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
Q15797	O95819	0	phosphorylation	down-regulates activity	0.2	Msn kinases directly phosphorylate α-helix 1 of Smad. we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for α-helix 1 phosphorylation.	SIGNOR-276335
P06493	Q8WUF5	1	phosphorylation	up-regulates activity	0.505	Cyclin B/cyclin-dependent kinase 1 (CDK1) phosphorylates inhibitor of apoptosis stimulating protein of P53 (iASPP) to promote iASPP nucleus localization and its inhibitory effect on p53.	SIGNOR-273585
Q13233	P45985	1	phosphorylation	up-regulates activity	0.729	The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, sek1	SIGNOR-236380
P48729	P16220	1	phosphorylation	up-regulates	0.312	Ser108, ser111 and ser114, located in a region matching the consensus sequence for the casein kinase ii target, were required.These results strongly suggest that the casein kinase ii target region is involved in cell cycle-regulated phosphorylation of the creb protein and also in transcriptional enhancement.	SIGNOR-64258
P08581	Q6ZN28	0	transcriptional regulation	up-regulates quantity by expression	0.394	Human colon carcinoma SW480 cells express virtually no MACC1. MACC1 cDNA transfection led not only to strong increases in MACC1 mRNA expression (Fig. 3a), but also to a 40-fold upregulation of the HGF receptor MET mRNA expression (Fig. 3b). This was confirmed on the protein level	SIGNOR-266058
P60484	P68400	0	phosphorylation	down-regulates activity	0.68	The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity	SIGNOR-89830
Q00535	P42858	1	phosphorylation	up-regulates	0.447	Huntingtin is an antiapoptotic proteinwe show here that huntingtin is phosphorylated by the cyclin-dependent kinase 5 (cdk5) at serines 1181 and 1201. Phosphorylation can be induced by dna damage in vitro and in vivo. The state of huntingtin phosphorylation is a crucial regulator of neuronal cell death. Absence of phosphorylation of huntingtin at serines 1181 and 1201 confers toxic properties to wild-type huntingtin in a p53-dependent manner in striatal neurons and accelerates neuronal death induced by dna damage.	SIGNOR-156840
P12830	P15923	0	transcriptional regulation	down-regulates quantity by repression	0.31	The p21-activated kinase 5 (PAK5) is overexpressed in advanced cancer and the transcription factor E47 is a direct repressor of E-cadherin and inducer of epithelial-mesenchymal transition (EMT). \|In this study, we found that PAK5-mediated E47 phosphorylation promoted EMT in advanced colon cancer. PAK5 interacted with E47 and phosphorylated E47 on Ser39 under hepatocyte growth factor (HGF) stimulation	SIGNOR-275654
Q14457	Q9HD26	2	binding	up-regulates	0.523	Npist binds beclin 1 by a ccd	SIGNOR-171896
P33981	Q13257	1	phosphorylation	up-regulates activity	0.713	Mps1 is an upstream component of the spindle assembly checkpoint, which, in human cells, is required for checkpoint activation in response to spindle damage but not apparently during an unperturbed mitosis. Mps1 also recruits Mad1 and Mad2 to kinetochores.\|Thus, in human cells, Mps1 catalytic activity is required for spindle checkpoint function and recruitment of Mad2.	SIGNOR-252036
Q14653	Q12899	0	polyubiquitination	down-regulates quantity by destabilization	0.672	TRIM26 bound to IRF3 and promoted its K48-linked polyubiquitination and degradation in nucleus.	SIGNOR-272440
P0C6X7-PRO_0000037311	Q13114	1	deubiquitination	down-regulates activity	0.2	Overexpressing PLPro of SARS-CoV or MERS-CoV significantly reduced the expression of IFN-Î² and proinflammatory cytokines in MDA5-stimulated 293T cells (83).Also, SARS-CoVPLPro catalyzed deubiquitination of TNF-receptor-associated factor3 (TRAF3) and TRAF6, thereby suppressing IFN-I and proinflammatory cytokines induced by TLR7 agonist (63). The deubiquitinating activity of SARS-CoV PLPro also suppressed a constitutively active phosphomimetic IRF3, suggesting its involvement in the postactivation signaling of IRF3	SIGNOR-260246
Q9Y484	Q96BY7	2	binding	up-regulates activity	0.648	WIPI4 interacts with ATG2, AMPK and ULK1. Upon starvation and AMPK activation, WIPI4-ATG2 dissociates from AMPK and ULK1 and localizes at nascent autophagosomes, potentially supporting further autophagosome maturation.	SIGNOR-268484
P31749	P35222	1	phosphorylation	up-regulates	0.805	Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activity\|we have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo.	SIGNOR-252499
P49915	P19474	0	ubiquitination	down-regulates	0.326	Cytoplasmic sequestration of gmps requires ubiquitylation by trim21, a ubiquitin ligase associated with autoimmune disease.	SIGNOR-204478
P35236	Q16539	2	binding	down-regulates	0.59	Thus, beta(2)ar stimulation on a b cell phosphorylates and inactivates heptp in a gs/camp/pka-dependent manner to release bound p38 mapk, making more available for phosphorylation and subsequent ige regulation	SIGNOR-182525
P45983	Q14451	1	phosphorylation	down-regulates quantity by destabilization	0.262	Our data show that phosphorylation of Grb7 protein on the Ser194-Pro motif by c-Jun N-terminal kinase facilitates its binding with the WW domain of Pin1. Subsequently, Grb7 is degraded by the ubiquitin- and proteasome-dependent proteolytic pathway. I	SIGNOR-277280
Q13308	P12931	0	phosphorylation	up-regulates activity	0.279	Because Ptk7 lacks intrinsic kinase activitiy, we suggest a positive feedback model in which pre-existing active Src phosphorylates PTK7 enabling it to interact with the SH2 domain of additional Src molecules to result in further activation.	SIGNOR-279123
Q05209	Q14161	1	dephosphorylation	down-regulates	0.344	Conversely, a gfp-pkl phosphorylation mutant, y286/392/592f (gfp-pkl triple yf) (brown et al., 2005), was not phosphorylated during adhesion and the addition of ptp-pest had no effect, suggesting one or more of these tyrosine residues are dephosphorylated by ptppest. Taken together, these data strongly suggest pkl as a direct substrate for ptp-pest.	SIGNOR-142719
Q7Z434	Q99942	0	ubiquitination	down-regulates quantity by destabilization	0.456	In this study, we showed that the E3 ubiquitin ligase RING-finger protein 5 (RNF5) interacted with VISA at mitochondria in a viral infection-dependent manner. Domain mapping experiments indicated that the C-terminal transmembrane domain of VISA was required for its interaction with RNF5. RNF5 targeted VISA at K362 and K461 for K48-linked ubiquitination and degradation after viral infection, whereas knockdown of RNF5 reversed virus-induced downregulation of VISA at the early phase.	SIGNOR-271489
Q9Y490	P26010	2	binding	up-regulates activity	0.585	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257633
Q03113	P41231	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-257145
P49841	P19793	1	phosphorylation	up-regulates activity	0.275	GSK3β-induced RXRα phosphorylation decreased for RXRα-S49A, RXRα-S66A and RXRα-S78A in HEK293 cells compared with RXRα WT by western blot analysis.	SIGNOR-277371
P62993	Q92918	2	binding	up-regulates	0.453	The first and second proline-rich motifs containing the grb2 n-sh3-binding consensus sequence (-p-x-x-p-x-r/k-) were implicated in the binding of hpk1 to grb2.	SIGNOR-63994
