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
Q9Y644	P46531	1	binding	up-regulates	0.647	We demonstrate that egf 12, a portion of the ligand-binding site, is modified with o-fucose and that this site is evolutionarily conserved. We also show that endogenous fringe proteins in chinese hamster ovary cells (lunatic fringe and radical fringe) as well as exogenous manic fringe modify o-fucose on many but not all egf repeats of mouse notch1.	SIGNOR-96561
O75460	P17861	1	phosphorylation	up-regulates activity	0.647	IRE1\u03b1 phosphorylates and activates the XBP1 transcription factor XBP1 via its kinase activity.	SIGNOR-279712
P67775	P27361	1	dephosphorylation	down-regulates	0.647	P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3).	SIGNOR-103162
O75460	P17861-2	1	post transcriptional regulation	up-regulates quantity by expression	0.647	Upon activation by oligomerization and autophosphorylation, the cytosolic RNase domain of IRE1 mediates an unconventional splicing of the mRNA of X-box-binding protein 1 (XBP1). The spliced and frameshifted transcript encodes XBP1S, a bZIP transcription factor inducing the expression of numerous UPR effector genes that enhance ER folding capacity.	SIGNOR-260183
P31749	P08670	1	phosphorylation	up-regulates quantity by stabilization	0.647	The binding of akt (tail region) to vim (head region) results in vim ser39 phosphorylation enhancing the ability of vim to induce motility and invasion while protecting vim from caspase-induced proteolysis.	SIGNOR-252511
P49662	P57764	1	cleavage	up-regulates activity	0.647	Co-expression of GSDMD with caspase-1, 4, 5 or 11 but not apoptotic caspases (caspase-2, 8 and 9) in 293T cells induced the same cleavage of GSDMD\|inflammatory caspases specifically cleave GSDMD after the 272FLTD275 (or 273LLSD276) sequence \|	SIGNOR-256417
P19174	Q07889	1	binding	up-regulates	0.647	We provide evidence that sos1, a p21ras-specific guanine nucleotide exchange factor, directly binds to the sh3 domain of plc-gamma1, and that the sh3 domain of plc-gamma1 is involved in sos1-mediated p21ras activation.	SIGNOR-80024
Q16620	P19174	1	phosphorylation	up-regulates activity	0.647	Both Shc and PLCgamma1 are phosphorylated by TrkB, thereby initiating Shc/Ras/MAP kinase and PLCgamma1 signaling respectively.\|We conclude that activation of pY783 PLCgamma1 is due mainly to TrkB activation in these models and that TrkB induced PLCgamma1 signaling promotes limbic epileptogenesis.	SIGNOR-279241
Q05655	P35568	1	phosphorylation	down-regulates activity	0.646	Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101).	SIGNOR-249267
P56706	Q9ULW2	1	binding	up-regulates	0.646	Wnt7b can bind to fzd1 and -10 on the cell surface and cooperatively activate canonical wnt signaling	SIGNOR-137934
Q13464	P24844	1	phosphorylation	up-regulates	0.646	Rho-kinase phosphorylates the mlc of intact myosin and activates its mgatpase activity in a gtp_?Rho-dependent manner.	SIGNOR-43031
Q96J02	Q7Z434	1	ubiquitination	down-regulates quantity by destabilization	0.646	These data collectively indicate that AIP4 is the E3 ligase for MAVS.\|We generated single substitutions (K362A, K371A or K420A) and combined point substitutions of MAVS and tested their degradation. K371A or K420A MAVS showed partial resistance to PCBP2-induced degradation (data not shown), whereas MAVS with the combined substitutions K371A and K420A (KK-AA) completely withstood the degradation	SIGNOR-260362
Q15366	Q7Z434	1	binding	down-regulates quantity by destabilization	0.646	PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4.	SIGNOR-260360
O00755	Q9NPG1	1	binding	up-regulates activity	0.646	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-131897
P27540	P04798	1	transcriptional regulation	up-regulates quantity by expression	0.646	Kaempferol proved to be capable of inhibiting binding of agonist and agonist-induced formation of the AHR/ARNT DNA-binding complex and upregulation of the AHR target gene, CYP1A1.	SIGNOR-259910
Q16828	Q13164	1	dephosphorylation	down-regulates activity	0.646	However, whilst the interaction itself might be difficult to monitor, DUSP6 should still be able to promote the de-phosphorylation of ERK5 in cells if it is an ERK5 phosphatase.To test this HEK293 cells were transiently transfected with HA-ERK2 or HA-ERK5 together with EGFP-MEK1E (a constitutively active version of MEK1) or EGFP-MEK5D (a constitutively active version of MEK5).\|Whilst one can envisage scenarios in which the interaction between DUSPs and their substrates might be transient, DUSP6 should still be able to promote the de-phosphorylation and inactivation of ERK5.	SIGNOR-277007
