) significantly abolishes SRC-3-mediated transcriptional output

SIGNOR-267269

P19447

P68400

0

phosphorylation

down-regulates activity

0.2

Phosphorylation of S751 by CKII inhibits 5′ incision.

SIGNOR-276013

P40818

P08581

1

destabilization

down-regulates quantity

0.456

Degradation of acutely stimulated receptor tyrosine kinases, epidermal growth factor receptor and Met, is strongly inhibited in UBPY knockdown cells suggesting that UBPY function is essential for growth factor receptor down-regulation.

SIGNOR-266903

P27361

P01100

1

phosphorylation

up-regulates activity

0.717

In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity.

SIGNOR-118023

Q12913

P09619

1

dephosphorylation

down-regulates activity

0.582

Primary sequence determinants responsible for site-selective dephosphorylation of the PDGF beta-receptor by the receptor-like protein tyrosine phosphatase DEP-1|DEP-1 dephosphorylation of original and chimeric phospho-peptides spanning the preferred pY1021

SIGNOR-248704

Q99835

P63096

2

binding

up-regulates

0.516

Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling.

SIGNOR-199159

O43318

Q86WV6

1

phosphorylation

up-regulates activity

0.2

Activated TAK1 directly mediates STING phosphorylation on serine 355, which facilitates its interaction with STING ER exit protein (STEEP) and thereby promotes its oligomerization and translocation to the ERGIC for subsequent activation

SIGNOR-277887

O43474

P11831

2

binding

down-regulates

0.368

Klf4 antagonizes contractile gene expression through diverse mechanisms including (i) inhibiting the binding of srf-myocd or srf-mrtfs to the carg box by direct association with srf.

SIGNOR-174258

Q00987

Q13547

1

ubiquitination

down-regulates quantity by destabilization

0.468

MDM2 induces ubiquitination of HDAC1 in VSMCs.|Under calcification inducing conditions, proteasomal degradation of HDAC1 precedes VC and it is mediated by MDM2 E3 ubiquitin ligase that initiates HDAC1 K74 ubiquitination.

SIGNOR-278761

P08069

Q9UNH7

2

binding

down-regulates quantity

0.2

Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures.

SIGNOR-269445

Q9NYA1

P19525

0

phosphorylation

up-regulates activity

0.2

This suggests that PKR is critical in the phosphorylation of SPHK1 at Ser225.|We confirmed that phosphorylated PKR activates SPHK1 kinase activity, but it remained necessary to determine whether there has mutual correlation or any reciprocal effect between these two kinases in stressed cells.

SIGNOR-278514

Q15437

O75385

0

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

Q13002

O60260

0

ubiquitination

down-regulates quantity by destabilization

0.2

Parkin interacts with and ubiquitinates the GluK2 KAR subunit and regulates GluK2 levels and KAR currents.|The loss of parkin function increases surface and total GluK2 levels, and consistently increases KAR currents.

SIGNOR-278541

P25963

P19525

0

phosphorylation

down-regulates quantity by destabilization

0.532

As described for other stimuli, following pIC treatment, PKR phosphorylates the NF-kappa B inhibitor I kappa B alpha at serine 32 before degradation.

SIGNOR-249335

P17252

Q13976

1

phosphorylation

up-regulates

0.344

Antibodies generated against phosphorylated threonine 58 were used to demonstrate phosphorylation in response to pma treatment of the cells with kinetics similar to vasodilator-stimulated phosphoprotein phosphorylation. A phospho-mimetic mutation at this site (t58e) generated a partially activated pkg that was more sensitive to cgmp levels. A phospho- mutation (t58a) revealed that this residue is important but not sufficient for pkg activation by pkc.

SIGNOR-98803

Q92769

P00519

0

phosphorylation

up-regulates quantity by stabilization

0.285

C-Abl stabilizes HDAC2 levels by tyrosine phosphorylation repressing neuronal gene expression in Alzheimer's disease.

SIGNOR-260928

P50542

P28328

0

ubiquitination

down-regulates quantity by destabilization

0.579

Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle.

