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
Q13131	O75385	2	phosphorylation	up-regulates activity	0.572	Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition.	SIGNOR-173038
Q12852	P45985	1	phosphorylation	up-regulates activity	0.572	As expected, DLK significantly increased MKK4 phosphorylation on Ser257 / Thr261, and myrAKT1 enhanced MKK4 phosphorylation on Ser78 (XREF_FIG).\|While MKK4 activated by DLK had strong activity in phosphorylating JNK3, MKK4 expressed with DLK and AKT1 together exhibited little activity, even though the two samples had similar levels of Ser257 / Thr261 phosphorylation (XREF_FIG).	SIGNOR-279629
P17706	P29353	1	dephosphorylation	down-regulates activity	0.572	However, TC45 inhibited the EGF-induced association of p52Shc with Grb2, which was attributed to the ability of the PTP to recognize specifically p52Shc phosphorylated on Y239. These results indicate that TC45 recognizes not only selected substrates in a cellular context but also specific sites within substrates and thus may regulate discrete signaling events.	SIGNOR-248397
Q9Y6Y8	Q15436	1	binding	up-regulates activity	0.572	The results showed that the N-terminal region of p125 is important for the interaction with Sec23p. We confirmed the interaction between the two proteins by a yeast two-hybrid assay. Overexpression of p125, like that of mammalian Sec23p, caused disorganization of the endoplasmic reticulum-Golgi intermediate compartment and Golgi apparatus, suggesting its role in the early secretory pathway.	SIGNOR-265307
Q15303	P22681	1	binding	up-regulates	0.572	Erbb4 might not be able to directly recruit cbl, and therefore downregulation of this receptor is slow.	SIGNOR-147841
Q16539	Q92945	1	phosphorylation	down-regulates activity	0.572	KSRP, an important factor for AU-rich element (ARE)-directed mRNA decay, undergoes p38-dependent phosphorylation during muscle differentiation. KSRP phosphorylated by p38 displays compromised binding to ARE-containing transcripts and fails to promote their rapid decay, although it retains the ability to interact with the mRNA degradation machinery	SIGNOR-235856
P04626	P03372	1	phosphorylation	up-regulates	0.572	The results presented here show for the first time that er redistribution to the cytoplasm and its interaction with her2 are important downstream effects of her2 overexpression, that erk1/2 is important for er cytoplasmic localization, and that subcellular localization of er may play a mechanistic role in determining the responsiveness of breast cancer cells to tamoxifen.	SIGNOR-124962
O75385	Q13131	2	phosphorylation	down-regulates activity	0.572	Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity.	SIGNOR-173047
O60346	P23443	1	dephosphorylation	down-regulates activity	0.572	Here we report the identification of ribosomal protein S6 kinase 1 (S6K1) as a novel substrate of PHLPP.	SIGNOR-237454
O43663	Q02241	1	binding	up-regulates activity	0.572	These data indicate that PRC1 binds to KIF4, MKLP1 and CENP-E during late mitosis; however, it apparently does not interact simultaneously with more than one of these motor proteins.	SIGNOR-265989
O15530	Q04759	1	phosphorylation	up-regulates	0.572	We demonstrate that 3-phosphoinositide-dependent kinase 1 (pdk1) has an essential role in this pathway by regulating the activation of pkc and through signal-dependent recruiting of both pkc and card11 to lipid rafts.	SIGNOR-134869
P12931	P06396	1	phosphorylation	up-regulates	0.572	Identification of tyr438 as the major in vitro c-src phosphorylation site in human gelsolin recently	SIGNOR-67014
P35548	P56178	2	binding	down-regulates activity	0.572	We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities.	SIGNOR-240990
P29459	P42701	1	binding	up-regulates	0.572	Like il-12, il-23 binds to the il-12r subunit il-12rbeta1.	SIGNOR-87677
P31749	Q9Y3M2	1	phosphorylation	up-regulates activity	0.572	These observations argue that Chibby is a bona fide Akt substrate and that Akt kinase phosphorylates Chibby at the serine 20 residue.	SIGNOR-279002
P06241	P43146	1	phosphorylation	up-regulates activity	0.572	Fyn tyrosine kinase, but not Src, regulates the phosphorylation of DCC in N1E-115 neuroblastoma cells.Both DCC phosphorylation and Netrin-1-induced axon outgrowth are impaired in Fyn(-/-) CN and spinal cord explants. We propose that DCC is regulated by tyrosine phosphorylation and that Fyn is essential for the response of axons to Netrin-1. these results show that DCC is phosphorylated by Fyn, but not Src, in N1E-115 cells, and that tyrosines 1261 and 1418 are the major phosphorylation sites of Fyn in vivo.	SIGNOR-268176
P06493	Q14674	1	phosphorylation	down-regulates	0.572	Both cdc2/cyclinb1 and mapk (erk2) efficiently phosphorylate separase at its major inhibitory site in vitro	SIGNOR-113126
O15111	O43524	1	phosphorylation	down-regulates	0.572	Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation.	SIGNOR-124203
Q6XZF7	P60953	1	guanine nucleotide exchange factor	up-regulates activity	0.572	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-260547
P38435	P04070	1	carboxylation	up-regulates activity	0.572	Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z	SIGNOR-265925
O15297	O96017	1	dephosphorylation	up-regulates activity	0.572	an in vitro phosphatase assay revealed that Wip1 (WT), but not Wip1 (D314A), dephosphorylates Thr68 on phosphorylated Chk2 in vitro, resulting in the inhibition of Chk2 kinase activity toward glutathione S-transferase-Cdc25C.	SIGNOR-248318
P56178	P35548	2	binding	down-regulates activity	0.572	We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities.	SIGNOR-240925
O96014	O75581	1	binding	up-regulates activity	0.572	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-131637
Q96BY2	Q9NS23	1	binding	up-regulates activity	0.572	Modulator of apoptosis 1 (MOAP-1) is a BH3-like protein that plays key roles in cell death or apoptosis. It is an integral partner to the tumor suppressor protein, Ras association domain family 1A (RASSF1A), and functions to activate the Bcl-2 family pro-apoptotic protein Bax.	SIGNOR-272914