Q05397	P27986	2	binding	up-regulates	0.555	Pi3-kinase has also been shown to bind fak in a cell cell adhesion-dipendent manner at the major autophosphorylation site y397. This association could live to activation of pi3-kinase and its downstream effectors.	SIGNOR-53979
Q12851	Q13200	1	phosphorylation	up-regulates activity	0.2	Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).	SIGNOR-273900
P04070	P12259	1	cleavage	down-regulates activity	0.601	The mechanism of inactivation of human factor V and human factor Va by activated protein C\|Membrane-bound human factor V (250 nM) is cleaved by APC (2.5 nM) to give M(r) = 200,000, 70,000, 45,000, and 30,000 fragments and an M(r) = 22/20,000 doublet. These fragments are released after four sequential cleavages of the membrane-bound procofactor at Arg306, Arg506, Arg679, and Lys994.	SIGNOR-263629
O95747	Q9H4A3	0	phosphorylation	up-regulates	0.484	Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1)	SIGNOR-151659
Q05397	P08069	1	phosphorylation	up-regulates quantity	0.535	Taken together, our data suggest that FAK mediates the phosphorylation of IGF-1R and stabilizes the receptor.In this study we demonstrate that FAK, mainly known for its role in integrin signaling pathways, associates with and phosphorylates IGF-1R independently of IGF-1R 's intrinsic tyrosine kinase activity.\|The impact of FAK on the expression levels of IGF-1R could be multilateral	SIGNOR-279565
O00255	Q04206	2	binding	down-regulates	0.462	Menin represses p65-mediated transcriptional activation on nf-kappab sites in a dose-dependent and specific manner.	SIGNOR-110067
Q13283	P68400	0	phosphorylation	down-regulates activity	0.239	We also show that casein kinase 2 phosphorylates G3BP1 at serine 149 in vitro and in cells. These data support a role for casein kinase 2 in regulation of protein synthesis by downregulating stress granule formation through G3BP1.CK2 regulates SG disassembly during stress recovery.G3BP1 is among the strongest SG nucleating proteins, and previous work indicated that G3BP1 phosphorylation at S149 restricts stress granule assembly by partly inhibiting G3BP1 oligomerization	SIGNOR-260748
P27449	Q8N6D2	0	polyubiquitination	down-regulates quantity by destabilization	0.466	The data indicated that RNF182 targeted ATP6V0C for degradation by the ubiquitin-proteosome pathway.	SIGNOR-271771
P49137	Q15717	1	phosphorylation	up-regulates	0.303	Mk2 and mk3 participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating the are-binding proteins ttp and hur, and by regulating eef2k	SIGNOR-166622
Q9Y4R8	Q9UK97	2	binding	down-regulates quantity by destabilization	0.441	Here we report that Tel2 and Tti1 are targeted for degradation within mTORC1 by the SCFFbxo9 ubiquitin ligase to adjust mTOR signalling to growth factor availability. The interaction between Tel2/Tti1 and Fbxo9 identified by mass spectrometry suggests that SCFFbxo9 is probably the ubiquitin ligase that mediates degradation of both proteins.	SIGNOR-271996
Q969U6	Q15437	1	ubiquitination	down-regulates quantity by destabilization	0.2	SCFFBXW5 interacts with SEC23B and targets it for ubiquitylation and proteasome-mediated degradation.	SIGNOR-265286
P49841	Q9Y6R4	2	binding	down-regulates	0.367	Gsk3beta binding to mekk4 blocks mekk4 dimerization that is required for mekk4 activation, effectively inhibiting mekk4 stimulation of the jnk and p38 mapk pathways	SIGNOR-157541
P05129	O15530	0	phosphorylation	up-regulates	0.2	One of the most studiedevents controlled by ptdins(3,4,5)p3, comprises the activation of aof agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated.	SIGNOR-126072
Q92993	P00519	0	phosphorylation	down-regulates activity	0.647	We present evidence that Tip60 is modified on tyrosine 327 by Abl kinase. We show that this causes functional changes in HAT activity and the subcellular localization of TIP60, which forms a complex with Abl kinase. The Tip60 mutation Y327F abolished tyrosine phosphorylation, reduced the inhibition of Tip60 HAT activity, and caused G0-G1 arrest and association with FE65.	SIGNOR-276598
Q8IXI2	O60260	0	ubiquitination	down-regulates quantity by destabilization	0.2	We observe that Parkin efficiently ubiquitylates Miro1 at highly conserved lysine residues, 153, 230, 235, 330 and 572, upon phosphorylation by PINK1.	SIGNOR-278561
Q00535	Q14814	1	phosphorylation	down-regulates activity	0.415	In this case, cdk5 phosphorylates MEF2D on Ser444 suppressing its transcriptional activity.	SIGNOR-279509
P16104	P45983	0	phosphorylation	up-regulates	0.2	The stress-response kinase jnk1, activated by dna damage and initiating a pro-apoptotic program, has been recently shown to translocate into the nucleus upon activation where it phosphorylates substrates including h2ax s139, an event critical for dna degradation mediated by caspase-activated dnase (cad) in apoptotic cells	SIGNOR-184146
Q96PY5	P17252	0	phosphorylation	up-regulates activity	0.2	PKCα associates with and phosphorylates FMNL2 at S1072 within its Diaphanous autoregulatory region, leading to the release of formin autoinhibition.	SIGNOR-273796
P00533	Q8IVM0	1	phosphorylation	down-regulates activity	0.415	We also detected tyrosine phosphorylation of Ymer by EGF stimulation as previously reported (Fig. 1A). Furthermore, we verified that EGF receptor-mediated tyrosine phosphorylation of Ymer is inhibited by AG1478, which is known as an EGF receptor tyrosine kinase inhibitor (Fig. 1B). A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling.	SIGNOR-262851
O95239	P06493	0	phosphorylation	up-regulates activity	0.489	Identification of Cdk phosphorylation of Kif4A at T1161 in early mitosis. We show that Cdk phosphorylation of Kif4A licenses its chromosome localization.	SIGNOR-265994
P04049	P28482	0	phosphorylation	down-regulates activity	0.632	Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. \| Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.\|FLAG-Raf-1 phosphorylated by activated ERK2	SIGNOR-249441
P51812	P05114	1	phosphorylation	down-regulates activity	0.364	We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets.	SIGNOR-249100
Q15139	Q9BST9	1	phosphorylation	up-regulates activity	0.355	Here, we show that rhotekin, an effector of RhoA GTPase, is a novel substrate of PKD. We identified Ser-435 in rhotekin as the potential site targeted by PKD in vivo. Expression of a phosphomimetic S435E rhotekin mutant resulted in an increase of endogenous active RhoA GTPase levels. Phosphorylation of rhotekin by PKD2 modulates the anchoring of the RhoA in the plasma membrane.	SIGNOR-275511
P61586	P50148	2	binding	up-regulates	0.576	Recently, the dbl-family guanine nucleotide exchange factor (gef) p63rhogef/geft has been described as a novel mediator of galpha(q/11) signaling to rhoa based on its ability to synergize with galpha(q/11) resulting in enhanced rhoa signaling in cells.	SIGNOR-156534
Q09472	P28562	1	acetylation	up-regulates	0.309	A recent report shows that mkp1 may also be regulated by acetylation. When raw macrophages are stimulated with lps, mkp1 becomes acetylated on lys57 by p300	SIGNOR-166581
