GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels float64 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
Q13535	O15360	1	phosphorylation	up-regulates	0.598	The s1449a mutant failed to completely correct a variety of fa-associated phenotypes. The dna damage response is coordinated by phosphorylation events initiated by apical kinases atm (ataxia telangectasia mutated) and atr (atm and rad3-related), and atr is essential for proper fa pathway function. Serine 1449 is in a consensus atm/atr site	SIGNOR-182953
P06493	O95997	1	phosphorylation	up-regulates	0.598	Hpttg is phosphorylated by cdc2 at ser165 these results suggest that hpttg is induced by, and may have a role in, regulatory pathways involved in the control of cell proliferation.	SIGNOR-74619
O14745	P07550	1	binding	up-regulates activity	0.598	The Na+/H+ exchanger regulatory factor (NHERF) binds to the tail of the beta2-adrenergic receptor and plays a role in adrenergic regulation of Na+/H+ exchange. NHERF contains two PDZ domains, the first of which is required for its interaction with the beta2 receptor.	SIGNOR-262598
O75116	O14950	1	phosphorylation	up-regulates activity	0.598	In addition, an in vitro kinase assay with mixed recombinant GST-ROCK2 and MLC2 revealed that ROCK2 phosphorylated WT MLC2, but not MLC2 S15A mutant, indicating that it phosphorylates MLC2 at S15 in vitro (XREF_FIG).	SIGNOR-279103
Q02962	P19544	2	transcriptional regulation	up-regulates quantity by expression	0.598	Cotransfection of Pax2 with the Wt1 reporter construct led to moderate activation of the Wt1 promoter.	SIGNOR-252290
Q9ULV1	O14640	1	binding	up-regulates activity	0.598	Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin.	SIGNOR-258955
P19544	Q02962	2	transcriptional regulation	down-regulates quantity by repression	0.598	A marked increase in WT1 protein levels coincided precisely with down-regulation of the Pax-2 gene in the individual precursor cells of the visceral glomerular epithelium, suggesting a direct effect of the WT1 repressor protein on Pax-2 regulatory elements. To examine whether WT1 could directly repress Pax-2 transcription, binding of WT1 to three high affinity sites in the 5' untranslated Pax-2 leader sequence was demonstrated by DNAseI footprinting analysis	SIGNOR-252298
Q13671	P01116	1	binding	up-regulates	0.598	We demonstrate that the ras effector protein rin1 binds to activated ras with an affinity (k(d), 22 nm) similar to that observed for raf1.	SIGNOR-113970
Q13616	P35222	1	ubiquitination	down-regulates quantity by destabilization	0.598	These results indicate that the cul1/skp1/beta-trcp complex forms a ubiquitin ligase that mediates the degradation of beta-catenin.	SIGNOR-64499
Q8IZQ1	Q9H1Y0	1	binding	up-regulates quantity	0.598	Alfy is recruited to intracellular inclusions and scaffolds a complex between p62(SQSTM1)-positive proteins and the autophagic effectors Atg5, Atg12, Atg16L and LC3. Alfy directly interacts with Atg5 and can be found in a complex with Atg5, Atg12 and Atg16L	SIGNOR-266791
P84022	P17676	1	binding	down-regulates activity	0.597	Thus, repression of the activity of C/EBPs by Smad3/4 at C/EBP binding sites inhibited transcription from the PPAR2 and leptin promoters	SIGNOR-250567
Q05513	P49841	1	phosphorylation	down-regulates	0.597	Phospho-gsk3b-specific antibodies also revolved that lkb1 regulates gsk3b phosphorylation at a known inhibitory site, serine-9. This localized phosphorylation is cdc42 and pkc-zeta-dependent.	SIGNOR-119889
Q8WYL5	P53667	1	dephosphorylation	down-regulates activity	0.597	In addition to its cofilin\u2013phosphatase activity, SSH1 can also dephosphorylate LIMK1 and LIMK2, although LIMK1 is a better substrate than LIMK2 [63] .\|SSH1 suppresses the kinase activity of LIMK1 toward cofilin by dephosphorylation at Thr 508 in the kinase catalytic domain and other autophosphorylated residues [63].	SIGNOR-277096
P04899	Q08828	1	binding	down-regulates activity	0.597	Adenylate cyclase is regulated by stimulatory hormones through Gs(alpha s beta gamma) and inhibitory hormones through Gi(alpha i beta gamma)	SIGNOR-256499
Q92585	P49336	1	binding	up-regulates	0.597	Mastermind recruits cycc:cdk8 to phosphorylate the notch icd and coordinate activation with turnover	SIGNOR-130715
P0C2W1	O15350	1	binding	down-regulates quantity by destabilization	0.597	The F-box protein FBXO45 promotes the proteasome-dependent degradation of p73.Importantly, SCFFBXO45 ubiquitylates p73 both in vivo and in vitro. Expression of Cul1 dominant negative mutant, but not Cul2, Cul3, Cul4 and Cul5 dominant negative mutants, increased p73 levels (Figure 1c) to an extent similar to that observed in the ts41 cell line at not permissive temperature, suggesting that a Cul1-associated activity is required for p73 protein stability.	SIGNOR-271876
Q9Y6X2	P84022	1	binding	up-regulates activity	0.597	We have further shown that PIAS3, Smad3, and p300 can form a ternary complex, which is significantly increased by TGF-_ treatment. Taken together, these results suggest that PIAS3 stimulates Smad transcriptional activity through formation of a complex with Smad proteins and p300/CBP.	SIGNOR-217725
P19793	Q07869	1	binding	up-regulates	0.597	Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology	SIGNOR-105345
P00519	O43586	1	phosphorylation	up-regulates activity	0.597	PSTPIP1 was phosphorylated by c-Abl. Tyr-344 is a major c-Abl phosphorylation site.PSTPIP1 was able to bridge c-Abl to the PEST-type PTPs.	SIGNOR-251431
P06241	Q05655	1	phosphorylation	up-regulates activity	0.597	In conclusion, our in vitro data and previous report ( xref ) demonstrate that Fyn phosphorylation of Y311 on PKC\u03b4 activates the apoptotic signaling cascade in DAergic neurons in response to neurotoxic insults.	SIGNOR-279737
P53041	Q99683	1	dephosphorylation	down-regulates activity	0.597	After exposure of cells to H2O2, ASK1 is transiently activated by autophosphorylation at Thr845. The protein then associates with PP5 (protein serine/threonine phosphatase 5), which inactivates ASK1 by dephosphorylation of Thr845.	SIGNOR-248540
P04637	P11166	1	transcriptional regulation	down-regulates quantity by repression	0.597	P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway.	SIGNOR-267464
Q9HBW0	P50148	1	binding	up-regulates activity	0.597	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-257382
Q12933	O43318	1	ubiquitination	up-regulates activity	0.597	Tumor necrosis factor receptor-associated factors 2 and 6 (traf2 and -6) act as the ubiquitin e3 ligases to mediate lys63-linked tak1 polyubiquitination at the lys158 residue in vivo and in vitro. Lys(63)-linked TAK1 polyubiquitination at the Lys(158) residue is required for TAK1-mediated IKK complex recruitment.	SIGNOR-162638
P28482	P23443	1	phosphorylation	up-regulates	0.596	Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase	SIGNOR-28800
Q9UQ13	P62136	1	binding	up-regulates activity	0.596	Using a proteomics approach, we have identified a complex comprised of Shoc2/Sur-8 and the catalytic subunit of protein phosphatase 1 (PP1c) as a highly specific M-Ras effector. M-Ras targets Shoc2-PP1c to stimulate Raf activity by dephosphorylating the S259 inhibitory site	SIGNOR-251647