Q92973	P09651	1	relocalization	up-regulates activity	0.572	TNPO1 only mediates the nuclear import of a subset of proteins.\|Among TNPO1 cargos, the most extensively characterized is the RNA binding protein heterogeneous nuclear ribonucleoprotein 1 (hnRNPA1) (27), which functions in several processes including mRNA biogenesis and promotion of transcription factor activity (28–30). NPC protein NUP153 is also a target for TNPO1-mediated nuclear import	SIGNOR-262099
O15391	P04637	1	transcriptional regulation	up-regulates quantity by expression	0.572	YY2 activated the p53 promoter. However, in contrast to YY1, which represses the activity of c-Fos, YY2 increased the activity of the c-Fos promoter.	SIGNOR-266213
Q16539	P19634	1	phosphorylation	up-regulates	0.571	Trophic factor withdrawal: p38 mitogen-activated protein kinase activates nhe1, which induces intracellular alkalinization. activated p38 mapk directly phosphorylated the c terminus of nhe1 within a 40-amino-acid region. Analysis by mass spectroscopy identified four phosphorylation sites on nhe1, thr 717, ser 722, ser 725, and ser 728.	SIGNOR-111043
P21728	P38405	1	binding	up-regulates activity	0.571	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-256939
O60729	Q16659	1	dephosphorylation	down-regulates quantity by destabilization	0.571	Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.\|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3.	SIGNOR-248336
Q13315	Q15831	1	phosphorylation	up-regulates	0.571	We demonstrate that both dna-pk and atm efficiently phosphorylate lkb1 at thr-366 in vitro and provide evidence that atm mediates this phosphorylation in vivo.	SIGNOR-92873
O94989	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.571	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-260540
P50613	P24941	2	phosphorylation	up-regulates activity	0.571	Phosphorylation of monomeric human CDK2 by CAK1 is more efficient than phosphorylation of the binary CDK2-cyclin A complex. Phosphorylated CDK2 exhibits histone H1 kinase activity corresponding to approximately 0.3% of that observed with the fully activated phosphorylated CDK2-cyclin A complex. Fluorescence measurements have shown that Thr160 phosphorylation increases the affinity of CDK2 for both histone substrate and ATP and decreases its affinity for ADP.	SIGNOR-250768
Q13387	P45984	1	binding	up-regulates	0.571	These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins.	SIGNOR-70866
Q6ZW49	Q02962	1	binding	up-regulates activity	0.571	PTIP promotes assembly of the ALR complex and H3K4 methylation at a PAX2-binding DNA element. Without PTIP, Pax2 binds to this element but does not assemble the ALR complex	SIGNOR-251711
Q12837	P03372	1	binding	up-regulates activity	0.571	the POU domain of Brn-3a and Brn-3b was shown to interact with the DNA-binding domain of the ER. Brn-3-ER interactions also affect transcriptional activity of an ERE-containing promoter, such that in estradiol-stimulated cells, Brn-3b strongly activated the promoter via the ERE, while Brn-3a had a mild inhibitory effect.	SIGNOR-241208
Q9GZT5	O75197	1	binding	up-regulates	0.571	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-131619
Q14703	Q96BA8	1	cleavage	up-regulates	0.571	Cleavage of oasis by site-1 and site-2 proteases / oasis is cleaved at the membrane under er stress conditions and that its cleaved n-terminal domain translocates into the nucleus;and then activates transcription of target genes	SIGNOR-143785
P24941	P50613	2	phosphorylation	up-regulates	0.571	Threonine-170 of cdk7 is phosphorylated in vitro by cdk2. Full activation of cdk7 requires phorylation of a conserved threonine residue at position 170 in its own t loop.	SIGNOR-85013
Q14258	P31947	1	ubiquitination	down-regulates quantity by destabilization	0.571	Here we show that Efp is a RING-finger-dependent ubiquitin ligase (E3) that targets proteolysis of 14-3-3 sigma, a negative cell cycle regulator that causes G2 arrest.	SIGNOR-271548
Q13547	Q04206	1	binding	down-regulates	0.571	Phosphorylation at thr505 by the chk1 inhibits rela transactivation and results in its increased association with hdac1.	SIGNOR-151425
P07949	Q14451	1	binding	up-regulates	0.571	Grb7 and grb10, likely relay signals emanating from ret to other, as yet, unidentified targets within the cell	SIGNOR-41765
P07384	Q15078	1	cleavage	up-regulates activity	0.571	Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain	SIGNOR-251583
Q16576	P26358	1	binding	down-regulates activity	0.571	AMPK inhibited DNMT1 through phosphorylation of Ser730 in DNMT1 and Ser314 in RBBP7\|association with RBBP7 could inhibit DNMT1	SIGNOR-264785
P19525	P04637	1	phosphorylation	up-regulates	0.571	The double-stranded rna activated protein kinase pkr physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro.	SIGNOR-68033
Q9NRL3	P67775	1	binding	up-regulates activity	0.571	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-261697
P06239	P04234	1	phosphorylation	up-regulates activity	0.571	Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex.	SIGNOR-259929
Q13315	P54274	1	phosphorylation	up-regulates activity	0.571	Telomeric protein pin2/trf1 as an important atm target in response to double strand dna breaks. activated atm directly phosphorylated pin2/trf1 preferentially on the conserved ser(219)-gln site in vitro and in vivo.	SIGNOR-108419
P00813	P30542	1	binding	up-regulates activity	0.571	The results show that human ADA, apart from reducing the adenosine concentration and thus preventing A(1)R desensitization, binds to A(1)R behaving as an allosteric effector that markedly enhances agonist affinity and increases receptor functionality.	SIGNOR-269105
P17252	P48058	1	phosphorylation	up-regulates	0.57	Receptor internalization, altered;intracellular localization	SIGNOR-97554
P06400	P00519	1	binding	down-regulates	0.57	A domain in the c-terminus of rb, outside of the a/b pocket, binds to the atp-binding lobe of the c-abl tyrosine kinase, resulting in kinase inhibition.	SIGNOR-37139
P61244	Q8IWI9	1	binding	up-regulates activity	0.57	the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences.	SIGNOR-240261
Q9UNE7	P84022	1	ubiquitination	down-regulates quantity by destabilization	0.57	These results suggest that Smad3 could be easily ubiquitinated and degraded by CHIP when Hsp90 activity was inhibited.To demonstrate the role of Hsp70 and Hsp90 on the regulation of Smad3 by CHIP, we over-expressed Hsp70 and Hsp90 in mammalian cells.	SIGNOR-278785