Q07889	O43609	2	binding	down-regulates	0.386	Taken together, these results establish mammalian sprouty proteins as important negative regulators of growth factor signaling and suggest that sprouty proteins act downstream of the grb2.Sos Complex to selectively uncouple growth factor signals from ras activation and the map kinase pathway.	SIGNOR-110948
Q96FA3	Q13489	1	ubiquitination	up-regulates quantity by stabilization	0.455	Notably, Pellino-1 directly interacted with cIAP2 and stabilized cIAP2 through lysine63-mediated polyubiquitination via its E3 ligase activity.	SIGNOR-259395
P17612	Q9NPC2	1	phosphorylation	up-regulates	0.2	Patch clamp analysis, flow cytometry, and immunocytochemistry studies of hek293 transfected with wt hk2p3.1 and cultured in the presence of pka activators or inhibitors all confirm that activation of pka resulted in an increase in hk2p3.1 current expression (figs. 4_4?6) and demonstrate the dynamic regulatory effect of pka activity on k2p3.1 channel expression.	SIGNOR-172466
P35222	P41225	2	binding	down-regulates	0.497	Two additional sox proteins, xsox17alfa and xsox3, likewise bind to beta-catenin and inhibit its tcf-mediated signaling activity.	SIGNOR-72039
Q9BXM7	P10636	1	phosphorylation	down-regulates activity	0.384	Simultaneously overexpressing PINK1 significantly reduced the levels of exogenous total and phosphorylated tau proteins (Figures 4A,B,E).\|Taken together, our data revealed that PINK1 overexpression promoted degradation of abnormal accumulated tau via the autophagy-lysosome pathway, indicating that PINK1 may be a potential target for AD treatment.	SIGNOR-279250
Q8TCQ1	P79483	1	polyubiquitination	down-regulates quantity by destabilization	0.2	Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination.	SIGNOR-271410
Q13315	Q5VTR2	1	phosphorylation	up-regulates	0.522	E3 ubiquitin ligase, a heterodimeric complex of the ringfinger rfn20/rfn40 is phosphorylated by atm.	SIGNOR-174949
P00734	P01008	0	cleavage	down-regulates activity	0.948	Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1	SIGNOR-264136
P18031	P05787	1	dephosphorylation	down-regulates activity	0.2	Keratin 8 phospho-Tyr-267 is dephosphorylated by PTP1B and promotes insolubility and filament organization, as does the paralogous GFAP tyrosine.	SIGNOR-265495
P55211	P36507	0	phosphorylation	down-regulates activity	0.347	Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK\|The opposing protein kinase activity is overcome by treatment with the broad-specificity kinase inhibitor staurosporine or with inhibitors of MEK1/2	SIGNOR-249386
Q969R5	Q14676	2	binding	up-regulates activity	0.2	L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling.	SIGNOR-266786
Q15013	Q15645	2	binding	up-regulates activity	0.47	We have indeed showed that TRIP13 action to disassemble the Cdc20–Mad2 complex requires the presence of p31comet (Fig. 3A). We furthermore found that the joint action of TRIP13 and p31comet is also required for the release of Mad2 from MCC, for the complete disassembly of MCC and for relieving APC/C from checkpoint inhibition (Figs. 3 and and4).4).	SIGNOR-265971
P38398	Q9BX63	2	binding	up-regulates activity	0.796	BRCA1 interacts in vivo with a novel protein, BACH1, a member of the DEAH helicase family. BACH1 binds directly to the BRCT repeats of BRCA1. Moreover, BACH1 likely contributes to the DNA repair function of BRCA1 [].	SIGNOR-259185
P29376	Q9HCU5	1	phosphorylation	down-regulates activity	0.2	Furthermore, we show that LTK interacts with and phosphorylates Sec12. Expression of a phosphoablating mutant of Sec12 reduces the efficiency of ER export. Thus, LTK-to-Sec12 signaling represents the first example of an ER-resident signaling module with the potential to regulate proteostasis.Altogether, we propose that Sec12 is phosphorylated in a manner dependent on LTK and that this phosphorylation affects ERES function.	SIGNOR-273650
P56705	Q8N474	2	binding	down-regulates	0.72	Sfrp-1 binds wnt-4 with considerable avidity and inhibits the dna-binding activity of tcf, an effector of wnt signaling,	SIGNOR-106556
P50613	P13631	1	phosphorylation	up-regulates activity	0.418	RARg Is Phosphorylated by cdk7 in Its B and F Regions \| Mutation into alanine of Ser-77 and Ser-79 located in the A/B region reduced the transcriptional activity of hRARg1 (Fig. 9A), confirming that these phosphorylation sites are required for optimal transcription.	SIGNOR-259853
Q04912	P31749	0	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
Q13315	Q09472	1	phosphorylation	up-regulates	0.4	Atm mediates phosphorylation of p300 in response to dna damageexpression of nonphosphorylatable serine to alanine form of p300 (s106a) destabilized both p300 and nbs1 proteins, after dna damage	SIGNOR-165567
P84022	P43699	2	binding	down-regulates activity	0.29	TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. Repression is mediated by SMAD3 through interactions with NKX2.1 and FOXA1, two key transcription factors that are positive regulators of SpB transcription. In this study, we found that SMAD3 interacts through its MAD domains, MH1 and MH2 with NKX2.1 and FOXA1 proteins. The sites of interaction on NKX2.1 are located within the NH2 and COOH domains, known to be involved in transactivation function.	SIGNOR-254169
P63000	P35125	1	relocalization	up-regulates	0.338	In quiescent cells, tre17 is localized to intracellular filamentous and punctate structures in the cytoplasm, folded in an inactive conformation. Upon growth factor addition, cdc42 and rac1 become activated and recruit tre17 to the plasma membrane. Stable membrane localization of tre17 also requires polymerized actin. This recruitment process leads to a conformational change in tre17, such that the n-terminal portion of the molecule further stimulates the accumulation of cortical actin.	SIGNOR-98938
Q06330	P28562	2	binding	up-regulates	0.249	Notch induction of mkp-1 depends on an rbp-j-dependent mechanism.	SIGNOR-236851
P51149	P04629	2	binding	down-regulates activity	0.471	Endogenous TrkA and Rab7 form a complex. Inhibition of Rab7 potentiates the signaling of TrkA in response to brief stimulations with NGF	SIGNOR-261305
O14654	P06213	0	phosphorylation	up-regulates activity	0.518	The binding of insulin to the subunit of IR not only concentrates insulin at its site of action, but also induces conformational changes in the receptor, which in turn stimulates the tyrosine kinase activity intrinsic to the _ subunit of the IR and triggers the signaling cascades (Fig. 3). Insulin receptors trans phosphorylate several immediate substrates (on Tyr residues) including IRS1-4, Shc, and Gab 1, Cbl, APS, and P60dok.	SIGNOR-217897
Q07820	Q13627	0	phosphorylation	up-regulates quantity	0.2	Furthermore, DYRK1A likely directly bound and phosphorylated Mcl-1, thereby enhancing Mcl-1 protein stability and contributing to the development of acquired resistance to Bcl-2 inhibitors.\|DYRK1A upregulates Mcl-1 expression in NSCLC cells.\|We demonstrated that DYRK1A suppression by siRNA or harmine decreased the phosphorylation of Mcl-1 at Ser159/Thr163.	SIGNOR-279704