P18031	P29597	1	dephosphorylation	down-regulates activity	0.646	Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5.	SIGNOR-134564
P06239	Q9UN19	1	phosphorylation	up-regulates activity	0.646	Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell lines\|yrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins.	SIGNOR-249373
Q14164	Q9UHD2	2	binding	up-regulates activity	0.646	STING recruits TBK1 and IKKε and forms the TBK1-IKKε complex via the association with TRAF3. The TBK1 complex induces the phosphorylation, dimerization, and nuclear translocation of IRF3.	SIGNOR-260155
P29350	P23458	1	dephosphorylation	down-regulates	0.646	We find, for the first time, that shp-1 down-regulates the level of tyk2 kinase in h9 cells and of jak1 kinase in htb26 cells, by accelerating their degradation.	SIGNOR-119197
P31751	Q99683	1	phosphorylation	down-regulates activity	0.646	Akt2 interacts with and phosphorylates ask1 at ser-83 resulting in inhibition of its kinase activity	SIGNOR-100588
Q9UHD2	Q14164	2	binding	up-regulates activity	0.646	Whereas nemo assembles some but not all ikk complexes [12,13], recent reports provide strong experimental evidence for a role of tank [also called traf-interacting protein (i-traf)], nak-associated protein (nap1) and similar to nap1 tbk1 adaptor (sintbad) in the assembly of tbk1 and ikk-e kinase complexes that phosphorylate irf3 and irf7 and promote type i ifn gene induction	SIGNOR-178053
O43318	O14733	1	phosphorylation	up-regulates activity	0.645	Upon TNFα stimulation, MEKK1, ASK1, and TAK1 phosphorylate and activate MKK7, which in turn activates JNK	SIGNOR-274146
Q9P2B4	O43815	1	binding	up-regulates activity	0.645	Although CTTNBP2 and CTTNBP2NL are different in terms of tissue and subcellular distribution, our data indicate that, similar to CTTNBP2NL, CTTNBP2 associates with members of the striatin family, namely striatin and zinedin. Moreover, CTTNBP2 is critical for the distribution of striatin and zinedin in dendritic spines. The role of CTTNBP2 in the regulation of the synaptic distribution of striatin and zinedin suggests that CTTNBP2 regulates synaptic signaling through PP2A.	SIGNOR-261702
Q9NTX7	O15169	1	ubiquitination	down-regulates quantity by destabilization	0.645	Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation.	SIGNOR-263335
Q9NPF7	P42701	1	binding	up-regulates	0.645	Like il-12, il-23 binds to the il-12r subunit il-12rbeta1.	SIGNOR-87739
Q9Y3M8	P61586	1	gtpase-activating protein	down-regulates activity	0.645	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260521
P49336	P51946	1	phosphorylation	down-regulates	0.645	Cdk8 phosphorylates mammalian cyclin h in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of tfiih to activate transcription and its ctd kinase activity	SIGNOR-82033
Q13153	P35240	1	phosphorylation	down-regulates	0.645	Merlin contains a c-terminal serine 518, which is phosphorylated both by p21-activated kinase (pak) and protein kinase a (pka) (shaw et al., 2001;kissil et al., 2002;xiao et al., 2002;alfthan et al., 2004). Phosphorylation at this site is predicted to result in a more open conformation incapable of inhibiting cell growth,	SIGNOR-159764
P27361	P15056	1	phosphorylation	down-regulates	0.645	Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity.	SIGNOR-144827
Q07326	Q5H8A4	1	binding	up-regulates quantity by stabilization	0.645	We show that the human homolog of Gpi7p, termed hGPI7, binds to and is stabilized by PIG-F and that hGPI7 competes with PIG-O for binding to PIG-F. PIG-F Binds to and Stabilizes hGPI7 and PIG-O Independently. These results are consistent with the hypothesis that overexpression of hGPI7 decreases the biosynthetic activity of PIG-O by decreasing the available PIG-F, thereby destabilizing PIG-O.	SIGNOR-261358
P22681	P16333	1	ubiquitination	down-regulates quantity by destabilization	0.644	Taken together, these results show that lysine 178 in Nck1 is the acceptor site for ubiquitin transferred by c-Cbl, and that the ubiquitination of Nck1 by c-Cbl is blocked in the presence of synaptopodin.	SIGNOR-278606