Q8IWU2	P62136	1	phosphorylation	down-regulates activity	0.57	Kpi-2 kinase domain phosphorylated protein phosphatase-1 (pp1c) at thr(320), which attenuated pp1c activity.	SIGNOR-94631
O75376	P41182	1	binding	up-regulates activity	0.57	The POZ domains of BCL-6 and several other POZ proteins interact with corepressors N-CoR and SMRT.	SIGNOR-252239
O14965	Q14511	2	phosphorylation	up-regulates activity	0.57	HEF1 interacts with AurA and is required for the activation of AurA kinase. Together, these data suggest a model in which an initial interaction of HEF1 with AurA prior to mitotic entry activates AurA, which then phosphorylates HEF1, promoting dissociation of the two proteins.	SIGNOR-262654
O00571	P11940	1	binding	up-regulates activity	0.57	In the present study, we indentified the SG marker PABP1 [poly(A)-binding protein 1] as another direct interaction partner of DDX3. Interestingly, down-regulation of DDX3 interfered with SG assembly, led to nuclear accumulation of PABP1 and reduced cell viability following stress. Conversely, supplementation with a shRNA (short hairpin RNA)-resistant DDX3 restored SG formation, the translocation of PABP1 into SGs and cell survival.	SIGNOR-269201
P31751	P35222	1	phosphorylation	up-regulates	0.57	Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activitywe have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo.	SIGNOR-152958
P29350	P78314	1	dephosphorylation	down-regulates	0.57	Shp-1 dephosphorylates 3bp2 and potentially downregulates 3bp2-mediated t cell antigen receptor signaling	SIGNOR-146508
P29323	O43426	1	phosphorylation	down-regulates	0.57	Ephb2 causes tyrosine phosphorylation in the proline-rich domain of synaptojanin 1, and inhibits both the interaction with endophilin and the 5'-phosphatase activity of synaptojanin 1	SIGNOR-135274
O43541	O43318	1	binding	down-regulates activity	0.57	Smad6 interacts with tak1 and tab1, and smad7 with tab1. The interaction of i-smads with tak1 and/or tab1 implies that several mechanisms exist underlying the repression of the tak1-p38 kinase pathway by i-smads.	SIGNOR-235571
Q9Y297	O15534	1	ubiquitination	down-regulates	0.57	We have found that per1 interacts with both _-trcp1 and _-trcp2 in a manner that depends on casein kinase 1 activity, and depletion of both _-trcp1 and _-trcp2 by rnai leads to dramatic stabilization of per1	SIGNOR-137755
Q00987	Q92630	1	ubiquitination	down-regulates quantity by destabilization	0.57	Under normal conditions, nuclear and not cytoplasmic DYRK2 is ubiquitinated by MDM2, resulting in its constitutive degradation.\|Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus.	SIGNOR-275579
P08908	P08754	1	binding	up-regulates activity	0.57	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-256836
P37173	O95405	1	binding	up-regulates activity	0.57	Sara functions to recruit smad2 to the tgfbeta receptor by controlling the subcellular localization of smad2 and by interacting with the tgfbeta receptor complex	SIGNOR-245093
Q14393	Q06418	1	binding	up-regulates	0.57	We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function.	SIGNOR-34414
Q14511	O14965	2	binding	up-regulates activity	0.57	HEF1 interacts with AurA and is required for the activation of AurA kinase. Together, these data suggest a model in which an initial interaction of HEF1 with AurA prior to mitotic entry activates AurA, which then phosphorylates HEF1, promoting dissociation of the two proteins.	SIGNOR-262653
P06493	O75122	1	phosphorylation	up-regulates activity	0.569	Overall, these results support the idea that phosphorylation of CLASP2 on S1234 by Cdk1, but not phosphorylation of the CLASP2 C terminal by Plk1, is required to maintain mitotic spindle bipolarity.\|We propose that Cdk1 and Plk1 mediate a CLASP2 phospho-switch that is necessary to stabilize KT-MT attachments in human cells.	SIGNOR-278233
O00141	Q92597	1	phosphorylation	up-regulates	0.569	Transient expression of active (sgk1-s422d) and inactive (sgk1-k127a) sgk1 mutants confirmed that activating sgk1 stimulates ndrg1-thr(346/356/366) phosphorylation. dexamethasone (0.2 mum) acutely activated sgk1 and the peak of this response (2-3 h) coincided with the induction of g (na), and both responses were pi3k-dependent. While these data suggest that sgk1 might mediate the rise in g (na), transient expression of the inactive sgk1-k127a mutant did not affect the hormonal induction of g (na) but did suppress the activation of sgk1.	SIGNOR-180821
Q05655	P29353	1	phosphorylation	up-regulates	0.569	Pkc delta phosphorylates p52shca at ser29 to regulate erk activation in response to h2o2.	SIGNOR-149398
O60307	P60484	1	binding	up-regulates	0.569	Pten binds to and is phosphorylated by mast kinases./ Pdz domain-mediated binding to pten facilitates its phosphorylation by mast kinases / pdz domain binding increases pten protein stability.	SIGNOR-138077
Q13976	P78347	1	phosphorylation	up-regulates	0.569	G-kinase phosphorylated tfii-i in vitro and in vivo on ser(371) and ser(743) outside of the interaction domain. G-kinase strongly enhanced tfii-i transactivation of a serum-response element-containing promoter in cos7 cells	SIGNOR-89849
Q99759	O14920	1	phosphorylation	up-regulates activity	0.569	Genetic analysis showed that MEKK3, which is thought to activate IKK2 through phosphorylation (Yang et al., 2001), is necessary for TNF-alpha-induced NF-kappaB activation.\|Our results also suggest that IKK2 is phosphorylated on S177 and S181 on its activation loop by MEKK3.	SIGNOR-279468
P20810	P20807	1	binding	down-regulates activity	0.569	In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains\|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain	SIGNOR-251603
Q9NR28	O15392	2	binding	down-regulates	0.569	Diablo seem to function as a general iaps neutralizer by binding to these protein. Diablo promotes casp9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. mitochondrial survivin associated with smac/diablo, delaying its release.	SIGNOR-80212
Q9UQB8	Q8N8S7	1	binding	up-regulates activity	0.569	We conclude that the interaction of Cdc42 with the partial CRIB motif of IRSp53 relieves an intramolecular, autoinhibitory interaction with the N terminus, allowing the recruitment of Mena to the IRSp53 SH3 domain. This IRSp53:Mena complex initiates actin filament assembly into filopodia.	SIGNOR-268423