O60674	Q92915	1	phosphorylation	up-regulates activity	0.2	JAK2 regulates Nav1.6 channel function via FGF14Y158 phosphorylation\|Patch-clamp electrophysiology revealed that through Y158, JAK2 controls FGF14-dependent modulation of Nav1.6 channels. In hippocampal CA1 pyramidal neurons, the JAK2 inhibitor Fedratinib reduced firing by a mechanism that is dependent upon expression of FGF14.	SIGNOR-275747
P01019	P24158	0	cleavage	up-regulates activity	0.259	Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen.	SIGNOR-256314
P63000	Q15669	0	relocalization	down-regulates activity	0.41	Therefore, RhoH functions as a Rac1 antagonist by inhibiting Rac1 translocation to the cell plasma membrane in the regulation of cell migration and F-actin assembly of HPCs	SIGNOR-259085
P15172	O14647	2	binding	up-regulates activity	0.2	CHD2 also showed an interaction with MyoD, a master regulator of skeletal muscle differentiation, and together MyoD and CHD2 bind to myogenic gene promoters.	SIGNOR-264525
P12931	P61978	1	phosphorylation	down-regulates	0.603	We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown).	SIGNOR-88911
Q06330	Q96T58	2	binding	down-regulates	0.703	We identified sharp as an rbp-jkappa/cbf-1-interacting corepressor in a yeast two-hybrid screen.	SIGNOR-94201
O60716	P49674	0	phosphorylation	down-regulates	0.288	Moreover, in response to wnt3a, p120-catenin is phosphorylated at ser268, a modification dependent on ck1epsilon activity, which disrupts its interaction with e-cadherin and, subsequently, with lrp5/6, promoting the release of ck1epsilon/p120-catenin from the wnt receptor complex.	SIGNOR-24443
Q15389	P35590	2	binding	up-regulates	0.451	We reasoned that there may be cooperative interactions among the angiopoietins (i.e., ligands for tie2) and tie1, the orphan receptor.	SIGNOR-105199
Q06413	P15172	2	binding	up-regulates activity	0.743	Myod-e protein heterodimers interact with mef2 proteins to synergistically activate myogenesis.	SIGNOR-54089
O14757	P67775	0	dephosphorylation	down-regulates activity	0.496	Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit\|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo.	SIGNOR-248615
P29474	P00519	0	phosphorylation	up-regulates activity	0.2	Two kinases, i.e. abelson-tyrosine protein kinase (ABL)1 and Src were identified as eNOS Tyr81 kinases as their inhibition and down-regulation significantly reduced the basal and Yoda1-induced tyrosine phosphorylation and activity of eNOS.	SIGNOR-277519
Q13191	Q06418	2	ubiquitination	up-regulates activity	0.35	Consistent with these data, we also found that Tyro3 is ubiquitinated by Cbl-b.\|These data suggest that not only was Tyro3 a ubiquitination target of Cbl-b, but also that Cbl-b was a phosphorylation target of Tyro3.	SIGNOR-278807
Q96DR7	P60953	1	guanine nucleotide exchange factor	up-regulates activity	0.585	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-260545
O43172	P21127	0	phosphorylation	up-regulates activity	0.2	Furthermore, hPRP4 interacted directly with Clk1 on its COOH terminus, and the arginine and serine rich domain of hPRP4 was phosphorylated by Clk1 in vitro.\|Overexpression of Clk1 caused redistribution of hPRP4, from the speckled to the diffuse pattern in nucleoplasm, whereas inactive mutant of Clk1 caused no change of hPRP4 localization.	SIGNOR-280208
P06493	O75170	1	phosphorylation	down-regulates activity	0.261	We found that many interactions were abolished upon kinase inhibition; however, a subset was protected from phosphatase opposition or was unopposed, resulting in persistent interaction of the substrate with Plk1. This subset includes phosphoprotein phosphatase 6 (PP6), whose activity toward Aurora kinase A (Aurora A) was inhibited by Plk1. Our data suggest that this Plk1-PP6 interaction generates a feedback loop that coordinates and reinforces the activities of Plk1 and Aurora A during mitotic entry and is terminated by the degradation of Plk1 during mitotic exit.	SIGNOR-273587
P01112	Q9Y397	0	palmitoylation	up-regulates activity	0.435	Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein.	SIGNOR-261352
P29350	P32927	1	dephosphorylation	down-regulates	0.522	However, inhibition of shp2 binding to betac, did not prevent tyrosine phosphorylation of shp2. Interestingly, this same phosphopeptide served as a substrate for the tyrosine phosphatase activity of both shp1 and shp2.	SIGNOR-114597
P00558	Q15118	1	phosphorylation	up-regulates activity	0.428	Mitochondrial PGK1 acts as a protein kinase to phosphorylate pyruvate dehydrogenase kinase 1 (PDHK1) at T338, which activates PDHK1 to phosphorylate and inhibit the pyruvate dehydrogenase (PDH) complex.	SIGNOR-278365
O43791	Q9UER7	1	ubiquitination	down-regulates quantity	0.483	These results suggest that SPOP/Cul3-ubiquitin ligase plays an essential role in the control of Daxx level and, thus, in the regulation of Daxx-mediated cellular processes, including transcriptional regulation and apoptosis.	SIGNOR-268858
O95837	P07550	2	binding	up-regulates activity	0.314	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-257192
P06702	Q15109	2	binding	up-regulates activity	0.346	RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells Once secreted, S100A8 and S100A9 induce immune and inflammatory responses9 through interaction with receptors such as Toll-like receptor 4 (TLR4), receptor for advanced glycation end-product (RAGE), and CD33	SIGNOR-261920
P22681	Q8TF42	2	binding	down-regulates	0.443	Sts-1 and sts-2 contain sh3 domains that interacted with cbl, ub-associated domains, which bound directly to mono-ub or to the egfr/ub chimera as well as phosphoglycerate mutase domains that mediated oligomerization of sts-1/2. Ligand-induced recruitment of sts-1/sts-2 into activated egfr complexes led to inhibition of receptor internalization, reduction in the number of egfr-containing endocytic vesicles, and subsequent block of receptor degradation followed by prolonged activation of mitogenic signaling pathways.	SIGNOR-124897
Q96SW2	Q9UKT9	1	ubiquitination	down-regulates quantity by destabilization	0.581	IMiD compounds cause selective ubiquitination and degradation of IKZF1 in CD34+ cells by the CRBN E3 ubiquitin ligase.	SIGNOR-272319
Q9HC78	P02771	1	transcriptional regulation	down-regulates quantity by repression	0.44	Zinc finger and BTB domain-containing 20 (ZBTB20), a member of BTB/POZ family, functions in neurogenesis and represses α-fetoprotein gene transcription in liver.	SIGNOR-266867
Q2V2M9	Q13464	0	phosphorylation	up-regulates activity	0.275	In addition we were able to throw light on the mechanism of activation of FHOD3 by ROCK1 and could demonstrate the effects of constitutively active FHOD3 on actin filament synthesis in cardiomyocytes.\|ROCK1 can directly phosphorylate FHOD3 and FHOD3 seems to be the downstream mediator of the exaggerated actin filament formation phenotype that is induced in cardiomyocytes upon the overexpression of constitutively active ROCK1.	SIGNOR-278903
P63096	Q99705	2	binding	up-regulates activity	0.437	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-257034
P78357	P12931	0	phosphorylation	down-regulates activity	0.336	If that is the case, then our genetic results support the notion that p190 is negatively regulated by both Src and integrin.\|The Src family of tyrosine kinases phosphorylate mammalian p190.	SIGNOR-279572