Q9NR61	P46531	1	binding	up-regulates activity	0.644	Expression analysis of known notch ligands suggests that dll4 is the only ligand that exhibits spatial and temporal expression consistent with the activation of notch1 and notch4 during vascular development. The identification of dll4 reveals a candidate ligand for notch receptors involved in blood vessel biology	SIGNOR-112649
P05155	P00748	1	binding	down-regulates activity	0.644	C1INH is a serine protease inhibitor (serpin) that acts on both the complement pathway and the contact system and is the main inhibitor of the contact system by targeting both FXIIa and PK 9. Additionally, FXIIa can be inhibited by α1‐antitrypsin and plasminogen activator inhibitor‐1 (PAI‐1).	SIGNOR-263517
P78504	Q9UM47	1	binding	up-regulates	0.644	Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch.	SIGNOR-179625
Q96J02	P46531	1	ubiquitination	down-regulates	0.644	Itch binds to the n-terminal portion of the notch intracellular domain via its ww domains and promotes ubiquitination of notch through its hect ubiquitin ligase domain.	SIGNOR-80702
Q12955	Q01082	1	binding	up-regulates activity	0.644	Ankyrin-G is a molecular partner of E-cadherin in epithelial cells and early embryos. Ankyrin-G also recruits beta-2-spectrin to E-cadherin-beta-catenin complexes, thus providing a direct connection between E-cadherin and the spectrin/actin skeleton.	SIGNOR-266711
P57059	Q53ET0	1	phosphorylation	down-regulates	0.644	These results suggested that sik1 could phosphorylate all torcs and thereby repress their transactivation activities.	SIGNOR-147707
P28482	P08047	1	phosphorylation	up-regulates	0.644	Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. Mutation of these sites to alanines decreases by half the mapk-dependent transcriptional activity of sp1. Phosphorylated extracellular signal-regulated protein kinases 1 and 2 phosphorylate sp1 on serine 59 and regulate cellular senescence via transcription of p21sdi1/cip1/waf1.	SIGNOR-116158
Q9HCK8	P35222	1	binding	down-regulates	0.644	Duplin (axis duplication inhibitor) interacts with beta-catenin and prevents its binding to tcf, thereby inhibiting downstream wnt signaling	SIGNOR-128976
Q9HAU4	O15198	1	ubiquitination	down-regulates	0.644	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps	SIGNOR-193390
P11309	O95644	1	phosphorylation	up-regulates activity	0.643	Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells.	SIGNOR-276775
Q13526	Q14653	1	binding	down-regulates quantity by destabilization	0.643	Here we report that activation of IRF3 is negatively regulated by the peptidyl-prolyl isomerase Pin1. After stimulation by double-stranded RNA, induced phosphorylation of the Ser339–Pro340 motif of IRF3 led to its interaction with Pin1 and finally polyubiquitination and then proteasome-dependent degradation of IRF3. Suppression of Pin1 by RNA interference or genetic deletion resulted in enhanced IRF-3-dependent production of interferon-beta, with consequent reduction of virus replication.	SIGNOR-252256
Q13535	P30307	1	phosphorylation	up-regulates activity	0.643	We also found that activated ATR phosphorylates CDC25C (Cell Division Cycle 25C) at serine 216, which in turn inactivates the cyclin B1/Cyclin-Dependent Kinase 1(CDK1) complex and induces G2-phase arrest.	SIGNOR-279008
P30556	P50148	1	binding	up-regulates activity	0.643	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-257017
Q9UQQ2	O60674	1	binding	down-regulates activity	0.643	we identified Lnk as a physiological negative regulator of JAK2 in stem cells and TPO/Mpl/JAK2/Lnk as a major regulatory pathway in controlling stem cell self-renewal and quiescence. we identify a direct interaction between Lnk and the Mpl/JAK2 complex that regulates various HSC functions.	SIGNOR-260075
P10082	Q15761	1	binding	up-regulates	0.643	Maml3 forms complexes in vivo with icn and csl and functiosn as transcriptional coactivators for notch signaling.	SIGNOR-114749
Q16825	P12931	1	dephosphorylation	up-regulates	0.643	Ptpd1 activates src tyrosine kinase and increases the magnitude and duration of epidermal growth factor (egf) signaling.	SIGNOR-124774
Q13535	P30304	1	phosphorylation	down-regulates activity	0.643	ATR and CHK1 mediated loss of CDC25A activity suspends CDKs, such as CDK2, in an inactive phosphorylated state, blocking initiation of DNA replication origins.\|In the presence of replication stalling, activated CHK1 and ATR phosphorylates CDC25A and promotes its degradation.	SIGNOR-280183