P08887	O60674	1	phosphorylation	up-regulates activity	0.569	On binding of IL-6 to its receptor IL-6R, JAK2 is phosphorylated, then STAT3 is phosphorylated by JAK2	SIGNOR-254405
P06239	Q9UQQ2	1	phosphorylation	up-regulates	0.569	In vitro tyrosine phosphorylation of lnk by lck and zap-70. Tyrosine 297 would appear to be an attractive target for phosphorylation within the c-terminal domain. Our studies suggest that although lnk may participate in tcr signaling, its functions are in no way limiting during t cell development or activation.	SIGNOR-48850
Q9Y5X3	P11717	1	binding	down-regulates quantity	0.569	Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures.	SIGNOR-269442
Q9UEW8	Q9UHW9	1	phosphorylation	down-regulates activity	0.569	We observed that in vitro activated STE20/SPS1-related proline/alanine-rich kinase (SPAK) complexed to its regulatory MO25 subunit phosphorylated KCC3 at Ser-96 and that in Xenopus laevis oocytes Ser-96 of human KCC3 is phosphorylated in isotonic conditions and becomes dephosphorylated during incubation in hypotonicity, leading to a dramatic increase in KCC3 function.	SIGNOR-276597
O15105	Q9NYJ8	1	binding	up-regulates	0.569	The formation of smad7-tab2 and smad7-tab3 complexes resulted in the suppression of tnf signaling	SIGNOR-153917
P41240	P12931	1	phosphorylation	down-regulates	0.569	The catalytic activity of the src family of tyrosine kinases is suppressed by phosphorylation on a tyrosine residue located near the c terminus (tyr 527 in c-src), which is catalyzed by c-terminal src kinase (csk).	SIGNOR-179417
P01106	P11802	1	transcriptional regulation	up-regulates quantity by expression	0.569	C-myc directly activates transcription of cyclin d1, cyclin d2 and cdk4, and leads to cdk 4/6 activation	SIGNOR-102734
O15392	Q9NR28	2	binding	down-regulates	0.569	Mitochondrial survivin associated with smac/diablo, delaying its release.	SIGNOR-155361
Q13608	P50542	1	binding	up-regulates activity	0.569	Pex1, Pex6, and Pex26 are involved in Pex5 export from peroxisomes., we found that Pex1 and Pex6 bind to Pex5 (Fig. (Fig.6). Therefore, it is conceivable that Pex1 and Pex6 pull out Pex5 from peroxisome membranes in an ATP-dependent manner.	SIGNOR-253619
Q92696	P20336	1	lipidation	up-regulates activity	0.569	Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional	SIGNOR-265574
P61586	P07737	1	null	up-regulates activity	0.569	We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dia1 (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells.\|Data presented thus far demonstrated that Rho, Dia1, and profilin-1 were required for R-cadherin junction formation in N480 cells.	SIGNOR-253109
P17612	Q08499	1	phosphorylation	up-regulates	0.569	Phosphorylation and activation of a camp-specific phosphodiesterase by the camp-dependent protein kinase.	SIGNOR-42515
Q5S007	O00429	1	phosphorylation	up-regulates activity	0.568	LRRK2 G2019S directly bound to and phosphorylated Drp1 at Threonine595, whereas P110 treatment abolished this phosphorylation.Threonine595 phosphorylation of Drp1 by LRRK2 G2019S is required for Drp1-mediated mitochondrial fragmentation and excessive autophagy	SIGNOR-276495
O43541	Q15750	1	binding	down-regulates	0.568	Smad6 interacts with tak1 and tab1, and smad7 with tab1. The interaction of i-smads with tak1 and/or tab1 implies that several mechanisms exist underlying the repression of the tak1-p38 kinase pathway by i-smads.	SIGNOR-112642
Q03164	Q01196	1	binding	up-regulates quantity by stabilization	0.568	Similar to CBFβ, we show that MLL binds to AML1 abrogating its proteasome-dependent degradation.Furthermore, we demonstrate that MLL binds to a region of AML1 (that is conserved in AML2 and AML3) and increases AML1 (AML2 and AML3) protein levels	SIGNOR-255707
P35625	P50281	1	binding	down-regulates activity	0.568	FAP cilia regulated the expression of TIMP3, a secreted metalloproteinase inhibitor, that inhibited MMP14 to block adipogenesis.	SIGNOR-255908
O43462	Q96BA8	1	cleavage	up-regulates	0.568	Cleavage of oasis by site-1 and site-2 proteases / oasis is cleaved at the membrane under er stress conditions and that its cleaved n-terminal domain translocates into the nucleus;and then activates transcription of target genes	SIGNOR-143820
Q14CB8	P61586	1	gtpase-activating protein	down-regulates activity	0.568	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-260471
P05129	P17302	1	phosphorylation	down-regulates activity	0.568	Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.\|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication.	SIGNOR-249050
O95239	O43663	1	binding	up-regulates activity	0.568	These results suggest that KIF4 and its binding partner PRC1 play essential roles in the organization of central spindles and midzone formation. KIF4 deficiency leads to mislocalization of PRC1, MKLP1, CENP-E and chromosomal passenger proteins	SIGNOR-265988
Q9Y6I7	Q9H2X6	1	ubiquitination	down-regulates	0.568	Ubiquitination and degradation of homeodomain-interacting protein kinase 2 by wd40 repeat/socs box protein wsb-1	SIGNOR-160032
Q9NV92	P46934	1	relocalization	down-regulates activity	0.568	Ndfip1 is primarily localized in the Golgi apparatus where it recruits Nedd4-2 to mediate the degradation of mature hERG proteins during channel trafficking to the plasma membrane. Although Ndfip2 directs Nedd4-2 to the Golgi apparatus, it also recruits Nedd4-2 to the multivesicular bodies (MVBs), which may impair MVB function and impede the degradation of mature hERG proteins mediated by Nedd4-2.	SIGNOR-260995
P50876	P78527	1	polyubiquitination	down-regulates quantity by destabilization	0.568	We show that RNF144A induces ubiquitination of DNA-PKcs in vitro and in vivo and promotes its degradation.	SIGNOR-272213
Q9Y6R4	P45985	1	phosphorylation	up-regulates activity	0.568	When truncated mapkkk4 (deltamapkkk4) was overexpressed in hek293 cells, it was constitutively activeco-expressed map kinase kinase (mkk)-1, mkk-4, mkk-3 and mkk-6 were activated in vivo by deltamapkkk4. All of the above mkks purified from escherichia coli were phosphorylated and activated by deltamapkkk4 immunoprecipitates in vitro.	SIGNOR-62369
P48729	P10070	1	phosphorylation	down-regulates	0.568	Gli2 can also be phosphorylated directly by ck-1 at the non-optimal sites	SIGNOR-146112