Q05655	P40763	1	phosphorylation	up-regulates	0.596	Abrogation of pkcdelta activity inhibited insulin-induced stat3 phosphorylation, pkcdelta-stat3 association and nuclear translocation.	SIGNOR-143828
O00327	Q07869	2	transcriptional regulation	up-regulates quantity by expression	0.596	We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression.	SIGNOR-268025
Q9UQM7	P10636	1	phosphorylation	down-regulates activity	0.596	We found that when tau was first phosphorylated by A-kinase, C-kinase, cdk5, or CaM kinase II and then by GSK-3, its binding to microtubules was inhibited by 45, 61, 78, and 79%, respectively. Further, the kinase combinations cdk5/GSK-3 and CaM kinase II/GSK-3 rapidly phosphorylated the sites Thr 231 and Ser 235. When these sites were individually replaced by Ala and the phosphorylation experiments repeated, tau binding to microtubules was inhibited by 54 and 71%, respectively. By comparison, when Ser 262 was replaced by Ala, tau binding to microtubules was inhibited by only 8% after phosphorylation by CaM kinase II.	SIGNOR-249315
O15530	Q9HBY8	1	phosphorylation	up-regulates activity	0.596	SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB.	SIGNOR-250277
P28482	P50548	1	phosphorylation	up-regulates	0.596	The experiments presented here indicate that erf is regulated during nuclear import and/or export and that this process depends on its phosphorylation by erks our analysis indicates that in addition to t526 (position 7), s161 (position 2), s246 (position 3), and s251 (position 4) are also phosphorylated in vitro by erk2 and in vivo after mitogenic stimulation (fig. 3a).	SIGNOR-67524
Q6KF10	P36894	1	binding	up-regulates	0.596	We found that transfection of small hairpin rna for bmprii and actriia in mc3t3 cells suppressed the signaling of gdf6, gdf7, and bmp10.	SIGNOR-139090
P78352	Q9C0D5	1	binding	up-regulates activity	0.596	In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. our results indicate that TANC-dependent spine/synapse maintenance requires TANC binding to PSD-95, which promotes synaptic localization of TANC proteins. Thus, it is likely that interaction with PSD-95 concentrates TANC proteins at synapses, where they play a role in mediating PSD-95-dependent maintenance of spines and synapses.	SIGNOR-266894
Q96PV0	P78352	1	binding	up-regulates activity	0.596	The reversible removal of AIDA-1 from the PSD core under excitatory conditions is similar to the redistribution of another abundant PSD protein, SynGAP. Both SynGAP-alpha1 and AIDA-1 are known to bind PSD-95.	SIGNOR-264229
Q6Y7W6	Q13322	1	binding	up-regulates activity	0.596	We demonstrated that, in cultured cells and mammalian brains, GIGYF2 interacts and colocalises with Grb10, promoting ligand‐induced ubiquitination of IGF‐1R, and thereby regulates receptor degradation	SIGNOR-260057
Q02363	P15884	1	binding	down-regulates activity	0.596	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241376
Q66GS9	Q6UVJ0	1	binding	up-regulates activity	0.596	In this study, we demonstrate that the human microcephaly protein, CEP135, directly interacts with hSAS-6 via its carboxyl-terminus and with MTs via its amino-terminus. Unexpectedly, CEP135 also interacts with another microcephaly protein CPAP via its amino terminal domain. Depletion of CEP135 not only perturbed the centriolar localization of CPAP, but also blocked CPAP-induced centriole elongation. We propose that CEP135 may serve as a linker protein that directly connects the central hub protein, hSAS-6, to the outer MTs, and suggest that this interaction stabilizes the proper cartwheel structure for further CPAP-mediated centriole elongation.	SIGNOR-269676
P06241	P11912	1	phosphorylation	up-regulates activity	0.596	Lyn and Fyn phosphorylated the CD79a cytoplasmic portion of the fusion proteins well, with >80% of phosphorylation occurring at Y182. CD79a and CD79b function as transducers of B cell antigen receptor signals via a cytoplasmic sequence, termed the immunoreceptor tyrosine-based activation motif (ITAM).	SIGNOR-251153
P53350	Q12888	1	phosphorylation	down-regulates activity	0.596	Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.\|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks \|Addition of the inhibitors for PLK1 and the p38 MAPK leads to a complete loss of pT1609/pS1618 signal within 3 hr in mitotic cells	SIGNOR-264413
Q12778	P40763	1	binding	down-regulates activity	0.596	FoxO1, which is up-regulated during early stages of diet-induced leptin resistance, directly interacts with STAT3 and prevents STAT3 from binding to specificity protein 1 (SP1)-pro-opiomelanocortin (POMC) promoter complex, and thereby inhibits STAT3-mediated regulation of POMC transcription.	SIGNOR-263496
Q07869	O00327	2	transcriptional regulation	up-regulates quantity by expression	0.596	We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression.	SIGNOR-268024
Q9Y6I3	P00533	1	relocalization	down-regulates	0.596	Epsin 1 is involved in recruitment of ubiquitinated egf receptors into clathrin-coated pits this supports the contention that epsin 1 promotes endocytosis of the ubiquitinated egfr.	SIGNOR-182562
Q13233	O14920	1	phosphorylation	up-regulates activity	0.595	These results suggested that IKK\u03b2 was a likely substrate for MEKK1 and that MEKK1 phosphorylation of IKK\u03b2 increased its kinase activity.	SIGNOR-279339
O75385	Q8IVP5	1	phosphorylation	up-regulates activity	0.595	Here, we show that ULK1 is upregulated and translocates to fragmented mitochondria upon mitophagy induction by either hypoxia or mitochondrial uncouplers. At mitochondria, ULK1 interacts with FUNDC1, phosphorylating it at serine 17, which enhances FUNDC1 binding to LC3.	SIGNOR-273606
P27361	O43524	1	phosphorylation	down-regulates quantity by destabilization	0.595	Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway	SIGNOR-184569
O14905	O75197	1	binding	up-regulates	0.595	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-132114
Q13043	Q12778	1	phosphorylation	up-regulates	0.595	Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1.	SIGNOR-191847
Q9NZN1	P62166	1	binding	up-regulates activity	0.595	IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis. our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. Taken together, our data suggest that IL1RAPL may regulate calcium-dependent exocytosis and provide insight into the understanding of physiopathological mechanisms underlying cognitive impairment resulting from IL1RAPL dysfunction.	SIGNOR-263962
P68400	P11388	1	phosphorylation	down-regulates quantity by destabilization	0.595	This study also reports the novel finding that topoIIα may be a target of GSK3β phosphorylation. Evidence suggests that CK2 serves as a priming kinase, through phosphorylation at Ser1365, for GSK3β-mediated phosphorylation at Ser1361.	SIGNOR-276300