Q00535	P46527	1	phosphorylation	down-regulates activity	0.643	CDK5 knockdown in HEY cells significantly prolonged the half-life of TP53 and p27 Kip1 proteins (XREF_FIG).\|During neural stem cell differentiation, CDK5 can phosphorylate p27 at Thr187 and at Ser10, promoting neurite outgrowth as neurons differentiate .	SIGNOR-279681
O00238	Q15797	1	phosphorylation	up-regulates	0.643	Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression.	SIGNOR-187190
P06239	P51692	1	phosphorylation	up-regulates activity	0.643	A constitutively active Lck kinase promotes cell proliferation and resistance to apoptosis through signal transducer and activator of transcription 5b activation.\|Expression of the active Lck kinase induces both tyrosine phosphorylation and DNA binding activity of signal transducer and activator of transcription 5b (STAT5b), a STAT family member activated in a variety of tumor cells.	SIGNOR-279056
Q00987	P38936	1	binding	down-regulates quantity by destabilization	0.643	MDM2 facilitates p21 degradation independent of ubiquitination and the E3 ligase function of MDM2. Instead, MDM2 promotes p21 degradation by facilitating binding of p21 with the proteasomal C8 subunit. The physical interaction between p21 and MDM2 was demonstrated both in vitro and in vivo with the binding region in amino acids 180-298 of the MDM2 protein.	SIGNOR-272954
P15976	Q01196	1	binding	up-regulates activity	0.643	We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha. In particular, we will elaborate on recent data which suggest that GATA-1 targets RUNX1 for modification, in particular phosphorylation by cyclin-dependent kinases. Furthermore, targeting of RUNX1 by GATA-1 for phosphorylation may convert RUNX1 from a repressor to an activator. This is a potential mechanism of transcriptional cooperation and may be an essential step in megakaryocytic differentiation.	SIGNOR-254194
Q9P107	P61586	1	gtpase-activating protein	down-regulates activity	0.643	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-260505
P52945	P01308	1	transcriptional regulation	up-regulates quantity by expression	0.643	In conclusion, Pdx1 confers the expression of pancreatic β-cell-specific genes, such as genes encoding insulin, islet amyloid polypeptide, Glut2, and Nkx6.1.	SIGNOR-255541
Q00987	Q16665	1	ubiquitination	down-regulates quantity by destabilization	0.643	We find that p53 promotes Mdm2-mediated ubiquitination and proteasomal degradation of the HIF-1alpha subunit of hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that regulates cellular energy metabolism and angiogenesis in response to oxygen deprivation.	SIGNOR-271385
O14641	Q9NPB6	1	binding	up-regulates	0.643	In pcp , dvl binds to proteins such as pkc, atypical pkc (apkc), dvl-associated activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58.	SIGNOR-199500
Q16665	P01588	1	transcriptional regulation	up-regulates quantity by expression	0.643	Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor that regulates hypoxia-inducible genes including the human erythropoietin (EPO) gene.	SIGNOR-253695
P04083	P25090	1	binding	up-regulates activity	0.643	We show that the mimetic N-terminal annexin 1 peptide Ac1-25 is able to activate and desensitize not only FPR but also FPRL1 and FPRL2.	SIGNOR-259437
P08311	P01019	1	cleavage	up-regulates activity	0.643	Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen.	SIGNOR-256312
O14793	Q13705	1	binding	up-regulates activity	0.642	The purified C-terminal myostatin dimer was capable of binding the activin type II receptors, Act RIIB and, to a lesser extent, Act RIIA	SIGNOR-235153
O14920	Q92574	1	phosphorylation	down-regulates	0.642	Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression.	SIGNOR-157296
Q96S42	P36896	1	binding	up-regulates activity	0.642	Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors.	SIGNOR-251939
P31751	O60343	1	phosphorylation	down-regulates activity	0.642	AKT2 phosphorylation blocks AS160 function enhancing GLUT4 intracellular vesicular transport, and as such promotes glucose uptake following insulin release .\|Notable mechanisms promoting this involves AKT2 mediated phosphorylation of the Rab-GTPase-activating protein TBC1D4, also known as AS160.	SIGNOR-280179