Q13131

O75385

2

phosphorylation

up-regulates activity

0.572

Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition.

SIGNOR-173038

Q12852

P45985

1

phosphorylation

up-regulates activity

0.572

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

SIGNOR-279629

P17706

P29353

1

dephosphorylation

down-regulates activity

0.572

However, TC45 inhibited the EGF-induced association of p52Shc with Grb2, which was attributed to the ability of the PTP to recognize specifically p52Shc phosphorylated on Y239. These results indicate that TC45 recognizes not only selected substrates in a cellular context but also specific sites within substrates and thus may regulate discrete signaling events.

SIGNOR-248397

Q9Y6Y8

Q15436

1

binding

up-regulates activity

0.572

The results showed that the N-terminal region of p125 is important for the interaction with Sec23p. We confirmed the interaction between the two proteins by a yeast two-hybrid assay. Overexpression of p125, like that of mammalian Sec23p, caused disorganization of the endoplasmic reticulum-Golgi intermediate compartment and Golgi apparatus, suggesting its role in the early secretory pathway.

SIGNOR-265307

Q15303

P22681

1

binding

up-regulates

0.572

Erbb4 might not be able to directly recruit cbl, and therefore downregulation of this receptor is slow.

SIGNOR-147841

Q16539

Q92945

1

phosphorylation

down-regulates activity

0.572

KSRP, an important factor for AU-rich element (ARE)-directed mRNA decay, undergoes p38-dependent phosphorylation during muscle differentiation. KSRP phosphorylated by p38 displays compromised binding to ARE-containing transcripts and fails to promote their rapid decay, although it retains the ability to interact with the mRNA degradation machinery

SIGNOR-235856

P04626

P03372

1

phosphorylation

up-regulates

0.572

The results presented here show for the first time that er redistribution to the cytoplasm and its interaction with her2 are important downstream effects of her2 overexpression, that erk1/2 is important for er cytoplasmic localization, and that subcellular localization of er may play a mechanistic role in determining the responsiveness of breast cancer cells to tamoxifen.

SIGNOR-124962

O75385

Q13131

2

phosphorylation

down-regulates activity

0.572

Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity.

SIGNOR-173047

O60346

P23443

1

dephosphorylation

down-regulates activity

0.572

Here we report the identification of ribosomal protein S6 kinase 1 (S6K1) as a novel substrate of PHLPP.

SIGNOR-237454

O43663

Q02241

1

binding

up-regulates activity

0.572

These data indicate that PRC1 binds to KIF4, MKLP1 and CENP-E during late mitosis; however, it apparently does not interact simultaneously with more than one of these motor proteins.

SIGNOR-265989

O15530

Q04759

1

phosphorylation

up-regulates

0.572

We demonstrate that 3-phosphoinositide-dependent kinase 1 (pdk1) has an essential role in this pathway by regulating the activation of pkc and through signal-dependent recruiting of both pkc and card11 to lipid rafts.

SIGNOR-134869

P12931

P06396

1

phosphorylation

up-regulates

0.572

Identification of tyr438 as the major in vitro c-src phosphorylation site in human gelsolin recently

SIGNOR-67014

P35548

P56178

2

binding

down-regulates activity

0.572

We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities.

SIGNOR-240990

P29459

P42701

1

binding

up-regulates

0.572

Like il-12, il-23 binds to the il-12r subunit il-12rbeta1.

SIGNOR-87677

P31749

Q9Y3M2

1

phosphorylation

up-regulates activity

0.572

These observations argue that Chibby is a bona fide Akt substrate and that Akt kinase phosphorylates Chibby at the serine 20 residue.

SIGNOR-279002

P06241

P43146

1

phosphorylation

up-regulates activity

0.572

Fyn tyrosine kinase, but not Src, regulates the phosphorylation of DCC in N1E-115 neuroblastoma cells.Both DCC phosphorylation and Netrin-1-induced axon outgrowth are impaired in Fyn(-/-) CN and spinal cord explants. We propose that DCC is regulated by tyrosine phosphorylation and that Fyn is essential for the response of axons to Netrin-1. these results show that DCC is phosphorylated by Fyn, but not Src, in N1E-115 cells, and that tyrosines 1261 and 1418 are the major phosphorylation sites of Fyn in vivo.

SIGNOR-268176

P06493

Q14674

1

phosphorylation

down-regulates

0.572

Both cdc2/cyclinb1 and mapk (erk2) efficiently phosphorylate separase at its major inhibitory site in vitro

SIGNOR-113126

O15111

O43524

1

phosphorylation

down-regulates

0.572

Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation.

SIGNOR-124203

Q6XZF7

P60953

1

guanine nucleotide exchange factor

up-regulates activity

0.572

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-260547

P38435

P04070

1

carboxylation

up-regulates activity

0.572

Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z

SIGNOR-265925

O15297

O96017

1

dephosphorylation

up-regulates activity

0.572

an in vitro phosphatase assay revealed that Wip1 (WT), but not Wip1 (D314A), dephosphorylates Thr68 on phosphorylated Chk2 in vitro, resulting in the inhibition of Chk2 kinase activity toward glutathione S-transferase-Cdc25C.

SIGNOR-248318

P56178

P35548

2

binding

down-regulates activity

0.572

We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities.

SIGNOR-240925

O96014

O75581

1

binding

up-regulates activity

0.572

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-131637

Q96BY2

Q9NS23

1

binding

up-regulates activity

0.572

Modulator of apoptosis 1 (MOAP-1) is a BH3-like protein that plays key roles in cell death or apoptosis. It is an integral partner to the tumor suppressor protein, Ras association domain family 1A (RASSF1A), and functions to activate the Bcl-2 family pro-apoptotic protein Bax.

SIGNOR-272914

Q92973

P09651

1

relocalization

up-regulates activity

0.572

TNPO1 only mediates the nuclear import of a subset of proteins.|Among TNPO1 cargos, the most extensively characterized is the RNA binding protein heterogeneous nuclear ribonucleoprotein 1 (hnRNPA1) (27), which functions in several processes including mRNA biogenesis and promotion of transcription factor activity (28–30). NPC protein NUP153 is also a target for TNPO1-mediated nuclear import

SIGNOR-262099

O15391

P04637

1

transcriptional regulation

up-regulates quantity by expression

0.572

YY2 activated the p53 promoter. However, in contrast to YY1, which represses the activity of c-Fos, YY2 increased the activity of the c-Fos promoter.