Q15797

O95819

0

phosphorylation

down-regulates activity

0.2

Msn kinases directly phosphorylate α-helix 1 of Smad. we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for α-helix 1 phosphorylation.

SIGNOR-276335

P06493

Q8WUF5

1

phosphorylation

up-regulates activity

0.505

Cyclin B/cyclin-dependent kinase 1 (CDK1) phosphorylates inhibitor of apoptosis stimulating protein of P53 (iASPP) to promote iASPP nucleus localization and its inhibitory effect on p53.

SIGNOR-273585

Q13233

P45985

1

phosphorylation

up-regulates activity

0.729

The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, sek1

SIGNOR-236380

P48729

P16220

1

phosphorylation

up-regulates

0.312

Ser108, ser111 and ser114, located in a region matching the consensus sequence for the casein kinase ii target, were required.These results strongly suggest that the casein kinase ii target region is involved in cell cycle-regulated phosphorylation of the creb protein and also in transcriptional enhancement.

SIGNOR-64258

P08581

Q6ZN28

0

transcriptional regulation

up-regulates quantity by expression

0.394

Human colon carcinoma SW480 cells express virtually no MACC1. MACC1 cDNA transfection led not only to strong increases in MACC1 mRNA expression (Fig. 3a), but also to a 40-fold upregulation of the HGF receptor MET mRNA expression (Fig. 3b). This was confirmed on the protein level

SIGNOR-266058

P60484

P68400

0

phosphorylation

down-regulates activity

0.68

The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity

SIGNOR-89830

Q00535

P42858

1

phosphorylation

up-regulates

0.447

Huntingtin is an antiapoptotic proteinwe show here that huntingtin is phosphorylated by the cyclin-dependent kinase 5 (cdk5) at serines 1181 and 1201. Phosphorylation can be induced by dna damage in vitro and in vivo. The state of huntingtin phosphorylation is a crucial regulator of neuronal cell death. Absence of phosphorylation of huntingtin at serines 1181 and 1201 confers toxic properties to wild-type huntingtin in a p53-dependent manner in striatal neurons and accelerates neuronal death induced by dna damage.

SIGNOR-156840

P12830

P15923

0

transcriptional regulation

down-regulates quantity by repression

0.31

The p21-activated kinase 5 (PAK5) is overexpressed in advanced cancer and the transcription factor E47 is a direct repressor of E-cadherin and inducer of epithelial-mesenchymal transition (EMT). |In this study, we found that PAK5-mediated E47 phosphorylation promoted EMT in advanced colon cancer. PAK5 interacted with E47 and phosphorylated E47 on Ser39 under hepatocyte growth factor (HGF) stimulation

SIGNOR-275654

Q14457

Q9HD26

2

binding

up-regulates

0.523

Npist binds beclin 1 by a ccd

SIGNOR-171896

P33981

Q13257

1

phosphorylation

up-regulates activity

0.713

Mps1 is an upstream component of the spindle assembly checkpoint, which, in human cells, is required for checkpoint activation in response to spindle damage but not apparently during an unperturbed mitosis. Mps1 also recruits Mad1 and Mad2 to kinetochores.|Thus, in human cells, Mps1 catalytic activity is required for spindle checkpoint function and recruitment of Mad2.

SIGNOR-252036

Q14653

Q12899

0

polyubiquitination

down-regulates quantity by destabilization

0.672

TRIM26 bound to IRF3 and promoted its K48-linked polyubiquitination and degradation in nucleus.

SIGNOR-272440

P0C6X7-PRO_0000037311

Q13114

1

deubiquitination

down-regulates activity

0.2

Overexpressing PLPro of SARS-CoV or MERS-CoV significantly reduced the expression of IFN-Î² and proinflammatory cytokines in MDA5-stimulated 293T cells (83).Also, SARS-CoVPLPro catalyzed deubiquitination of TNF-receptor-associated factor3 (TRAF3) and TRAF6, thereby suppressing IFN-I and proinflammatory cytokines induced by TLR7 agonist (63). The deubiquitinating activity of SARS-CoV PLPro also suppressed a constitutively active phosphomimetic IRF3, suggesting its involvement in the postactivation signaling of IRF3

SIGNOR-260246

Q9Y484

Q96BY7

2

binding

up-regulates activity

0.648

WIPI4 interacts with ATG2, AMPK and ULK1. Upon starvation and AMPK activation, WIPI4-ATG2 dissociates from AMPK and ULK1 and localizes at nascent autophagosomes, potentially supporting further autophagosome maturation.

SIGNOR-268484

P31749

P35222

1

phosphorylation

up-regulates

0.805

Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activity|we have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo.

SIGNOR-252499

P49915

P19474

0

ubiquitination

down-regulates

0.326

Cytoplasmic sequestration of gmps requires ubiquitylation by trim21, a ubiquitin ligase associated with autoimmune disease.

SIGNOR-204478

P35236

Q16539

2

binding

down-regulates

0.59

Thus, beta(2)ar stimulation on a b cell phosphorylates and inactivates heptp in a gs/camp/pka-dependent manner to release bound p38 mapk, making more available for phosphorylation and subsequent ige regulation

SIGNOR-182525

P45983

Q14451

1

phosphorylation

down-regulates quantity by destabilization

0.262

Our data show that phosphorylation of Grb7 protein on the Ser194-Pro motif by c-Jun N-terminal kinase facilitates its binding with the WW domain of Pin1. Subsequently, Grb7 is degraded by the ubiquitin- and proteasome-dependent proteolytic pathway. I

SIGNOR-277280

Q13308

P12931

0

phosphorylation

up-regulates activity

0.279

Because Ptk7 lacks intrinsic kinase activitiy, we suggest a positive feedback model in which pre-existing active Src phosphorylates PTK7 enabling it to interact with the SH2 domain of additional Src molecules to result in further activation.

SIGNOR-279123

Q05209

Q14161

1

dephosphorylation

down-regulates

0.344

Conversely, a gfp-pkl phosphorylation mutant, y286/392/592f (gfp-pkl triple yf) (brown et al., 2005), was not phosphorylated during adhesion and the addition of ptp-pest had no effect, suggesting one or more of these tyrosine residues are dephosphorylated by ptppest. Taken together, these data strongly suggest pkl as a direct substrate for ptp-pest.

SIGNOR-142719

Q7Z434

Q99942

0

ubiquitination

down-regulates quantity by destabilization

0.456

In this study, we showed that the E3 ubiquitin ligase RING-finger protein 5 (RNF5) interacted with VISA at mitochondria in a viral infection-dependent manner. Domain mapping experiments indicated that the C-terminal transmembrane domain of VISA was required for its interaction with RNF5. RNF5 targeted VISA at K362 and K461 for K48-linked ubiquitination and degradation after viral infection, whereas knockdown of RNF5 reversed virus-induced downregulation of VISA at the early phase.

SIGNOR-271489

Q9Y490

P26010

2

binding

up-regulates activity

0.585

Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.