P53350	P30291	1	phosphorylation	down-regulates quantity by destabilization	0.642	In the present study, we show that phosphorylation of S123 (pS123) by CDK promoted the binding of Wee1A to beta-TrCP through three independent mechanisms. S123 phosphorylation creates a PBD-binding motif and accelerates S53 phosphorylation by Plk1.	SIGNOR-276040
Q13616	P46527	1	ubiquitination	down-regulates quantity by destabilization	0.642	Furthermore, c-myc activation can also promote the degradation of p27kip1 protein by directly activating the cul1 gene, which encodes a critical component of the ubiquitin ligase scfskp2	SIGNOR-102725
P13385	P27037	1	binding	down-regulates	0.642	Here we show that cripto can form a complex with activin and actrii/iib cripto inhibited crosslinking of activin to alk4 and the association of alk4 with actrii/iib.	SIGNOR-100052
Q9BY41	Q9UPR3	1	binding	up-regulates quantity by stabilization	0.642	Here, we report that the human ortholog of the yeast ever-shorter telomeres 1B (EST1B) binds HDAC8. This interaction is regulated by protein kinase A-mediated HDAC8 phosphorylation and protects human EST1B (hEST1B) from ubiquitin-mediated degradation.	SIGNOR-272650
O15169	Q6ZNA4	1	binding	up-regulates	0.642	Here, we show that axin activates tgf-beta signaling by forming a multimeric complex consisting of smad7 and ubiquitin e3 ligase arkadia. Axin is a scaffold protein in tgf-beta signaling that promotes degradation of smad7 by arkadia.	SIGNOR-119660
P78504	P46531	1	binding	up-regulates activity	0.642	We identify functional fragments of human notch-1 (n-1) and jagged-1 (j-1) which interact in a calcium-dependent manner.	SIGNOR-219253
Q92734	O15027	1	binding	up-regulates	0.642	We identify tfg-1, a new conserved regulator of protein secretion that interacts directly with sec-16 and controls the export of cargoes from the endoplasmic reticulum in caenorhabditis elegans. Hydrodynamic studies indicate that tfg-1 forms hexamers that facilitate the co-assembly of sec-16 with copii subunits.	SIGNOR-173242
P27448	Q8IVT5	1	phosphorylation	down-regulates activity	0.642	C-TAK1 phosphorylates KSR1 at S392, forming a 14-3-3 binding site.\|In mammalian cells, C-TAK1 has been shown to negatively regulate KSR1 by phosphorylation of Ser392.	SIGNOR-279225
Q92973	P35637	1	relocalization	up-regulates activity	0.642	The C-terminal nuclear localization sequence of FUsed in Sarcoma (FUS-NLS) is critical for its nuclear import mediated by transportin (Trn1).	SIGNOR-262101
Q9UJM3	P00533	2	binding	down-regulates activity	0.641	The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2	SIGNOR-252076
Q9UNH5	Q16659	1	dephosphorylation	down-regulates	0.641	Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.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.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis.	SIGNOR-164412
P06493	P16949	1	phosphorylation	up-regulates activity	0.641	null	SIGNOR-279803
P00533	Q9UJM3	2	phosphorylation	up-regulates activity	0.641	here we found that the epidermal growth factor receptor (EGFR) phosphorylates Mig6 on Y394 and that this phosphorylation is primed by prior phosphorylation of an adjacent residue, Y395, by Src.	SIGNOR-252091
Q76N89	O14640	1	ubiquitination	down-regulates quantity by destabilization	0.641	We have also found that NEDL1 targets Dishevelled-1 (Dvl1) for ubiquitination-mediated degradation and that mutant (but not wild-type) SOD1 affects the function of Dvl1.	SIGNOR-271499
Q9Y283	O14640	1	ubiquitination	down-regulates	0.641	Inversin inhibits the canonical wnt pathway by targeting cytoplasmic dishevelled (dsh or dvl1) for degradation	SIGNOR-135766
P50148	P01112	1	binding	up-regulates	0.641	Galfaq/11 subunits also activate p21ras	SIGNOR-50104
Q15746	Q05682	1	phosphorylation	down-regulates	0.641	Phosphorylation of caldesmon by myosin light chain kinase increases its binding affinity for phosphorylated myosin filaments.	SIGNOR-166049
P38405	O60266	1	binding	up-regulates activity	0.641	Subsequently, the Gaolf subunit activates the integral membrane protein adenylyl cyclase type III (AC3), leading to the conversion of adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP)	SIGNOR-278072