SIGNOR-266213

Q16539

P19634

1

phosphorylation

up-regulates

0.571

Trophic factor withdrawal: p38 mitogen-activated protein kinase activates nhe1, which induces intracellular alkalinization. activated p38 mapk directly phosphorylated the c terminus of nhe1 within a 40-amino-acid region. Analysis by mass spectroscopy identified four phosphorylation sites on nhe1, thr 717, ser 722, ser 725, and ser 728.

SIGNOR-111043

P21728

P38405

1

binding

up-regulates activity

0.571

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-256939

O60729

Q16659

1

dephosphorylation

down-regulates quantity by destabilization

0.571

Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3.

SIGNOR-248336

Q13315

Q15831

1

phosphorylation

up-regulates

0.571

We demonstrate that both dna-pk and atm efficiently phosphorylate lkb1 at thr-366 in vitro and provide evidence that atm mediates this phosphorylation in vivo.

SIGNOR-92873

O94989

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.571

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-260540

P50613

P24941

2

phosphorylation

up-regulates activity

0.571

Phosphorylation of monomeric human CDK2 by CAK1 is more efficient than phosphorylation of the binary CDK2-cyclin A complex. Phosphorylated CDK2 exhibits histone H1 kinase activity corresponding to approximately 0.3% of that observed with the fully activated phosphorylated CDK2-cyclin A complex. Fluorescence measurements have shown that Thr160 phosphorylation increases the affinity of CDK2 for both histone substrate and ATP and decreases its affinity for ADP.

SIGNOR-250768

Q13387

P45984

1

binding

up-regulates

0.571

These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins.

SIGNOR-70866

Q6ZW49

Q02962

1

binding

up-regulates activity

0.571

PTIP promotes assembly of the ALR complex and H3K4 methylation at a PAX2-binding DNA element. Without PTIP, Pax2 binds to this element but does not assemble the ALR complex

SIGNOR-251711

Q12837

P03372

1

binding

up-regulates activity

0.571

the POU domain of Brn-3a and Brn-3b was shown to interact with the DNA-binding domain of the ER. Brn-3-ER interactions also affect transcriptional activity of an ERE-containing promoter, such that in estradiol-stimulated cells, Brn-3b strongly activated the promoter via the ERE, while Brn-3a had a mild inhibitory effect.

SIGNOR-241208

Q9GZT5

O75197

1

binding

up-regulates

0.571

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-131619

Q14703

Q96BA8

1

cleavage

up-regulates

0.571

Cleavage of oasis by site-1 and site-2 proteases / oasis is cleaved at the membrane under er stress conditions and that its cleaved n-terminal domain translocates into the nucleus;and then activates transcription of target genes

SIGNOR-143785

P24941

P50613

2

phosphorylation

up-regulates

0.571

Threonine-170 of cdk7 is phosphorylated in vitro by cdk2. Full activation of cdk7 requires phorylation of a conserved threonine residue at position 170 in its own t loop.

SIGNOR-85013

Q14258

P31947

1

ubiquitination

down-regulates quantity by destabilization

0.571

Here we show that Efp is a RING-finger-dependent ubiquitin ligase (E3) that targets proteolysis of 14-3-3 sigma, a negative cell cycle regulator that causes G2 arrest.

SIGNOR-271548

Q13547

Q04206

1

binding

down-regulates

0.571

Phosphorylation at thr505 by the chk1 inhibits rela transactivation and results in its increased association with hdac1.

SIGNOR-151425

P07949

Q14451

1

binding

up-regulates

0.571

Grb7 and grb10, likely relay signals emanating from ret to other, as yet, unidentified targets within the cell

SIGNOR-41765

P07384

Q15078

1

cleavage

up-regulates activity

0.571

Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain

SIGNOR-251583

Q16576

P26358

1

binding

down-regulates activity

0.571

AMPK inhibited DNMT1 through phosphorylation of Ser730 in DNMT1 and Ser314 in RBBP7|association with RBBP7 could inhibit DNMT1

SIGNOR-264785

P19525

P04637

1

phosphorylation

up-regulates

0.571

The double-stranded rna activated protein kinase pkr physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro.

SIGNOR-68033

Q9NRL3

P67775

1

binding

up-regulates activity

0.571

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-261697

P06239

P04234

1

phosphorylation

up-regulates activity

0.571

Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex.

SIGNOR-259929

Q13315

P54274

1

phosphorylation

up-regulates activity

0.571

Telomeric protein pin2/trf1 as an important atm target in response to double strand dna breaks. activated atm directly phosphorylated pin2/trf1 preferentially on the conserved ser(219)-gln site in vitro and in vivo.

SIGNOR-108419

P00813

P30542

1

binding

up-regulates activity

0.571

The results show that human ADA, apart from reducing the adenosine concentration and thus preventing A(1)R desensitization, binds to A(1)R behaving as an allosteric effector that markedly enhances agonist affinity and increases receptor functionality.

SIGNOR-269105

P17252

P48058

1

phosphorylation

up-regulates

0.57

Receptor internalization, altered;intracellular localization

SIGNOR-97554

P06400

P00519

1

binding

down-regulates

0.57

A domain in the c-terminus of rb, outside of the a/b pocket, binds to the atp-binding lobe of the c-abl tyrosine kinase, resulting in kinase inhibition.

SIGNOR-37139

P61244

Q8IWI9

1

binding

up-regulates activity

0.57

the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences.

SIGNOR-240261

Q9UNE7

P84022

1

ubiquitination

down-regulates quantity by destabilization

0.57

These results suggest that Smad3 could be easily ubiquitinated and degraded by CHIP when Hsp90 activity was inhibited.To demonstrate the role of Hsp70 and Hsp90 on the regulation of Smad3 by CHIP, we over-expressed Hsp70 and Hsp90 in mammalian cells.

SIGNOR-278785

Q8IWU2

P62136

1

phosphorylation

down-regulates activity

0.57

Kpi-2 kinase domain phosphorylated protein phosphatase-1 (pp1c) at thr(320), which attenuated pp1c activity.

SIGNOR-94631

O75376

P41182

1

binding

up-regulates activity

0.57

The POZ domains of BCL-6 and several other POZ proteins interact with corepressors N-CoR and SMRT.