SIGNOR-257633

Q03113

P41231

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-257145

P49841

P19793

1

phosphorylation

up-regulates activity

0.275

GSK3β-induced RXRα phosphorylation decreased for RXRα-S49A, RXRα-S66A and RXRα-S78A in HEK293 cells compared with RXRα WT by western blot analysis.

SIGNOR-277371

P62993

Q92918

2

binding

up-regulates

0.453

The first and second proline-rich motifs containing the grb2 n-sh3-binding consensus sequence (-p-x-x-p-x-r/k-) were implicated in the binding of hpk1 to grb2.

SIGNOR-63994

Q05397

P27986

2

binding

up-regulates

0.555

Pi3-kinase has also been shown to bind fak in a cell cell adhesion-dipendent manner at the major autophosphorylation site y397. This association could live to activation of pi3-kinase and its downstream effectors.

SIGNOR-53979

Q12851

Q13200

1

phosphorylation

up-regulates activity

0.2

Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).

SIGNOR-273900

P04070

P12259

1

cleavage

down-regulates activity

0.601

The mechanism of inactivation of human factor V and human factor Va by activated protein C|Membrane-bound human factor V (250 nM) is cleaved by APC (2.5 nM) to give M(r) = 200,000, 70,000, 45,000, and 30,000 fragments and an M(r) = 22/20,000 doublet. These fragments are released after four sequential cleavages of the membrane-bound procofactor at Arg306, Arg506, Arg679, and Lys994.

SIGNOR-263629

O95747

Q9H4A3

0

phosphorylation

up-regulates

0.484

Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1)

SIGNOR-151659

Q05397

P08069

1

phosphorylation

up-regulates quantity

0.535

Taken together, our data suggest that FAK mediates the phosphorylation of IGF-1R and stabilizes the receptor.In this study we demonstrate that FAK, mainly known for its role in integrin signaling pathways, associates with and phosphorylates IGF-1R independently of IGF-1R 's intrinsic tyrosine kinase activity.|The impact of FAK on the expression levels of IGF-1R could be multilateral

SIGNOR-279565

O00255

Q04206

2

binding

down-regulates

0.462

Menin represses p65-mediated transcriptional activation on nf-kappab sites in a dose-dependent and specific manner.

SIGNOR-110067

Q13283

P68400

0

phosphorylation

down-regulates activity

0.239

We also show that casein kinase 2 phosphorylates G3BP1 at serine 149 in vitro and in cells. These data support a role for casein kinase 2 in regulation of protein synthesis by downregulating stress granule formation through G3BP1.CK2 regulates SG disassembly during stress recovery.G3BP1 is among the strongest SG nucleating proteins, and previous work indicated that G3BP1 phosphorylation at S149 restricts stress granule assembly by partly inhibiting G3BP1 oligomerization

SIGNOR-260748

P27449

Q8N6D2

0

polyubiquitination

down-regulates quantity by destabilization

0.466

The data indicated that RNF182 targeted ATP6V0C for degradation by the ubiquitin-proteosome pathway.

SIGNOR-271771

P49137

Q15717

1

phosphorylation

up-regulates

0.303

Mk2 and mk3 participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating the are-binding proteins ttp and hur, and by regulating eef2k

SIGNOR-166622

Q9Y4R8

Q9UK97

2

binding

down-regulates quantity by destabilization

0.441

Here we report that Tel2 and Tti1 are targeted for degradation within mTORC1 by the SCFFbxo9 ubiquitin ligase to adjust mTOR signalling to growth factor availability. The interaction between Tel2/Tti1 and Fbxo9 identified by mass spectrometry suggests that SCFFbxo9 is probably the ubiquitin ligase that mediates degradation of both proteins.

SIGNOR-271996

Q969U6

Q15437

1

ubiquitination

down-regulates quantity by destabilization

0.2

SCFFBXW5 interacts with SEC23B and targets it for ubiquitylation and proteasome-mediated degradation.

SIGNOR-265286

P49841

Q9Y6R4

2

binding

down-regulates

0.367

Gsk3beta binding to mekk4 blocks mekk4 dimerization that is required for mekk4 activation, effectively inhibiting mekk4 stimulation of the jnk and p38 mapk pathways

SIGNOR-157541

P05129

O15530

0

phosphorylation

up-regulates

0.2

One of the most studiedevents controlled by ptdins(3,4,5)p3, comprises the activation of aof agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated.

SIGNOR-126072

Q92993

P00519

0

phosphorylation

down-regulates activity

0.647

We present evidence that Tip60 is modified on tyrosine 327 by Abl kinase. We show that this causes functional changes in HAT activity and the subcellular localization of TIP60, which forms a complex with Abl kinase. The Tip60 mutation Y327F abolished tyrosine phosphorylation, reduced the inhibition of Tip60 HAT activity, and caused G0-G1 arrest and association with FE65.

SIGNOR-276598

Q8IXI2

O60260

0

ubiquitination

down-regulates quantity by destabilization

0.2

We observe that Parkin efficiently ubiquitylates Miro1 at highly conserved lysine residues, 153, 230, 235, 330 and 572, upon phosphorylation by PINK1.

SIGNOR-278561

Q00535

Q14814

1

phosphorylation

down-regulates activity

0.415

In this case, cdk5 phosphorylates MEF2D on Ser444 suppressing its transcriptional activity.

SIGNOR-279509

P16104

P45983

0

phosphorylation

up-regulates

0.2

The stress-response kinase jnk1, activated by dna damage and initiating a pro-apoptotic program, has been recently shown to translocate into the nucleus upon activation where it phosphorylates substrates including h2ax s139, an event critical for dna degradation mediated by caspase-activated dnase (cad) in apoptotic cells

SIGNOR-184146

Q96PY5

P17252

0

phosphorylation

up-regulates activity

0.2

PKCα associates with and phosphorylates FMNL2 at S1072 within its Diaphanous autoregulatory region, leading to the release of formin autoinhibition.

SIGNOR-273796

P00533

Q8IVM0

1

phosphorylation

down-regulates activity

0.415

We also detected tyrosine phosphorylation of Ymer by EGF stimulation as previously reported (Fig. 1A). Furthermore, we verified that EGF receptor-mediated tyrosine phosphorylation of Ymer is inhibited by AG1478, which is known as an EGF receptor tyrosine kinase inhibitor (Fig. 1B). A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling.

SIGNOR-262851

O95239

P06493

0

phosphorylation

up-regulates activity

0.489

Identification of Cdk phosphorylation of Kif4A at T1161 in early mitosis. We show that Cdk phosphorylation of Kif4A licenses its chromosome localization.

SIGNOR-265994

P04049

P28482

0

phosphorylation

down-regulates activity

0.632

Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2

SIGNOR-249441

P51812

P05114

1

phosphorylation

down-regulates activity

0.364

We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets.

SIGNOR-249100

Q15139

Q9BST9

1

phosphorylation

up-regulates activity

0.355

Here, we show that rhotekin, an effector of RhoA GTPase, is a novel substrate of PKD. We identified Ser-435 in rhotekin as the potential site targeted by PKD in vivo. Expression of a phosphomimetic S435E rhotekin mutant resulted in an increase of endogenous active RhoA GTPase levels. Phosphorylation of rhotekin by PKD2 modulates the anchoring of the RhoA in the plasma membrane.

SIGNOR-275511

P61586

P50148

2

binding

up-regulates

0.576

Recently, the dbl-family guanine nucleotide exchange factor (gef) p63rhogef/geft has been described as a novel mediator of galpha(q/11) signaling to rhoa based on its ability to synergize with galpha(q/11) resulting in enhanced rhoa signaling in cells.