P78527	Q14191	1	phosphorylation	up-regulates	0.641	Here, we identify ser-440 and -467 in wrn as major phosphorylation sites mediated by dna-pk our findings indicate that phosphorylation of ser-440 and -467 in wrn are important for relocalization of wrn to nucleoli, and that it is required for efficient dsb repair.	SIGNOR-203737
Q14332	Q92997	1	binding	up-regulates activity	0.641	Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.	SIGNOR-258962
Q5T9L3	P56704	1	relocalization	up-regulates activity	0.641	WNT secretion requires its binding to the carrier protein wntless (WLS);	SIGNOR-256599
Q13467	Q92997	1	binding	up-regulates activity	0.641	Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.	SIGNOR-258963
P43403	Q9UJU6	1	phosphorylation	up-regulates	0.64	We found an interaction between the tyrosine kinase zap-70 and hip-55, which was induced by tcr stimulation. Zap-70 phosphorylated hip-55 at tyr-334 and tyr-344, which were shown to be the tyrosine phosphorylation sites of hip-55 in stimulated t cells.Our results demonstrate for the first time that hip-55 is an important adaptor protein for the jnk kinase cascade in tcr signaling.	SIGNOR-118695
O00744	Q14332	1	binding	up-regulates	0.64	Inhibition of adipogenesis by wnt10b is likely mediated by wnt receptors, frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 7	SIGNOR-89137
P35372	P09471	1	binding	up-regulates activity	0.64	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-256990
P12931	Q5TCZ1	1	phosphorylation	up-regulates activity	0.64	First, we observed that the co-expression of both activated Src and wild-type Tks5 stimulated gelatin degradation beyond that of Tks5 overexpression alone ( ).\|In melanoma cells Src dependent phosphorylation of Tks5 at tyrosine 557 is important for binding to Nck, for Nck recruitment to invadopodia, and for invadopodia associated matrix degradation activity .	SIGNOR-280134
Q13485	P01106	1	transcriptional regulation	down-regulates quantity by repression	0.64	Down-regulation of c-Myc is a critical event for growth inhibition induced by transforming growth factor-β (TGF-β) and is frequently impaired in cancer cells. We determined a Smad-responsive element in the c-mycpromoter.	SIGNOR-251493
P36897	P61586	1	null	up-regulates activity	0.64	Thus, TGF-_1 rapidly stimulates activity of both RhoA and Rac1 and this activation requires ALK5/T_RI kinase activity.	SIGNOR-227499
Q8IXL6	Q9GZV9	1	phosphorylation	down-regulates activity	0.64	Here we show that Fam20C directly phosphorylates FGF23 on Ser(180) \| Our above results support, phosphorylation of FGF23 at Ser180 inhibits O-glycosylation and would therefore promote hormone proteolysis and thus inactivation.	SIGNOR-260925
P52757	P63000	1	gtpase-activating protein	down-regulates activity	0.64	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-260500
P56704	Q9NPG1	1	binding	up-regulates activity	0.64	Here we focus on the role of Wnts, their putative receptors Frizzled and the soluble antagonist Frzb1 in regulating mammalian myogenesis. Although it is becoming evident that the signaling downstream of Frizzled receptors is much more complex than anticipated, it is conceivable that it may lead to transcriptional activation of Myf5 and MyoD and to initiation of myogenesis.	SIGNOR-73039
Q99835	Q9UMX1	1	binding	down-regulates activity	0.64	In addition to activating g(i), smo signals through its c-terminal tail to inhibit suppressor of fused, resulting in stabilization and activation of the gli family of transcription factors, which execute a transcriptional response to so-called canonical hh signaling.	SIGNOR-177656
P04637	O43819	1	transcriptional regulation	up-regulates quantity by expression	0.64	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-267463
P05198	P18848	1	transcriptional regulation	down-regulates quantity	0.64	ER stress, viral infection, and other cellular stress signals activate PERK, PKR, HRI, and GCN2 kinases that converge on phosphorylation of eIF2alpha, the core of ISR. This leads to global attenuation of Cap Âdependent translation while concomitantly initiates the preferential translation of ISR Âspecific mRNAs, such as ATF4. ATF4 is the main effector of the ISR. eIF2alpha phosphorylation causes a reduction in global protein synthesis while allowing the translation of selected genes including activating transcription factor 4 (ATF4), aiding cell survival and recovery	SIGNOR-260169
O14904	O75581	1	binding	up-regulates	0.64	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-132076