SIGNOR-252239

O14965

Q14511

2

phosphorylation

up-regulates activity

0.57

HEF1 interacts with AurA and is required for the activation of AurA kinase. Together, these data suggest a model in which an initial interaction of HEF1 with AurA prior to mitotic entry activates AurA, which then phosphorylates HEF1, promoting dissociation of the two proteins.

SIGNOR-262654

O00571

P11940

1

binding

up-regulates activity

0.57

In the present study, we indentified the SG marker PABP1 [poly(A)-binding protein 1] as another direct interaction partner of DDX3. Interestingly, down-regulation of DDX3 interfered with SG assembly, led to nuclear accumulation of PABP1 and reduced cell viability following stress. Conversely, supplementation with a shRNA (short hairpin RNA)-resistant DDX3 restored SG formation, the translocation of PABP1 into SGs and cell survival.

SIGNOR-269201

P31751

P35222

1

phosphorylation

up-regulates

0.57

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

SIGNOR-152958

P29350

P78314

1

dephosphorylation

down-regulates

0.57

Shp-1 dephosphorylates 3bp2 and potentially downregulates 3bp2-mediated t cell antigen receptor signaling

SIGNOR-146508

P29323

O43426

1

phosphorylation

down-regulates

0.57

Ephb2 causes tyrosine phosphorylation in the proline-rich domain of synaptojanin 1, and inhibits both the interaction with endophilin and the 5'-phosphatase activity of synaptojanin 1

SIGNOR-135274

O43541

O43318

1

binding

down-regulates activity

0.57

Smad6 interacts with tak1 and tab1, and smad7 with tab1. The interaction of i-smads with tak1 and/or tab1 implies that several mechanisms exist underlying the repression of the tak1-p38 kinase pathway by i-smads.

SIGNOR-235571

Q9Y297

O15534

1

ubiquitination

down-regulates

0.57

We have found that per1 interacts with both _-trcp1 and _-trcp2 in a manner that depends on casein kinase 1 activity, and depletion of both _-trcp1 and _-trcp2 by rnai leads to dramatic stabilization of per1

SIGNOR-137755

Q00987

Q92630

1

ubiquitination

down-regulates quantity by destabilization

0.57

Under normal conditions, nuclear and not cytoplasmic DYRK2 is ubiquitinated by MDM2, resulting in its constitutive degradation.|Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus.

SIGNOR-275579

P08908

P08754

1

binding

up-regulates activity

0.57

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-256836

P37173

O95405

1

binding

up-regulates activity

0.57

Sara functions to recruit smad2 to the tgfbeta receptor by controlling the subcellular localization of smad2 and by interacting with the tgfbeta receptor complex

SIGNOR-245093

Q14393

Q06418

1

binding

up-regulates

0.57

We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function.

SIGNOR-34414

Q14511

O14965

2

binding

up-regulates activity

0.57

HEF1 interacts with AurA and is required for the activation of AurA kinase. Together, these data suggest a model in which an initial interaction of HEF1 with AurA prior to mitotic entry activates AurA, which then phosphorylates HEF1, promoting dissociation of the two proteins.

SIGNOR-262653

P06493

O75122

1

phosphorylation

up-regulates activity

0.569

Overall, these results support the idea that phosphorylation of CLASP2 on S1234 by Cdk1, but not phosphorylation of the CLASP2 C terminal by Plk1, is required to maintain mitotic spindle bipolarity.|We propose that Cdk1 and Plk1 mediate a CLASP2 phospho-switch that is necessary to stabilize KT-MT attachments in human cells.

SIGNOR-278233

O00141

Q92597

1

phosphorylation

up-regulates

0.569

Transient expression of active (sgk1-s422d) and inactive (sgk1-k127a) sgk1 mutants confirmed that activating sgk1 stimulates ndrg1-thr(346/356/366) phosphorylation. dexamethasone (0.2 mum) acutely activated sgk1 and the peak of this response (2-3 h) coincided with the induction of g (na), and both responses were pi3k-dependent. While these data suggest that sgk1 might mediate the rise in g (na), transient expression of the inactive sgk1-k127a mutant did not affect the hormonal induction of g (na) but did suppress the activation of sgk1.

SIGNOR-180821

Q05655

P29353

1

phosphorylation

up-regulates

0.569

Pkc delta phosphorylates p52shca at ser29 to regulate erk activation in response to h2o2.

SIGNOR-149398

O60307

P60484

1

binding

up-regulates

0.569

Pten binds to and is phosphorylated by mast kinases./ Pdz domain-mediated binding to pten facilitates its phosphorylation by mast kinases / pdz domain binding increases pten protein stability.

SIGNOR-138077

Q13976

P78347

1

phosphorylation

up-regulates

0.569

G-kinase phosphorylated tfii-i in vitro and in vivo on ser(371) and ser(743) outside of the interaction domain. G-kinase strongly enhanced tfii-i transactivation of a serum-response element-containing promoter in cos7 cells

SIGNOR-89849

Q99759

O14920

1

phosphorylation

up-regulates activity

0.569

Genetic analysis showed that MEKK3, which is thought to activate IKK2 through phosphorylation (Yang et al., 2001), is necessary for TNF-alpha-induced NF-kappaB activation.|Our results also suggest that IKK2 is phosphorylated on S177 and S181 on its activation loop by MEKK3.

SIGNOR-279468

P20810

P20807

1

binding

down-regulates activity

0.569

In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain

SIGNOR-251603

Q9NR28

O15392

2

binding

down-regulates

0.569

Diablo seem to function as a general iaps neutralizer by binding to these protein. Diablo promotes casp9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. mitochondrial survivin associated with smac/diablo, delaying its release.

SIGNOR-80212

Q9UQB8

Q8N8S7

1

binding

up-regulates activity

0.569

We conclude that the interaction of Cdc42 with the partial CRIB motif of IRSp53 relieves an intramolecular, autoinhibitory interaction with the N terminus, allowing the recruitment of Mena to the IRSp53 SH3 domain. This IRSp53:Mena complex initiates actin filament assembly into filopodia.

SIGNOR-268423

P08887

O60674

1

phosphorylation

up-regulates activity

0.569

On binding of IL-6 to its receptor IL-6R, JAK2 is phosphorylated, then STAT3 is phosphorylated by JAK2

SIGNOR-254405

P06239

Q9UQQ2

1

phosphorylation

up-regulates

0.569

In vitro tyrosine phosphorylation of lnk by lck and zap-70. Tyrosine 297 would appear to be an attractive target for phosphorylation within the c-terminal domain. Our studies suggest that although lnk may participate in tcr signaling, its functions are in no way limiting during t cell development or activation.