SIGNOR-156534

Q09472

P28562

1

acetylation

up-regulates

0.309

A recent report shows that mkp1 may also be regulated by acetylation. When raw macrophages are stimulated with lps, mkp1 becomes acetylated on lys57 by p300

SIGNOR-166581

Q07889

O43609

2

binding

down-regulates

0.386

Taken together, these results establish mammalian sprouty proteins as important negative regulators of growth factor signaling and suggest that sprouty proteins act downstream of the grb2.Sos Complex to selectively uncouple growth factor signals from ras activation and the map kinase pathway.

SIGNOR-110948

Q96FA3

Q13489

1

ubiquitination

up-regulates quantity by stabilization

0.455

Notably, Pellino-1 directly interacted with cIAP2 and stabilized cIAP2 through lysine63-mediated polyubiquitination via its E3 ligase activity.

SIGNOR-259395

P17612

Q9NPC2

1

phosphorylation

up-regulates

0.2

Patch clamp analysis, flow cytometry, and immunocytochemistry studies of hek293 transfected with wt hk2p3.1 and cultured in the presence of pka activators or inhibitors all confirm that activation of pka resulted in an increase in hk2p3.1 current expression (figs. 4_4?6) and demonstrate the dynamic regulatory effect of pka activity on k2p3.1 channel expression.

SIGNOR-172466

P35222

P41225

2

binding

down-regulates

0.497

Two additional sox proteins, xsox17alfa and xsox3, likewise bind to beta-catenin and inhibit its tcf-mediated signaling activity.

SIGNOR-72039

Q9BXM7

P10636

1

phosphorylation

down-regulates activity

0.384

Simultaneously overexpressing PINK1 significantly reduced the levels of exogenous total and phosphorylated tau proteins (Figures 4A,B,E).|Taken together, our data revealed that PINK1 overexpression promoted degradation of abnormal accumulated tau via the autophagy-lysosome pathway, indicating that PINK1 may be a potential target for AD treatment.

SIGNOR-279250

Q8TCQ1

P79483

1

polyubiquitination

down-regulates quantity by destabilization

0.2

Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination.

SIGNOR-271410

Q13315

Q5VTR2

1

phosphorylation

up-regulates

0.522

E3 ubiquitin ligase, a heterodimeric complex of the ringfinger rfn20/rfn40 is phosphorylated by atm.

SIGNOR-174949

P00734

P01008

0

cleavage

down-regulates activity

0.948

Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1

SIGNOR-264136

P18031

P05787

1

dephosphorylation

down-regulates activity

0.2

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

SIGNOR-265495

P55211

P36507

0

phosphorylation

down-regulates activity

0.347

Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK|The opposing protein kinase activity is overcome by treatment with the broad-specificity kinase inhibitor staurosporine or with inhibitors of MEK1/2

SIGNOR-249386

Q969R5

Q14676

2

binding

up-regulates activity

0.2

L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling.

SIGNOR-266786

Q15013

Q15645

2

binding

up-regulates activity

0.47

We have indeed showed that TRIP13 action to disassemble the Cdc20–Mad2 complex requires the presence of p31comet (Fig. 3A). We furthermore found that the joint action of TRIP13 and p31comet is also required for the release of Mad2 from MCC, for the complete disassembly of MCC and for relieving APC/C from checkpoint inhibition (Figs. 3 and and4).4).

SIGNOR-265971

P38398

Q9BX63

2

binding

up-regulates activity

0.796

BRCA1 interacts in vivo with a novel protein, BACH1, a member of the DEAH helicase family. BACH1 binds directly to the BRCT repeats of BRCA1. Moreover, BACH1 likely contributes to the DNA repair function of BRCA1 [].

SIGNOR-259185

P29376

Q9HCU5

1

phosphorylation

down-regulates activity

0.2

Furthermore, we show that LTK interacts with and phosphorylates Sec12. Expression of a phosphoablating mutant of Sec12 reduces the efficiency of ER export. Thus, LTK-to-Sec12 signaling represents the first example of an ER-resident signaling module with the potential to regulate proteostasis.Altogether, we propose that Sec12 is phosphorylated in a manner dependent on LTK and that this phosphorylation affects ERES function.

SIGNOR-273650

P56705

Q8N474

2

binding

down-regulates

0.72

Sfrp-1 binds wnt-4 with considerable avidity and inhibits the dna-binding activity of tcf, an effector of wnt signaling,

SIGNOR-106556

P50613

P13631

1

phosphorylation

up-regulates activity

0.418

RARg Is Phosphorylated by cdk7 in Its B and F Regions | Mutation into alanine of Ser-77 and Ser-79 located in the A/B region reduced the transcriptional activity of hRARg1 (Fig. 9A), confirming that these phosphorylation sites are required for optimal transcription.

SIGNOR-259853

Q04912

P31749

0

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

Q13315

Q09472

1

phosphorylation

up-regulates

0.4

Atm mediates phosphorylation of p300 in response to dna damageexpression of nonphosphorylatable serine to alanine form of p300 (s106a) destabilized both p300 and nbs1 proteins, after dna damage

SIGNOR-165567

P84022

P43699

2

binding

down-regulates activity

0.29

TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. Repression is mediated by SMAD3 through interactions with NKX2.1 and FOXA1, two key transcription factors that are positive regulators of SpB transcription. In this study, we found that SMAD3 interacts through its MAD domains, MH1 and MH2 with NKX2.1 and FOXA1 proteins. The sites of interaction on NKX2.1 are located within the NH2 and COOH domains, known to be involved in transactivation function.

SIGNOR-254169

P63000

P35125

1

relocalization

up-regulates

0.338

In quiescent cells, tre17 is localized to intracellular filamentous and punctate structures in the cytoplasm, folded in an inactive conformation. Upon growth factor addition, cdc42 and rac1 become activated and recruit tre17 to the plasma membrane. Stable membrane localization of tre17 also requires polymerized actin. This recruitment process leads to a conformational change in tre17, such that the n-terminal portion of the molecule further stimulates the accumulation of cortical actin.

SIGNOR-98938

Q06330

P28562

2

binding

up-regulates

0.249

Notch induction of mkp-1 depends on an rbp-j-dependent mechanism.

SIGNOR-236851

P51149

P04629

2

binding

down-regulates activity

0.471

Endogenous TrkA and Rab7 form a complex. Inhibition of Rab7 potentiates the signaling of TrkA in response to brief stimulations with NGF

SIGNOR-261305

O14654

P06213

0

phosphorylation

up-regulates activity

0.518

The binding of insulin to the subunit of IR not only concentrates insulin at its site of action, but also induces conformational changes in the receptor, which in turn stimulates the tyrosine kinase activity intrinsic to the _ subunit of the IR and triggers the signaling cascades (Fig. 3). Insulin receptors trans phosphorylate several immediate substrates (on Tyr residues) including IRS1-4, Shc, and Gab 1, Cbl, APS, and P60dok.

SIGNOR-217897

Q07820

Q13627

0

phosphorylation

up-regulates quantity

0.2

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

SIGNOR-279704

O60674

Q92915

1

phosphorylation

up-regulates activity

0.2

JAK2 regulates Nav1.6 channel function via FGF14Y158 phosphorylation|Patch-clamp electrophysiology revealed that through Y158, JAK2 controls FGF14-dependent modulation of Nav1.6 channels. In hippocampal CA1 pyramidal neurons, the JAK2 inhibitor Fedratinib reduced firing by a mechanism that is dependent upon expression of FGF14.