P06493	Q8ND76	1	phosphorylation	down-regulates activity	0.595	Therefore, CDK1 may trigger CFP1 degradation through some indirect mechanisms rather than CFP1 phosphorylation.\|This result suggests that, although CDK1 triggers both phosphorylation and degradation of CFP1 protein, phosphorylation of CFP1 by CDK1 is not a prerequisite for its degradation during cell division.	SIGNOR-279012
Q12772	Q14534	1	transcriptional regulation	up-regulates quantity by expression	0.595	The processed SREBP2, designated nuclear SREBP2 (nSREBP2), then enters the nucleus as a homodimer, binds to the sterol regulatory element (SRE) sequence in the promoters of target genes, including HMGCR and SQLE (encoding squalene monooxygenase), and upregulates their transcription	SIGNOR-265162
P00533	Q05397	1	phosphorylation	up-regulates	0.595	In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases.	SIGNOR-167646
Q9HAU4	P37173	1	ubiquitination	down-regulates activity	0.595	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps.	SIGNOR-195681
P08754	Q08828	1	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
P00519	P46527	1	phosphorylation	down-regulates quantity	0.595	A conserved tyrosine residue (Y88) in the Cdk-binding domain of p27 can be phosphorylated by the Src-family kinase Lyn and the oncogene product BCR-ABL	SIGNOR-245293
P23443	P03372	1	phosphorylation	up-regulates	0.595	Serine 167 is the major phosphorylation site on the human estrogen receptor. Phosphorylation is mediated by casein kinase ii.	SIGNOR-34117
Q6ZNA4	P12755	1	ubiquitination	down-regulates	0.595	On tgf-beta treatment, the e3 ubiquitin ligase arkadia mediates degradation of ski in a smad-dependent manner	SIGNOR-178598
O43815	P62714	1	binding	up-regulates activity	0.595	The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms	SIGNOR-261700
P24941	Q06609	1	phosphorylation	down-regulates quantity by destabilization	0.595	Phosphorylation of the BRCA2 C-terminal RAD51 binding site by CDK2 promotes RAD51 filament disassembly, leading to nucleolitic cleavage of newly synthesized DNA and compromised fork integrity.	SIGNOR-280213
Q13309	P24385	1	binding	down-regulates quantity by destabilization	0.594	We show that SK-UT-1B cells express a novel splice variant of Skp2 that localizes to the cytoplasm and that cyclin D1 ubiquitination takes place in the nucleus. We propose that the translocation of Skp2 into the nucleus is required for the ubiquitination of cyclin D1 and that the absence of the SCF(Skp2) complex in the nucleus of SK-UT-1B cells is the mechanism underlying the ubiquitination defect observed in this cell line.	SIGNOR-272575
P17947	Q02556	1	binding	up-regulates activity	0.594	We found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP.	SIGNOR-222880
P28482	Q9BUB5	1	phosphorylation	up-regulates	0.594	We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity toward a substrate, eukaryotic initiation factor-4e (eif-4e).	SIGNOR-48298
Q9UQM7	P16220	1	phosphorylation	down-regulates	0.594	Phosphorylation of creb1 at ser142 and ser143 is selectively activated by ca(2+) influx;phosphorylation of ser142 and ser143, disrupts the interaction of creb with its cofactor cbp. Phosphorylation of serine 142 in creb by camkii leads to dissociation of the creb dimer.	SIGNOR-82501
Q99683	O14733	1	phosphorylation	up-regulates	0.594	Ask1 is a member of a mapkkk family and functions as an upstream kinase engaged in c-jun nh2-terminal kinase (jnk)/p38 signaling via the phosphorylation and activation of mapkks, such as mkk3, -4, -6, and -7	SIGNOR-161766
Q01638	Q9Y4K3	1	binding	up-regulates activity	0.594	As shown in Figure 3D, MyD88, IRAK, IRAK4, and TRAF6 are all recruited to ST2 upon IL-33 stimulation.	SIGNOR-277707
P31749	Q15910	1	phosphorylation	down-regulates activity	0.594	Enhancer of zeste homolog 2 (ezh2) is a methyltransferase that plays an important role in many biological processes through its ability to trimethylate lysine 27 in histone h3. Here, we show that akt phosphorylates ezh2 at serine 21 and suppresses its methyltransferase activity by impeding ezh2 binding to histone h3	SIGNOR-141043
P45983	P55957	1	phosphorylation	up-regulates activity	0.594	(b) Phosphorylation of Bid at Thr59 by JNK1 and JNK2 (in vitro kinase assay).	SIGNOR-279076
P31749	P45985	1	phosphorylation	down-regulates	0.594	Akt phosphorylated sek1 on serine 78.	SIGNOR-236494
Q14703	Q12772	1	cleavage	up-regulates activity	0.594	We present evidence that SKI-1 processes peptides mimicking the cleavage sites of the SKI-1 prosegment, pro-brain-derived neurotrophic factor, and the sterol regulatory element-binding protein SREBP-2	SIGNOR-267496
Q99684	P17947	1	binding	down-regulates activity	0.594	Our data demonstrate that GFI-1 physically interacts with PU.1, repressing PU.1-dependent transcription. This repression is functionally significant, as GFI-1 blocked PU.1-induced macrophage differentiation of a multipotential hematopoietic progenitor cell line.	SIGNOR-256043
Q7Z460	Q9UDT6	1	binding	up-regulates activity	0.594	CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.\|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. \| Both EB1- and cortex-binding domains of CLASP are required to promote MT stability.	SIGNOR-265092
Q13547	P08151	1	deacetylation	up-regulates activity	0.594	Here, we identify a mechanism whereby Hh signalling is regulated, in which acetylation of Gli1 at Lys 518 represents a transcriptional inhibitory switch, while its HDAC1-mediated deacetylation is responsible for transcriptional activation.	SIGNOR-253544
P34947	P30989	1	phosphorylation	up-regulates activity	0.594	Here we report the unique phosphorylation\nof NTSR1 by GRK2 and GRK5, which belong to the GRK2 and GRK4 subfamilies,\nrespectively.	SIGNOR-278234
P09769	P43405	1	phosphorylation	up-regulates activity	0.594	Fgr associates with Fc\u03b5RI and phosphorylates Syk in antigen-stimulated mast cells.\|The overexpression of Fgr stimulates Syk, Syk dependent signaling molecules, and degranulation in RBL-2H3 cells and BMMCs.	SIGNOR-279332
Q9BXW4	Q8IZQ1	1	binding	up-regulates activity	0.594	Here, we show that ALFY binds selectively to LC3C and the GABARAPs through a LIR in its WD40 domain. Binding of ALFY to GABARAP is indispensable for its recruitment to LC3B-positive structures and, thus, for the clearance of certain p62 structures by autophagy.	SIGNOR-266795
Q9GZV5	Q15796	1	binding	up-regulates	0.593	Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal.	SIGNOR-169835
P31749	P46937	1	phosphorylation	down-regulates	0.593	One protein that associates with 14-3-3 in an akt-dependent manner is shown here to be the yes-associated protein (yap), which is phosphorylated by akt at serine 127, leading to binding to 14-3-3. Akt promotes yap localization to the cytoplasm, resulting in loss from the nucleus where it functions as a coactivator of transcription factors including p73.	SIGNOR-252593
O00444	Q8NHV4	1	phosphorylation	up-regulates activity	0.593	We found that PLK4-mediated phosphorylation of NEDD1 at its S325 amino acid residue directly promotes both NEDD1 binding to SAS-6 and recruiting SAS-6 to the centrosome. \|Collectively, our results demonstrate that PLK4-regulated NEDD1 facilitates initiation of the cartwheel assembly and of daughter centriole biogenesis in mammals.	SIGNOR-272996