SIGNOR-253021

P42345

Q96B36

1

phosphorylation

down-regulates activity

0.904

We propose that after mtorc1 kinase activation by upstream regulators, pras40 is phosphorylated directly by mtor, thus contributing to the relief of pras40-mediated substrate competitionwe also find that mutation of ser-221 to ala increases the inhibitory activity of pras40 toward mtorc1.

SIGNOR-178128

Q9H0A0

Q9Y6X9

2

binding

up-regulates activity

0.2

MORC2 directly interacts with PARP1. MORC2 mediates the interaction between PARP1 and NAT10 and thereby promotes NAT10-mediated PARP1 acetylation at K949, which blocks CHFR-mediated ubiquitination and degradation of PARP1.

SIGNOR-273716

Q9NYA4

Q15796

1

dephosphorylation

down-regulates

0.53

Here we demonstrate that myotubularin-related protein 4 (mtmr4), a fyve domain-containing dual-specificity protein phosphatase (dsp), attenuates tgfbeta signaling by reducing the phosphorylation level of r-smads in early endosomes.

SIGNOR-163031

Q13131

P36956

1

phosphorylation

down-regulates activity

0.36

Ampk was recently found to phosphorylate a conserved serine near the cleavage site within srebp1, suppressing its activation

SIGNOR-176497

Q13315

Q96J02

1

phosphorylation

up-regulates activity

0.264

Here we uncover ATM as a novel positive modulator of ITCH E3-ubiquitin ligase activity. A single residue on ITCH protein, S161, which is part of an ATM SQ consensus motif, is required for ATM-dependent activation of ITCH.

SIGNOR-276488

Q8NFU7

O15294

0

glycosylation

up-regulates activity

0.44

The DNA demethylation enzyme Tet1 interacts with Ogt and is O-GlcNAcylated. Tet1 protein stability is positively regulated by O-GlcNAcylation, and its repression function on targeting genes is dependent on Ogt.

SIGNOR-259184

Q01970

P17612

0

phosphorylation

down-regulates

0.26

These data indicate that pkc and pka act similarly in that they inhibit galpha(q)-stimulated plcbeta(3) as a result of phosphorylation of ser(1105).

SIGNOR-79148

Q99717

Q13485

1

phosphorylation

up-regulates

0.675

Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus.

SIGNOR-168737

Q92519

P23443

0

phosphorylation

down-regulates quantity by destabilization

0.356

Furthermore, Smurf1-mediated ubiquitination required phosphorylation of TRIB2 by p70 S6 kinase (p70S6K) via another domain (amino acids 69-85) that is also essential for correct TRIB2 subcellular localization. Mutation of Ser-83 diminished p70S6K-induced phosphorylation of TRIB2.

SIGNOR-275433

Q16539

P25098

0

phosphorylation

down-regulates

0.2

Phosphorylation of p38 by grk2 at the docking groove unveils a novel mechanism for inactivating p38mapk p38 associates with grk2 endogenously and is phosphorylated by grk2 at thr-123, a residue located at its docking groove. Mimicking phosphorylation at this site impairs the binding and activation of p38 by mkk6 and diminishes the capacity of p38 to bind and phosphorylate its substrates

SIGNOR-150152

Q9NR48

P68431

1

trimethylation

up-regulates activity

0.2

We show that human ASH1L specifically methylates histone H3 Lys-36. Our data implicate that there may be a regulatory mechanism of ASH1L histone methyltransferases

SIGNOR-269055

Q9HBW0

P38405

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-256927

Q99835

O00141

2

binding

down-regulates

0.2

SGK1 is known to inhibit another intrinsic pathway, the Hedgehog pathway, through downregulation of SMO and the GLI transcription factor family

SIGNOR-251673

Q92934

Q15818

0

relocalization

up-regulates activity

0.2

Immunofluorescence staining and subcellular fractionation analyses revealed increased mitochondrial translocation of Bad and Bax proteins from cytoplasm following OGD (4 h) and simultaneously increased release of Cyt C from mitochondria followed by activation of caspase-3. NP1 protein was immunoprecipitated with Bad and Bax proteins; OGD caused increased interactions of NP1 with Bad and Bax, thereby, facilitating their mitochondrial translocation and dissipation of mitochondrial membrane potential

SIGNOR-261483