SIGNOR-275747

P01019

P24158

0

cleavage

up-regulates activity

0.259

Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen.

SIGNOR-256314

P63000

Q15669

0

relocalization

down-regulates activity

0.41

Therefore, RhoH functions as a Rac1 antagonist by inhibiting Rac1 translocation to the cell plasma membrane in the regulation of cell migration and F-actin assembly of HPCs

SIGNOR-259085

P15172

O14647

2

binding

up-regulates activity

0.2

CHD2 also showed an interaction with MyoD, a master regulator of skeletal muscle differentiation, and together MyoD and CHD2 bind to myogenic gene promoters.

SIGNOR-264525

P12931

P61978

1

phosphorylation

down-regulates

0.603

We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown).

SIGNOR-88911

Q06330

Q96T58

2

binding

down-regulates

0.703

We identified sharp as an rbp-jkappa/cbf-1-interacting corepressor in a yeast two-hybrid screen.

SIGNOR-94201

O60716

P49674

0

phosphorylation

down-regulates

0.288

Moreover, in response to wnt3a, p120-catenin is phosphorylated at ser268, a modification dependent on ck1epsilon activity, which disrupts its interaction with e-cadherin and, subsequently, with lrp5/6, promoting the release of ck1epsilon/p120-catenin from the wnt receptor complex.

SIGNOR-24443

Q15389

P35590

2

binding

up-regulates

0.451

We reasoned that there may be cooperative interactions among the angiopoietins (i.e., ligands for tie2) and tie1, the orphan receptor.

SIGNOR-105199

Q06413

P15172

2

binding

up-regulates activity

0.743

Myod-e protein heterodimers interact with mef2 proteins to synergistically activate myogenesis.

SIGNOR-54089

O14757

P67775

0

dephosphorylation

down-regulates activity

0.496

Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo.

SIGNOR-248615

P29474

P00519

0

phosphorylation

up-regulates activity

0.2

Two kinases, i.e. abelson-tyrosine protein kinase (ABL)1 and Src were identified as eNOS Tyr81 kinases as their inhibition and down-regulation significantly reduced the basal and Yoda1-induced tyrosine phosphorylation and activity of eNOS.

SIGNOR-277519

Q13191

Q06418

2

ubiquitination

up-regulates activity

0.35

Consistent with these data, we also found that Tyro3 is ubiquitinated by Cbl-b.|These data suggest that not only was Tyro3 a ubiquitination target of Cbl-b, but also that Cbl-b was a phosphorylation target of Tyro3.

SIGNOR-278807

Q96DR7

P60953

1

guanine nucleotide exchange factor

up-regulates activity

0.585

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-260545

O43172

P21127

0

phosphorylation

up-regulates activity

0.2

Furthermore, hPRP4 interacted directly with Clk1 on its COOH terminus, and the arginine and serine rich domain of hPRP4 was phosphorylated by Clk1 in vitro.|Overexpression of Clk1 caused redistribution of hPRP4, from the speckled to the diffuse pattern in nucleoplasm, whereas inactive mutant of Clk1 caused no change of hPRP4 localization.

SIGNOR-280208

P06493

O75170

1

phosphorylation

down-regulates activity

0.261

We found that many interactions were abolished upon kinase inhibition; however, a subset was protected from phosphatase opposition or was unopposed, resulting in persistent interaction of the substrate with Plk1. This subset includes phosphoprotein phosphatase 6 (PP6), whose activity toward Aurora kinase A (Aurora A) was inhibited by Plk1. Our data suggest that this Plk1-PP6 interaction generates a feedback loop that coordinates and reinforces the activities of Plk1 and Aurora A during mitotic entry and is terminated by the degradation of Plk1 during mitotic exit.

SIGNOR-273587

P01112

Q9Y397

0

palmitoylation

up-regulates activity

0.435

Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein.

SIGNOR-261352

P29350

P32927

1

dephosphorylation

down-regulates

0.522

However, inhibition of shp2 binding to betac, did not prevent tyrosine phosphorylation of shp2. Interestingly, this same phosphopeptide served as a substrate for the tyrosine phosphatase activity of both shp1 and shp2.

SIGNOR-114597

P00558

Q15118

1

phosphorylation

up-regulates activity

0.428

Mitochondrial PGK1 acts as a protein kinase to phosphorylate pyruvate dehydrogenase kinase 1 (PDHK1) at T338, which activates PDHK1 to phosphorylate and inhibit the pyruvate dehydrogenase (PDH) complex.

SIGNOR-278365

O43791

Q9UER7

1

ubiquitination

down-regulates quantity

0.483

These results suggest that SPOP/Cul3-ubiquitin ligase plays an essential role in the control of Daxx level and, thus, in the regulation of Daxx-mediated cellular processes, including transcriptional regulation and apoptosis.

SIGNOR-268858

O95837

P07550

2

binding

up-regulates activity

0.314

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-257192

P06702

Q15109

2

binding

up-regulates activity

0.346

RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells Once secreted, S100A8 and S100A9 induce immune and inflammatory responses9 through interaction with receptors such as Toll-like receptor 4 (TLR4), receptor for advanced glycation end-product (RAGE), and CD33

SIGNOR-261920

P22681

Q8TF42

2

binding

down-regulates

0.443

Sts-1 and sts-2 contain sh3 domains that interacted with cbl, ub-associated domains, which bound directly to mono-ub or to the egfr/ub chimera as well as phosphoglycerate mutase domains that mediated oligomerization of sts-1/2. Ligand-induced recruitment of sts-1/sts-2 into activated egfr complexes led to inhibition of receptor internalization, reduction in the number of egfr-containing endocytic vesicles, and subsequent block of receptor degradation followed by prolonged activation of mitogenic signaling pathways.

SIGNOR-124897

Q96SW2

Q9UKT9

1

ubiquitination

down-regulates quantity by destabilization

0.581

IMiD compounds cause selective ubiquitination and degradation of IKZF1 in CD34+ cells by the CRBN E3 ubiquitin ligase.

SIGNOR-272319

Q9HC78

P02771

1

transcriptional regulation

down-regulates quantity by repression

0.44

Zinc finger and BTB domain-containing 20 (ZBTB20), a member of BTB/POZ family, functions in neurogenesis and represses α-fetoprotein gene transcription in liver.

SIGNOR-266867

Q2V2M9

Q13464

0

phosphorylation

up-regulates activity

0.275

In addition we were able to throw light on the mechanism of activation of FHOD3 by ROCK1 and could demonstrate the effects of constitutively active FHOD3 on actin filament synthesis in cardiomyocytes.|ROCK1 can directly phosphorylate FHOD3 and FHOD3 seems to be the downstream mediator of the exaggerated actin filament formation phenotype that is induced in cardiomyocytes upon the overexpression of constitutively active ROCK1.

SIGNOR-278903

P63096

Q99705

2

binding

up-regulates activity

0.437

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-257034

P78357

P12931

0

phosphorylation

down-regulates activity

0.336

If that is the case, then our genetic results support the notion that p190 is negatively regulated by both Src and integrin.|The Src family of tyrosine kinases phosphorylate mammalian p190.

SIGNOR-279572