P45983	P45984	1	phosphorylation	up-regulates	0.593	Our studies revealed a novel mechanism in which phosphorylation of jnk2 is mediated by jnk1 before phosphorylation of p53, and then p53 is directly phosphorylated by jnk2 at ser6.	SIGNOR-155205
Q13258	P63092	1	binding	up-regulates activity	0.593	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-256755
P00533	Q9UM47	1	phosphorylation	up-regulates activity	0.593	Here, we report that treatment of EGFR mutated lung cancer cell lines with erlotinib, while showing robust cell death, enriches the ALDH+ stem like cells through EGFR dependent activation of Notch3.\|We also find a kinase-dependent physical association between the Notch3 and EGFR receptors and tyrosine phosphorylation of Notch3.	SIGNOR-280002
P06493	Q9H1A4	1	phosphorylation	up-regulates	0.592	Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation	SIGNOR-119705
P35442	Q08722	1	binding	up-regulates	0.592	We report here that iap is a receptor for the ts1 cbd and its vvm-containing peptides and that a function-blocking anti-iap mab inhibits the chemotactic response to ts1 and its cbd peptides in endothelial cells.	SIGNOR-39749
Q14451	Q92730	1	binding	up-regulates	0.592	We would like to propose that when cells are driven to divide by growth factor stimulation, grb7 relocalizes at the membrane, in the same subcellular compartment as rnd1, where they could interact in vivo.	SIGNOR-74914
Q16539	P05787	1	phosphorylation	up-regulates	0.592	Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif ((68)nqsllspl) and becomes phosphorylated in cultured cells and organs during mitosis, cell stress, and apoptosis. Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase.The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis.	SIGNOR-114079
Q06945	P35222	1	binding	up-regulates activity	0.592	We have demonstrated that Sox17 and Sox4 can directly interact with β-catenin and TCF/LEF proteins.Sox4 enhances β-catenin/TCF activity and the proliferation of SW480 cells.In contrast, Sox4 may function to stabilize β-catenin protein.	SIGNOR-256138
O00253	P41968	1	binding	down-regulates activity	0.592	AGRP is a potent antagonist of the melanocortin-3 receptor and the MC4R and has also been shown to have a lesser degree of inhibitory action at the melanocortin-5 receptor.	SIGNOR-252380
P00533	P52735	2	phosphorylation	up-regulates	0.592	To understand the mechanism of egf-dependent vav2 activation, we examined first the egf-dependent phosphorylation sites on vav2 and the nature of interaction of vav2 with the activated egf receptor. Based on our in vitro and in vivo data all three tyrosine residues (142, 159, and 172) in the n-terminal domain of vav2 can be phosphorylated by the egf receptor.	SIGNOR-95980
P14780	P01137	1	cleavage	up-regulates	0.592	We also demonstrate that mmp-9, as well as its relative, mmp-2, cleave latent transforming growth factor-_ (tgf-_), which constitutes a novel mechanism of tgf-_ activation.	SIGNOR-74461
P24394	Q9Y4H2	1	phosphorylation	up-regulates	0.592	Irs-1 and a homologous protein, irs-2 (also known as 4-phosphotyrosine substrate), are recruited to phosphorylated y497 of IL-4R After ligand binding, leading to phosphorylation and activation of irs-1 and irs-2.	SIGNOR-100771
P43405	Q9GZY6	1	phosphorylation	up-regulates activity	0.592	Our results indicated that human LAB was primarily phosphorylated on three membrane-distal tyrosines, Tyr(136), Tyr(193), and Tyr(233). Mutation of these three tyrosines abolished Grb2 binding and LAB function. Our data suggested that these tyrosines are the most important tyrosines for LAB function.The dramatic reduction in phosphorylation of the LAB Y233F mutant suggested that Tyr233 is a primary target of the Syk family kinases.	SIGNOR-273576
Q9UQM7	P48058	1	phosphorylation	up-regulates	0.592	Receptor internalization, altered;intracellular localization	SIGNOR-97546
P68400	P05412	1	phosphorylation	down-regulates	0.592	Casein kinase ii is a negative regulator of c-jun dna binding and ap-1 activitywe show that two of these sites, thr-231 and ser-249, are phosphorylated by casein kinase ii (ckii).	SIGNOR-19607
P51955	O14777	1	phosphorylation	up-regulates	0.592	Phosphorylation of the mitotic regulator protein hec1 by nek2 kinase is essential for faithful chromosome segregation.Hec1 (highly expressed in cancer) plays essential roles in chromosome segregation by interacting through its coiled-coil domains with several proteins that modulate the g(2)/m phase.Nek2 phosphorylates hec1 on serine residue 165, both in vitro and in vivo.	SIGNOR-94322
P06493	P33991	1	phosphorylation	down-regulates activity	0.592	We report here that human mcm4, a subunit of the putative dna replicative helicase, is extensively phosphorylated in hela cells when they are incubated in the presence of inhibitors of dna synthesis or are exposed to uv irradiation. The data presented here indicate that the consecutive actions of atr-chk1 and cdk2 kinases are involved in this phosphorylation in the presence of hydroxyurea. Phosphorylation of t19 correlates with lowered level of dna helicase activity of the purified mcm4,6,7 complex.	SIGNOR-100877
Q9NYY3	P04637	1	phosphorylation	up-regulates activity	0.592	Other investigators have demonstrated that Plk2 phosphorylates mutant p53 in a positive feedback loop.	SIGNOR-278980
P67775	P04049	1	dephosphorylation	up-regulates	0.592	Both pp2a holoenzymes were found to associate with raf1 and catalyze dephosphorylation of inhibitory phospho-ser-259. Together these findings indicate that pp2a abalphac and abdeltac holoenzymes function as positive regulators of raf1-mek1/2-erk1/2 signaling by targeting raf1.	SIGNOR-141170
Q6KF10	Q13873	1	binding	up-regulates	0.592	We found that transfection of small hairpin rna for bmprii and actriia in mc3t3 cells suppressed the signaling of gdf6, gdf7, and bmp10. Thus, the present approach provides a genomic paradigm for matching paralogous polypeptide ligands with a limited number of evolutionarily related receptors capable of activating specific downstream smad proteins.	SIGNOR-139093
P52735	P00533	2	binding	up-regulates	0.592	Oligomerization of receptor protein tyrosine kinases such as the epidermal growth factor receptor (egfr) by their cognate ligands leads to activation of the receptor.We Demonstrate that vav-2 is phosphorylated on tyrosine residues in response to egf and associates with the egfr in vivo.	SIGNOR-73874
P43405	P06239	1	phosphorylation	down-regulates activity	0.592	Our experiments indicate that the TCR-induced activation of Erk2 depends on the function of SH2 domain of Lck and is reduced by phosphorylation of wild type Lck at Tyr192 or by mutation of this site to a negatively charged amino acid. Such dependence on the SH2 domain has also been reported for the bulk of TCR-induced tyrosine phosphorylation and activation of the interleukin 2 gene (26). Thus, phosphorylation of Lck at Tyr192 may represent a negative feedback mechanism in the interplay between Src and Syk family PTKs in TCR signaling	SIGNOR-246562