Q9Y644

P46531

1

binding

up-regulates

0.647

We demonstrate that egf 12, a portion of the ligand-binding site, is modified with o-fucose and that this site is evolutionarily conserved. We also show that endogenous fringe proteins in chinese hamster ovary cells (lunatic fringe and radical fringe) as well as exogenous manic fringe modify o-fucose on many but not all egf repeats of mouse notch1.

SIGNOR-96561

O75460

P17861

1

phosphorylation

up-regulates activity

0.647

IRE1\u03b1 phosphorylates and activates the XBP1 transcription factor XBP1 via its kinase activity.

SIGNOR-279712

P67775

P27361

1

dephosphorylation

down-regulates

0.647

P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3).

SIGNOR-103162

O75460

P17861-2

1

post transcriptional regulation

up-regulates quantity by expression

0.647

Upon activation by oligomerization and autophosphorylation, the cytosolic RNase domain of IRE1 mediates an unconventional splicing of the mRNA of X-box-binding protein 1 (XBP1). The spliced and frameshifted transcript encodes XBP1S, a bZIP transcription factor inducing the expression of numerous UPR effector genes that enhance ER folding capacity.

SIGNOR-260183

P31749

P08670

1

phosphorylation

up-regulates quantity by stabilization

0.647

The binding of akt (tail region) to vim (head region) results in vim ser39 phosphorylation enhancing the ability of vim to induce motility and invasion while protecting vim from caspase-induced proteolysis.

SIGNOR-252511

P49662

P57764

1

cleavage

up-regulates activity

0.647

Co-expression of GSDMD with caspase-1, 4, 5 or 11 but not apoptotic caspases (caspase-2, 8 and 9) in 293T cells induced the same cleavage of GSDMD|inflammatory caspases specifically cleave GSDMD after the 272FLTD275 (or 273LLSD276) sequence |

SIGNOR-256417

P19174

Q07889

1

binding

up-regulates

0.647

We provide evidence that sos1, a p21ras-specific guanine nucleotide exchange factor, directly binds to the sh3 domain of plc-gamma1, and that the sh3 domain of plc-gamma1 is involved in sos1-mediated p21ras activation.

SIGNOR-80024

Q16620

P19174

1

phosphorylation

up-regulates activity

0.647

Both Shc and PLCgamma1 are phosphorylated by TrkB, thereby initiating Shc/Ras/MAP kinase and PLCgamma1 signaling respectively.|We conclude that activation of pY783 PLCgamma1 is due mainly to TrkB activation in these models and that TrkB induced PLCgamma1 signaling promotes limbic epileptogenesis.

SIGNOR-279241

Q05655

P35568

1

phosphorylation

down-regulates activity

0.646

Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101).

SIGNOR-249267

P56706

Q9ULW2

1

binding

up-regulates

0.646

Wnt7b can bind to fzd1 and -10 on the cell surface and cooperatively activate canonical wnt signaling

SIGNOR-137934

Q13464

P24844

1

phosphorylation

up-regulates

0.646

Rho-kinase phosphorylates the mlc of intact myosin and activates its mgatpase activity in a gtp_?Rho-dependent manner.

SIGNOR-43031

Q96J02

Q7Z434

1

ubiquitination

down-regulates quantity by destabilization

0.646

These data collectively indicate that AIP4 is the E3 ligase for MAVS.|We generated single substitutions (K362A, K371A or K420A) and combined point substitutions of MAVS and tested their degradation. K371A or K420A MAVS showed partial resistance to PCBP2-induced degradation (data not shown), whereas MAVS with the combined substitutions K371A and K420A (KK-AA) completely withstood the degradation

SIGNOR-260362

Q15366

Q7Z434

1

binding

down-regulates quantity by destabilization

0.646

PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4.

SIGNOR-260360

O00755

Q9NPG1

1

binding

up-regulates activity

0.646

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-131897

P27540

P04798

1

transcriptional regulation

up-regulates quantity by expression

0.646

Kaempferol proved to be capable of inhibiting binding of agonist and agonist-induced formation of the AHR/ARNT DNA-binding complex and upregulation of the AHR target gene, CYP1A1.

SIGNOR-259910

Q16828

Q13164

1

dephosphorylation

down-regulates activity

0.646

However, whilst the interaction itself might be difficult to monitor, DUSP6 should still be able to promote the de-phosphorylation of ERK5 in cells if it is an ERK5 phosphatase.To test this HEK293 cells were transiently transfected with HA-ERK2 or HA-ERK5 together with EGFP-MEK1E (a constitutively active version of MEK1) or EGFP-MEK5D (a constitutively active version of MEK5).|Whilst one can envisage scenarios in which the interaction between DUSPs and their substrates might be transient, DUSP6 should still be able to promote the de-phosphorylation and inactivation of ERK5.

SIGNOR-277007

P18031

P29597

1

dephosphorylation

down-regulates activity

0.646

Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5.

SIGNOR-134564

P06239

Q9UN19

1

phosphorylation

up-regulates activity

0.646

Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell lines|yrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins.

SIGNOR-249373

Q14164

Q9UHD2

2

binding

up-regulates activity

0.646

STING recruits TBK1 and IKKε and forms the TBK1-IKKε complex via the association with TRAF3. The TBK1 complex induces the phosphorylation, dimerization, and nuclear translocation of IRF3.

SIGNOR-260155

P29350

P23458

1

dephosphorylation

down-regulates

0.646

We find, for the first time, that shp-1 down-regulates the level of tyk2 kinase in h9 cells and of jak1 kinase in htb26 cells, by accelerating their degradation.