SIGNOR-48850

Q9Y5X3

P11717

1

binding

down-regulates quantity

0.569

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

SIGNOR-269442

Q9UEW8

Q9UHW9

1

phosphorylation

down-regulates activity

0.569

We observed that in vitro activated STE20/SPS1-related proline/alanine-rich kinase (SPAK) complexed to its regulatory MO25 subunit phosphorylated KCC3 at Ser-96 and that in Xenopus laevis oocytes Ser-96 of human KCC3 is phosphorylated in isotonic conditions and becomes dephosphorylated during incubation in hypotonicity, leading to a dramatic increase in KCC3 function.

SIGNOR-276597

O15105

Q9NYJ8

1

binding

up-regulates

0.569

The formation of smad7-tab2 and smad7-tab3 complexes resulted in the suppression of tnf signaling

SIGNOR-153917

P41240

P12931

1

phosphorylation

down-regulates

0.569

The catalytic activity of the src family of tyrosine kinases is suppressed by phosphorylation on a tyrosine residue located near the c terminus (tyr 527 in c-src), which is catalyzed by c-terminal src kinase (csk).

SIGNOR-179417

P01106

P11802

1

transcriptional regulation

up-regulates quantity by expression

0.569

C-myc directly activates transcription of cyclin d1, cyclin d2 and cdk4, and leads to cdk 4/6 activation

SIGNOR-102734

O15392

Q9NR28

2

binding

down-regulates

0.569

Mitochondrial survivin associated with smac/diablo, delaying its release.

SIGNOR-155361

Q13608

P50542

1

binding

up-regulates activity

0.569

Pex1, Pex6, and Pex26 are involved in Pex5 export from peroxisomes., we found that Pex1 and Pex6 bind to Pex5 (Fig. (Fig.6). Therefore, it is conceivable that Pex1 and Pex6 pull out Pex5 from peroxisome membranes in an ATP-dependent manner.

SIGNOR-253619

Q92696

P20336

1

lipidation

up-regulates activity

0.569

Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional

SIGNOR-265574

P61586

P07737

1

null

up-regulates activity

0.569

We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dia1 (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells.|Data presented thus far demonstrated that Rho, Dia1, and profilin-1 were required for R-cadherin junction formation in N480 cells.

SIGNOR-253109

P17612

Q08499

1

phosphorylation

up-regulates

0.569

Phosphorylation and activation of a camp-specific phosphodiesterase by the camp-dependent protein kinase.

SIGNOR-42515

Q5S007

O00429

1

phosphorylation

up-regulates activity

0.568

LRRK2 G2019S directly bound to and phosphorylated Drp1 at Threonine595, whereas P110 treatment abolished this phosphorylation.Threonine595 phosphorylation of Drp1 by LRRK2 G2019S is required for Drp1-mediated mitochondrial fragmentation and excessive autophagy

SIGNOR-276495

O43541

Q15750

1

binding

down-regulates

0.568

Smad6 interacts with tak1 and tab1, and smad7 with tab1. The interaction of i-smads with tak1 and/or tab1 implies that several mechanisms exist underlying the repression of the tak1-p38 kinase pathway by i-smads.

SIGNOR-112642

Q03164

Q01196

1

binding

up-regulates quantity by stabilization

0.568

Similar to CBFβ, we show that MLL binds to AML1 abrogating its proteasome-dependent degradation.Furthermore, we demonstrate that MLL binds to a region of AML1 (that is conserved in AML2 and AML3) and increases AML1 (AML2 and AML3) protein levels

SIGNOR-255707

P35625

P50281

1

binding

down-regulates activity

0.568

FAP cilia regulated the expression of TIMP3, a secreted metalloproteinase inhibitor, that inhibited MMP14 to block adipogenesis.

SIGNOR-255908

O43462

Q96BA8

1

cleavage

up-regulates

0.568

Cleavage of oasis by site-1 and site-2 proteases / oasis is cleaved at the membrane under er stress conditions and that its cleaved n-terminal domain translocates into the nucleus;and then activates transcription of target genes

SIGNOR-143820

Q14CB8

P61586

1

gtpase-activating protein

down-regulates activity

0.568

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-260471

P05129

P17302

1

phosphorylation

down-regulates activity

0.568

Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication.

SIGNOR-249050

O95239

O43663

1

binding

up-regulates activity

0.568

These results suggest that KIF4 and its binding partner PRC1 play essential roles in the organization of central spindles and midzone formation. KIF4 deficiency leads to mislocalization of PRC1, MKLP1, CENP-E and chromosomal passenger proteins

SIGNOR-265988

Q9Y6I7

Q9H2X6

1

ubiquitination

down-regulates

0.568

Ubiquitination and degradation of homeodomain-interacting protein kinase 2 by wd40 repeat/socs box protein wsb-1

SIGNOR-160032

Q9NV92

P46934

1

relocalization

down-regulates activity

0.568

Ndfip1 is primarily localized in the Golgi apparatus where it recruits Nedd4-2 to mediate the degradation of mature hERG proteins during channel trafficking to the plasma membrane. Although Ndfip2 directs Nedd4-2 to the Golgi apparatus, it also recruits Nedd4-2 to the multivesicular bodies (MVBs), which may impair MVB function and impede the degradation of mature hERG proteins mediated by Nedd4-2.

SIGNOR-260995

P50876

P78527

1

polyubiquitination

down-regulates quantity by destabilization

0.568

We show that RNF144A induces ubiquitination of DNA-PKcs in vitro and in vivo and promotes its degradation.

SIGNOR-272213

Q9Y6R4

P45985

1

phosphorylation

up-regulates activity

0.568

When truncated mapkkk4 (deltamapkkk4) was overexpressed in hek293 cells, it was constitutively activeco-expressed map kinase kinase (mkk)-1, mkk-4, mkk-3 and mkk-6 were activated in vivo by deltamapkkk4. All of the above mkks purified from escherichia coli were phosphorylated and activated by deltamapkkk4 immunoprecipitates in vitro.

SIGNOR-62369

P48729

P10070

1

phosphorylation

down-regulates

0.568

Gli2 can also be phosphorylated directly by ck-1 at the non-optimal sites

SIGNOR-146112