Q13535

O15360

1

phosphorylation

up-regulates

0.598

The s1449a mutant failed to completely correct a variety of fa-associated phenotypes. The dna damage response is coordinated by phosphorylation events initiated by apical kinases atm (ataxia telangectasia mutated) and atr (atm and rad3-related), and atr is essential for proper fa pathway function. Serine 1449 is in a consensus atm/atr site

SIGNOR-182953

P06493

O95997

1

phosphorylation

up-regulates

0.598

Hpttg is phosphorylated by cdc2 at ser165 these results suggest that hpttg is induced by, and may have a role in, regulatory pathways involved in the control of cell proliferation.

SIGNOR-74619

O14745

P07550

1

binding

up-regulates activity

0.598

The Na+/H+ exchanger regulatory factor (NHERF) binds to the tail of the beta2-adrenergic receptor and plays a role in adrenergic regulation of Na+/H+ exchange. NHERF contains two PDZ domains, the first of which is required for its interaction with the beta2 receptor.

SIGNOR-262598

O75116

O14950

1

phosphorylation

up-regulates activity

0.598

In addition, an in vitro kinase assay with mixed recombinant GST-ROCK2 and MLC2 revealed that ROCK2 phosphorylated WT MLC2, but not MLC2 S15A mutant, indicating that it phosphorylates MLC2 at S15 in vitro (XREF_FIG).

SIGNOR-279103

Q02962

P19544

2

transcriptional regulation

up-regulates quantity by expression

0.598

Cotransfection of Pax2 with the Wt1 reporter construct led to moderate activation of the Wt1 promoter.

SIGNOR-252290

Q9ULV1

O14640

1

binding

up-regulates activity

0.598

Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin.

SIGNOR-258955

P19544

Q02962

2

transcriptional regulation

down-regulates quantity by repression

0.598

A marked increase in WT1 protein levels coincided precisely with down-regulation of the Pax-2 gene in the individual precursor cells of the visceral glomerular epithelium, suggesting a direct effect of the WT1 repressor protein on Pax-2 regulatory elements. To examine whether WT1 could directly repress Pax-2 transcription, binding of WT1 to three high affinity sites in the 5' untranslated Pax-2 leader sequence was demonstrated by DNAseI footprinting analysis

SIGNOR-252298

Q13671

P01116

1

binding

up-regulates

0.598

We demonstrate that the ras effector protein rin1 binds to activated ras with an affinity (k(d), 22 nm) similar to that observed for raf1.

SIGNOR-113970

Q13616

P35222

1

ubiquitination

down-regulates quantity by destabilization

0.598

These results indicate that the cul1/skp1/beta-trcp complex forms a ubiquitin ligase that mediates the degradation of beta-catenin.

SIGNOR-64499

Q8IZQ1

Q9H1Y0

1

binding

up-regulates quantity

0.598

Alfy is recruited to intracellular inclusions and scaffolds a complex between p62(SQSTM1)-positive proteins and the autophagic effectors Atg5, Atg12, Atg16L and LC3. Alfy directly interacts with Atg5 and can be found in a complex with Atg5, Atg12 and Atg16L

SIGNOR-266791

P84022

P17676

1

binding

down-regulates activity

0.597

Thus, repression of the activity of C/EBPs by Smad3/4 at C/EBP binding sites inhibited transcription from the PPAR2 and leptin promoters

SIGNOR-250567

Q05513

P49841

1

phosphorylation

down-regulates

0.597

Phospho-gsk3b-specific antibodies also revolved that lkb1 regulates gsk3b phosphorylation at a known inhibitory site, serine-9. This localized phosphorylation is cdc42 and pkc-zeta-dependent.

SIGNOR-119889

Q8WYL5

P53667

1

dephosphorylation

down-regulates activity

0.597

In addition to its cofilin\u2013phosphatase activity, SSH1 can also dephosphorylate LIMK1 and LIMK2, although LIMK1 is a better substrate than LIMK2 [63] .|SSH1 suppresses the kinase activity of LIMK1 toward cofilin by dephosphorylation at Thr 508 in the kinase catalytic domain and other autophosphorylated residues [63].

SIGNOR-277096

P04899

Q08828

1

binding

down-regulates activity

0.597

Adenylate cyclase is regulated by stimulatory hormones through Gs(alpha s beta gamma) and inhibitory hormones through Gi(alpha i beta gamma)

SIGNOR-256499

Q92585

P49336

1

binding

up-regulates

0.597

Mastermind recruits cycc:cdk8 to phosphorylate the notch icd and coordinate activation with turnover

SIGNOR-130715

P0C2W1

O15350

1

binding

down-regulates quantity by destabilization

0.597

The F-box protein FBXO45 promotes the proteasome-dependent degradation of p73.Importantly, SCFFBXO45 ubiquitylates p73 both in vivo and in vitro. Expression of Cul1 dominant negative mutant, but not Cul2, Cul3, Cul4 and Cul5 dominant negative mutants, increased p73 levels (Figure 1c) to an extent similar to that observed in the ts41 cell line at not permissive temperature, suggesting that a Cul1-associated activity is required for p73 protein stability.

SIGNOR-271876

Q9Y6X2

P84022

1

binding

up-regulates activity

0.597

We have further shown that PIAS3, Smad3, and p300 can form a ternary complex, which is significantly increased by TGF-_ treatment. Taken together, these results suggest that PIAS3 stimulates Smad transcriptional activity through formation of a complex with Smad proteins and p300/CBP.

SIGNOR-217725

P19793

Q07869

1

binding

up-regulates

0.597

Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology

SIGNOR-105345

P00519

O43586

1

phosphorylation

up-regulates activity

0.597

PSTPIP1 was phosphorylated by c-Abl. Tyr-344 is a major c-Abl phosphorylation site.PSTPIP1 was able to bridge c-Abl to the PEST-type PTPs.

SIGNOR-251431

P06241

Q05655

1

phosphorylation

up-regulates activity

0.597

In conclusion, our in vitro data and previous report ( xref ) demonstrate that Fyn phosphorylation of Y311 on PKC\u03b4 activates the apoptotic signaling cascade in DAergic neurons in response to neurotoxic insults.

SIGNOR-279737

P53041

Q99683

1

dephosphorylation

down-regulates activity

0.597

After exposure of cells to H2O2, ASK1 is transiently activated by autophosphorylation at Thr845. The protein then associates with PP5 (protein serine/threonine phosphatase 5), which inactivates ASK1 by dephosphorylation of Thr845.

SIGNOR-248540

P04637

P11166

1

transcriptional regulation

down-regulates quantity by repression

0.597

P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway.

SIGNOR-267464

Q9HBW0

P50148

1

binding

up-regulates activity

0.597

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-257382

Q12933

O43318

1

ubiquitination

up-regulates activity

0.597

Tumor necrosis factor receptor-associated factors 2 and 6 (traf2 and -6) act as the ubiquitin e3 ligases to mediate lys63-linked tak1 polyubiquitination at the lys158 residue in vivo and in vitro. Lys(63)-linked TAK1 polyubiquitination at the Lys(158) residue is required for TAK1-mediated IKK complex recruitment.

SIGNOR-162638

P28482

P23443

1

phosphorylation

up-regulates

0.596

Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase

SIGNOR-28800

Q9UQ13

P62136

1

binding

up-regulates activity

0.596

Using a proteomics approach, we have identified a complex comprised of Shoc2/Sur-8 and the catalytic subunit of protein phosphatase 1 (PP1c) as a highly specific M-Ras effector. M-Ras targets Shoc2-PP1c to stimulate Raf activity by dephosphorylating the S259 inhibitory site

SIGNOR-251647

Q05655

P40763

1

phosphorylation

up-regulates

0.596

Abrogation of pkcdelta activity inhibited insulin-induced stat3 phosphorylation, pkcdelta-stat3 association and nuclear translocation.

SIGNOR-143828

O00327

Q07869

2

transcriptional regulation

up-regulates quantity by expression

0.596

We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression.

SIGNOR-268025

Q9UQM7

P10636

1

phosphorylation

down-regulates activity

0.596

We found that when tau was first phosphorylated by A-kinase, C-kinase, cdk5, or CaM kinase II and then by GSK-3, its binding to microtubules was inhibited by 45, 61, 78, and 79%, respectively. Further, the kinase combinations cdk5/GSK-3 and CaM kinase II/GSK-3 rapidly phosphorylated the sites Thr 231 and Ser 235. When these sites were individually replaced by Ala and the phosphorylation experiments repeated, tau binding to microtubules was inhibited by 54 and 71%, respectively. By comparison, when Ser 262 was replaced by Ala, tau binding to microtubules was inhibited by only 8% after phosphorylation by CaM kinase II.

SIGNOR-249315

O15530

Q9HBY8

1

phosphorylation

up-regulates activity

0.596

SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB.

SIGNOR-250277

P28482

P50548

1

phosphorylation

up-regulates

0.596

The experiments presented here indicate that erf is regulated during nuclear import and/or export and that this process depends on its phosphorylation by erks our analysis indicates that in addition to t526 (position 7), s161 (position 2), s246 (position 3), and s251 (position 4) are also phosphorylated in vitro by erk2 and in vivo after mitogenic stimulation (fig. 3a).

SIGNOR-67524

Q6KF10

P36894

1

binding

up-regulates

0.596

We found that transfection of small hairpin rna for bmprii and actriia in mc3t3 cells suppressed the signaling of gdf6, gdf7, and bmp10.

SIGNOR-139090

P78352

Q9C0D5

1

binding

up-regulates activity

0.596

In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. our results indicate that TANC-dependent spine/synapse maintenance requires TANC binding to PSD-95, which promotes synaptic localization of TANC proteins. Thus, it is likely that interaction with PSD-95 concentrates TANC proteins at synapses, where they play a role in mediating PSD-95-dependent maintenance of spines and synapses.

SIGNOR-266894

Q96PV0

P78352

1

binding

up-regulates activity

0.596

The reversible removal of AIDA-1 from the PSD core under excitatory conditions is similar to the redistribution of another abundant PSD protein, SynGAP. Both SynGAP-alpha1 and AIDA-1 are known to bind PSD-95.

SIGNOR-264229

Q6Y7W6

Q13322

1

binding

up-regulates activity

0.596

We demonstrated that, in cultured cells and mammalian brains, GIGYF2 interacts and colocalises with Grb10, promoting ligand‐induced ubiquitination of IGF‐1R, and thereby regulates receptor degradation

SIGNOR-260057

Q02363

P15884

1

binding

down-regulates activity

0.596

All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.

SIGNOR-241376

Q66GS9

Q6UVJ0

1

binding

up-regulates activity

0.596

In this study, we demonstrate that the human microcephaly protein, CEP135, directly interacts with hSAS-6 via its carboxyl-terminus and with MTs via its amino-terminus. Unexpectedly, CEP135 also interacts with another microcephaly protein CPAP via its amino terminal domain. Depletion of CEP135 not only perturbed the centriolar localization of CPAP, but also blocked CPAP-induced centriole elongation. We propose that CEP135 may serve as a linker protein that directly connects the central hub protein, hSAS-6, to the outer MTs, and suggest that this interaction stabilizes the proper cartwheel structure for further CPAP-mediated centriole elongation.

SIGNOR-269676

P06241

P11912

1

phosphorylation

up-regulates activity

0.596

Lyn and Fyn phosphorylated the CD79a cytoplasmic portion of the fusion proteins well, with >80% of phosphorylation occurring at Y182. CD79a and CD79b function as transducers of B cell antigen receptor signals via a cytoplasmic sequence, termed the immunoreceptor tyrosine-based activation motif (ITAM).

SIGNOR-251153

P53350

Q12888

1

phosphorylation

down-regulates activity

0.596

Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |Addition of the inhibitors for PLK1 and the p38 MAPK leads to a complete loss of pT1609/pS1618 signal within 3 hr in mitotic cells

SIGNOR-264413

Q12778

P40763

1

binding

down-regulates activity

0.596

FoxO1, which is up-regulated during early stages of diet-induced leptin resistance, directly interacts with STAT3 and prevents STAT3 from binding to specificity protein 1 (SP1)-pro-opiomelanocortin (POMC) promoter complex, and thereby inhibits STAT3-mediated regulation of POMC transcription.

SIGNOR-263496

Q07869

O00327

2

transcriptional regulation

up-regulates quantity by expression

0.596

We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression.

SIGNOR-268024

Q9Y6I3

P00533

1

relocalization

down-regulates

0.596

Epsin 1 is involved in recruitment of ubiquitinated egf receptors into clathrin-coated pits this supports the contention that epsin 1 promotes endocytosis of the ubiquitinated egfr.

SIGNOR-182562

Q13233

O14920

1

phosphorylation

up-regulates activity

0.595

These results suggested that IKK\u03b2 was a likely substrate for MEKK1 and that MEKK1 phosphorylation of IKK\u03b2 increased its kinase activity.

SIGNOR-279339

O75385

Q8IVP5

1

phosphorylation

up-regulates activity

0.595

Here, we show that ULK1 is upregulated and translocates to fragmented mitochondria upon mitophagy induction by either hypoxia or mitochondrial uncouplers. At mitochondria, ULK1 interacts with FUNDC1, phosphorylating it at serine 17, which enhances FUNDC1 binding to LC3.

SIGNOR-273606

P27361

O43524

1

phosphorylation

down-regulates quantity by destabilization

0.595

Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway

SIGNOR-184569

O14905

O75197

1

binding

up-regulates

0.595

Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.

SIGNOR-132114

Q13043

Q12778

1

phosphorylation

up-regulates

0.595

Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1.

SIGNOR-191847

Q9NZN1

P62166

1

binding

up-regulates activity

0.595

IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis. our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. Taken together, our data suggest that IL1RAPL may regulate calcium-dependent exocytosis and provide insight into the understanding of physiopathological mechanisms underlying cognitive impairment resulting from IL1RAPL dysfunction.

SIGNOR-263962

P68400

P11388

1

phosphorylation

down-regulates quantity by destabilization

0.595

This study also reports the novel finding that topoIIα may be a target of GSK3β phosphorylation. Evidence suggests that CK2 serves as a priming kinase, through phosphorylation at Ser1365, for GSK3β-mediated phosphorylation at Ser1361.

SIGNOR-276300

P06493

Q8ND76

1

phosphorylation

down-regulates activity

0.595

Therefore, CDK1 may trigger CFP1 degradation through some indirect mechanisms rather than CFP1 phosphorylation.|This result suggests that, although CDK1 triggers both phosphorylation and degradation of CFP1 protein, phosphorylation of CFP1 by CDK1 is not a prerequisite for its degradation during cell division.

SIGNOR-279012

Q12772

Q14534

1

transcriptional regulation

up-regulates quantity by expression

0.595

The processed SREBP2, designated nuclear SREBP2 (nSREBP2), then enters the nucleus as a homodimer, binds to the sterol regulatory element (SRE) sequence in the promoters of target genes, including HMGCR and SQLE (encoding squalene monooxygenase), and upregulates their transcription

SIGNOR-265162

P00533

Q05397

1

phosphorylation

up-regulates

0.595

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

SIGNOR-167646

Q9HAU4

P37173

1

ubiquitination

down-regulates activity

0.595

Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps.

SIGNOR-195681

P08754

Q08828

1

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

P00519

P46527

1

phosphorylation

down-regulates quantity

0.595

A conserved tyrosine residue (Y88) in the Cdk-binding domain of p27 can be phosphorylated by the Src-family kinase Lyn and the oncogene product BCR-ABL

SIGNOR-245293

P23443

P03372

1

phosphorylation

up-regulates

0.595

Serine 167 is the major phosphorylation site on the human estrogen receptor. Phosphorylation is mediated by casein kinase ii.

SIGNOR-34117

Q6ZNA4

P12755

1

ubiquitination

down-regulates

0.595

On tgf-beta treatment, the e3 ubiquitin ligase arkadia mediates degradation of ski in a smad-dependent manner

SIGNOR-178598

O43815

P62714

1

binding

up-regulates activity

0.595

The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms

SIGNOR-261700

P24941

Q06609

1

phosphorylation

down-regulates quantity by destabilization

0.595

Phosphorylation of the BRCA2 C-terminal RAD51 binding site by CDK2 promotes RAD51 filament disassembly, leading to nucleolitic cleavage of newly synthesized DNA and compromised fork integrity.

SIGNOR-280213

Q13309

P24385

1

binding

down-regulates quantity by destabilization

0.594

We show that SK-UT-1B cells express a novel splice variant of Skp2 that localizes to the cytoplasm and that cyclin D1 ubiquitination takes place in the nucleus. We propose that the translocation of Skp2 into the nucleus is required for the ubiquitination of cyclin D1 and that the absence of the SCF(Skp2) complex in the nucleus of SK-UT-1B cells is the mechanism underlying the ubiquitination defect observed in this cell line.

SIGNOR-272575

P17947

Q02556

1

binding

up-regulates activity

0.594

We found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP.

SIGNOR-222880

P28482

Q9BUB5

1

phosphorylation

up-regulates

0.594

We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity toward a substrate, eukaryotic initiation factor-4e (eif-4e).

SIGNOR-48298

Q9UQM7

P16220

1

phosphorylation

down-regulates

0.594

Phosphorylation of creb1 at ser142 and ser143 is selectively activated by ca(2+) influx;phosphorylation of ser142 and ser143, disrupts the interaction of creb with its cofactor cbp. Phosphorylation of serine 142 in creb by camkii leads to dissociation of the creb dimer.

SIGNOR-82501

Q99683

O14733

1

phosphorylation

up-regulates

0.594

Ask1 is a member of a mapkkk family and functions as an upstream kinase engaged in c-jun nh2-terminal kinase (jnk)/p38 signaling via the phosphorylation and activation of mapkks, such as mkk3, -4, -6, and -7

SIGNOR-161766

Q01638

Q9Y4K3

1

binding

up-regulates activity

0.594

As shown in Figure 3D, MyD88, IRAK, IRAK4, and TRAF6 are all recruited to ST2 upon IL-33 stimulation.

SIGNOR-277707

P31749

Q15910

1

phosphorylation

down-regulates activity

0.594

Enhancer of zeste homolog 2 (ezh2) is a methyltransferase that plays an important role in many biological processes through its ability to trimethylate lysine 27 in histone h3. Here, we show that akt phosphorylates ezh2 at serine 21 and suppresses its methyltransferase activity by impeding ezh2 binding to histone h3

SIGNOR-141043

P45983

P55957

1

phosphorylation

up-regulates activity

0.594

(b) Phosphorylation of Bid at Thr59 by JNK1 and JNK2 (in vitro kinase assay).

SIGNOR-279076

P31749

P45985

1

phosphorylation

down-regulates

0.594

Akt phosphorylated sek1 on serine 78.

SIGNOR-236494

Q14703

Q12772

1

cleavage

up-regulates activity

0.594

We present evidence that SKI-1 processes peptides mimicking the cleavage sites of the SKI-1 prosegment, pro-brain-derived neurotrophic factor, and the sterol regulatory element-binding protein SREBP-2

SIGNOR-267496

Q99684

P17947

1

binding

down-regulates activity

0.594

Our data demonstrate that GFI-1 physically interacts with PU.1, repressing PU.1-dependent transcription. This repression is functionally significant, as GFI-1 blocked PU.1-induced macrophage differentiation of a multipotential hematopoietic progenitor cell line.

SIGNOR-256043

Q7Z460

Q9UDT6

1

binding

up-regulates activity

0.594

CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. | Both EB1- and cortex-binding domains of CLASP are required to promote MT stability.

SIGNOR-265092

Q13547

P08151

1

deacetylation

up-regulates activity

0.594

Here, we identify a mechanism whereby Hh signalling is regulated, in which acetylation of Gli1 at Lys 518 represents a transcriptional inhibitory switch, while its HDAC1-mediated deacetylation is responsible for transcriptional activation.

SIGNOR-253544

P34947

P30989

1

phosphorylation

up-regulates activity

0.594

Here we report the unique phosphorylation\nof NTSR1 by GRK2 and GRK5, which belong to the GRK2 and GRK4 subfamilies,\nrespectively.

SIGNOR-278234

P09769

P43405

1

phosphorylation

up-regulates activity

0.594

Fgr associates with Fc\u03b5RI and phosphorylates Syk in antigen-stimulated mast cells.|The overexpression of Fgr stimulates Syk, Syk dependent signaling molecules, and degranulation in RBL-2H3 cells and BMMCs.

SIGNOR-279332

Q9BXW4

Q8IZQ1

1

binding

up-regulates activity

0.594

Here, we show that ALFY binds selectively to LC3C and the GABARAPs through a LIR in its WD40 domain. Binding of ALFY to GABARAP is indispensable for its recruitment to LC3B-positive structures and, thus, for the clearance of certain p62 structures by autophagy.

SIGNOR-266795

Q9GZV5

Q15796

1

binding

up-regulates

0.593

Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal.

SIGNOR-169835

P31749

P46937

1

phosphorylation

down-regulates

0.593

One protein that associates with 14-3-3 in an akt-dependent manner is shown here to be the yes-associated protein (yap), which is phosphorylated by akt at serine 127, leading to binding to 14-3-3. Akt promotes yap localization to the cytoplasm, resulting in loss from the nucleus where it functions as a coactivator of transcription factors including p73.

SIGNOR-252593

O00444

Q8NHV4

1

phosphorylation

up-regulates activity

0.593

We found that PLK4-mediated phosphorylation of NEDD1 at its S325 amino acid residue directly promotes both NEDD1 binding to SAS-6 and recruiting SAS-6 to the centrosome. |Collectively, our results demonstrate that PLK4-regulated NEDD1 facilitates initiation of the cartwheel assembly and of daughter centriole biogenesis in mammals.

SIGNOR-272996

P45983

P45984

1

phosphorylation

up-regulates

0.593

Our studies revealed a novel mechanism in which phosphorylation of jnk2 is mediated by jnk1 before phosphorylation of p53, and then p53 is directly phosphorylated by jnk2 at ser6.

SIGNOR-155205

Q13258

P63092

1

binding

up-regulates activity

0.593

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

SIGNOR-256755

P00533

Q9UM47

1

phosphorylation

up-regulates activity

0.593

Here, we report that treatment of EGFR mutated lung cancer cell lines with erlotinib, while showing robust cell death, enriches the ALDH+ stem like cells through EGFR dependent activation of Notch3.|We also find a kinase-dependent physical association between the Notch3 and EGFR receptors and tyrosine phosphorylation of Notch3.

SIGNOR-280002

P06493

Q9H1A4

1

phosphorylation

up-regulates

0.592

Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation

SIGNOR-119705

P35442

Q08722

1

binding

up-regulates

0.592

We report here that iap is a receptor for the ts1 cbd and its vvm-containing peptides and that a function-blocking anti-iap mab inhibits the chemotactic response to ts1 and its cbd peptides in endothelial cells.

SIGNOR-39749

Q14451

Q92730

1

binding

up-regulates

0.592

We would like to propose that when cells are driven to divide by growth factor stimulation, grb7 relocalizes at the membrane, in the same subcellular compartment as rnd1, where they could interact in vivo.

SIGNOR-74914

Q16539

P05787

1

phosphorylation

up-regulates

0.592

Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif ((68)nqsllspl) and becomes phosphorylated in cultured cells and organs during mitosis, cell stress, and apoptosis. Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase.The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis.

SIGNOR-114079

Q06945

P35222

1

binding

up-regulates activity

0.592

We have demonstrated that Sox17 and Sox4 can directly interact with β-catenin and TCF/LEF proteins.Sox4 enhances β-catenin/TCF activity and the proliferation of SW480 cells.In contrast, Sox4 may function to stabilize β-catenin protein.

SIGNOR-256138

O00253

P41968

1

binding

down-regulates activity

0.592

AGRP is a potent antagonist of the melanocortin-3 receptor and the MC4R and has also been shown to have a lesser degree of inhibitory action at the melanocortin-5 receptor.

SIGNOR-252380

P00533

P52735

2

phosphorylation

up-regulates

0.592

To understand the mechanism of egf-dependent vav2 activation, we examined first the egf-dependent phosphorylation sites on vav2 and the nature of interaction of vav2 with the activated egf receptor. Based on our in vitro and in vivo data all three tyrosine residues (142, 159, and 172) in the n-terminal domain of vav2 can be phosphorylated by the egf receptor.

SIGNOR-95980

P14780

P01137

1

cleavage

up-regulates

0.592

We also demonstrate that mmp-9, as well as its relative, mmp-2, cleave latent transforming growth factor-_ (tgf-_), which constitutes a novel mechanism of tgf-_ activation.

SIGNOR-74461

P24394

Q9Y4H2

1

phosphorylation

up-regulates

0.592

Irs-1 and a homologous protein, irs-2 (also known as 4-phosphotyrosine substrate), are recruited to phosphorylated y497 of IL-4R After ligand binding, leading to phosphorylation and activation of irs-1 and irs-2.

SIGNOR-100771

P43405

Q9GZY6

1

phosphorylation

up-regulates activity

0.592

Our results indicated that human LAB was primarily phosphorylated on three membrane-distal tyrosines, Tyr(136), Tyr(193), and Tyr(233). Mutation of these three tyrosines abolished Grb2 binding and LAB function. Our data suggested that these tyrosines are the most important tyrosines for LAB function.The dramatic reduction in phosphorylation of the LAB Y233F mutant suggested that Tyr233 is a primary target of the Syk family kinases.

SIGNOR-273576

Q9UQM7

P48058

1

phosphorylation

up-regulates

0.592

Receptor internalization, altered;intracellular localization

SIGNOR-97546

P68400

P05412

1

phosphorylation

down-regulates

0.592

Casein kinase ii is a negative regulator of c-jun dna binding and ap-1 activitywe show that two of these sites, thr-231 and ser-249, are phosphorylated by casein kinase ii (ckii).

SIGNOR-19607

P51955

O14777

1

phosphorylation

up-regulates

0.592

Phosphorylation of the mitotic regulator protein hec1 by nek2 kinase is essential for faithful chromosome segregation.Hec1 (highly expressed in cancer) plays essential roles in chromosome segregation by interacting through its coiled-coil domains with several proteins that modulate the g(2)/m phase.Nek2 phosphorylates hec1 on serine residue 165, both in vitro and in vivo.

SIGNOR-94322

P06493

P33991

1

phosphorylation

down-regulates activity

0.592

We report here that human mcm4, a subunit of the putative dna replicative helicase, is extensively phosphorylated in hela cells when they are incubated in the presence of inhibitors of dna synthesis or are exposed to uv irradiation. The data presented here indicate that the consecutive actions of atr-chk1 and cdk2 kinases are involved in this phosphorylation in the presence of hydroxyurea. Phosphorylation of t19 correlates with lowered level of dna helicase activity of the purified mcm4,6,7 complex.

SIGNOR-100877

Q9NYY3

P04637

1

phosphorylation

up-regulates activity

0.592

Other investigators have demonstrated that Plk2 phosphorylates mutant p53 in a positive feedback loop.

SIGNOR-278980

P67775

P04049

1

dephosphorylation

up-regulates

0.592

Both pp2a holoenzymes were found to associate with raf1 and catalyze dephosphorylation of inhibitory phospho-ser-259. Together these findings indicate that pp2a abalphac and abdeltac holoenzymes function as positive regulators of raf1-mek1/2-erk1/2 signaling by targeting raf1.

SIGNOR-141170

Q6KF10

Q13873

1

binding

up-regulates

0.592

We found that transfection of small hairpin rna for bmprii and actriia in mc3t3 cells suppressed the signaling of gdf6, gdf7, and bmp10. Thus, the present approach provides a genomic paradigm for matching paralogous polypeptide ligands with a limited number of evolutionarily related receptors capable of activating specific downstream smad proteins.

SIGNOR-139093

P52735

P00533

2

binding

up-regulates

0.592

Oligomerization of receptor protein tyrosine kinases such as the epidermal growth factor receptor (egfr) by their cognate ligands leads to activation of the receptor.We Demonstrate that vav-2 is phosphorylated on tyrosine residues in response to egf and associates with the egfr in vivo.

SIGNOR-73874

P43405

P06239

1

phosphorylation

down-regulates activity

0.592

Our experiments indicate that the TCR-induced activation of Erk2 depends on the function of SH2 domain of Lck and is reduced by phosphorylation of wild type Lck at Tyr192 or by mutation of this site to a negatively charged amino acid. Such dependence on the SH2 domain has also been reported for the bulk of TCR-induced tyrosine phosphorylation and activation of the interleukin 2 gene (26). Thus, phosphorylation of Lck at Tyr192 may represent a negative feedback mechanism in the interplay between Src and Syk family PTKs in TCR signaling

SIGNOR-246562