SIGNOR-119197

P31751

Q99683

1

phosphorylation

down-regulates activity

0.646

Akt2 interacts with and phosphorylates ask1 at ser-83 resulting in inhibition of its kinase activity

SIGNOR-100588

Q9UHD2

Q14164

2

binding

up-regulates activity

0.646

Whereas nemo assembles some but not all ikk complexes [12,13], recent reports provide strong experimental evidence for a role of tank [also called traf-interacting protein (i-traf)], nak-associated protein (nap1) and similar to nap1 tbk1 adaptor (sintbad) in the assembly of tbk1 and ikk-e kinase complexes that phosphorylate irf3 and irf7 and promote type i ifn gene induction

SIGNOR-178053

O43318

O14733

1

phosphorylation

up-regulates activity

0.645

Upon TNFα stimulation, MEKK1, ASK1, and TAK1 phosphorylate and activate MKK7, which in turn activates JNK

SIGNOR-274146

Q9P2B4

O43815

1

binding

up-regulates activity

0.645

Although CTTNBP2 and CTTNBP2NL are different in terms of tissue and subcellular distribution, our data indicate that, similar to CTTNBP2NL, CTTNBP2 associates with members of the striatin family, namely striatin and zinedin. Moreover, CTTNBP2 is critical for the distribution of striatin and zinedin in dendritic spines. The role of CTTNBP2 in the regulation of the synaptic distribution of striatin and zinedin suggests that CTTNBP2 regulates synaptic signaling through PP2A.

SIGNOR-261702

Q9NTX7

O15169

1

ubiquitination

down-regulates quantity by destabilization

0.645

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

SIGNOR-263335

Q9NPF7

P42701

1

binding

up-regulates

0.645

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

SIGNOR-87739

Q9Y3M8

P61586

1

gtpase-activating protein

down-regulates activity

0.645

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

SIGNOR-260521

P49336

P51946

1

phosphorylation

down-regulates

0.645

Cdk8 phosphorylates mammalian cyclin h in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of tfiih to activate transcription and its ctd kinase activity

SIGNOR-82033

Q13153

P35240

1

phosphorylation

down-regulates

0.645

Merlin contains a c-terminal serine 518, which is phosphorylated both by p21-activated kinase (pak) and protein kinase a (pka) (shaw et al., 2001;kissil et al., 2002;xiao et al., 2002;alfthan et al., 2004). Phosphorylation at this site is predicted to result in a more open conformation incapable of inhibiting cell growth,

SIGNOR-159764

P27361

P15056

1

phosphorylation

down-regulates

0.645

Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity.

SIGNOR-144827

Q07326

Q5H8A4

1

binding

up-regulates quantity by stabilization

0.645

We show that the human homolog of Gpi7p, termed hGPI7, binds to and is stabilized by PIG-F and that hGPI7 competes with PIG-O for binding to PIG-F. PIG-F Binds to and Stabilizes hGPI7 and PIG-O Independently. These results are consistent with the hypothesis that overexpression of hGPI7 decreases the biosynthetic activity of PIG-O by decreasing the available PIG-F, thereby destabilizing PIG-O.

SIGNOR-261358

P22681

P16333

1

ubiquitination

down-regulates quantity by destabilization

0.644

Taken together, these results show that lysine 178 in Nck1 is the acceptor site for ubiquitin transferred by c-Cbl, and that the ubiquitination of Nck1 by c-Cbl is blocked in the presence of synaptopodin.

SIGNOR-278606

Q9NR61

P46531

1

binding

up-regulates activity

0.644

Expression analysis of known notch ligands suggests that dll4 is the only ligand that exhibits spatial and temporal expression consistent with the activation of notch1 and notch4 during vascular development. The identification of dll4 reveals a candidate ligand for notch receptors involved in blood vessel biology

SIGNOR-112649

P05155

P00748

1

binding

down-regulates activity

0.644

C1INH is a serine protease inhibitor (serpin) that acts on both the complement pathway and the contact system and is the main inhibitor of the contact system by targeting both FXIIa and PK 9. Additionally, FXIIa can be inhibited by α1‐antitrypsin and plasminogen activator inhibitor‐1 (PAI‐1).

SIGNOR-263517

P78504

Q9UM47

1

binding

up-regulates

0.644

Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch.

SIGNOR-179625

Q96J02

P46531

1

ubiquitination

down-regulates

0.644

Itch binds to the n-terminal portion of the notch intracellular domain via its ww domains and promotes ubiquitination of notch through its hect ubiquitin ligase domain.

SIGNOR-80702

Q12955

Q01082

1

binding

up-regulates activity

0.644

Ankyrin-G is a molecular partner of E-cadherin in epithelial cells and early embryos. Ankyrin-G also recruits beta-2-spectrin to E-cadherin-beta-catenin complexes, thus providing a direct connection between E-cadherin and the spectrin/actin skeleton.

SIGNOR-266711

P57059

Q53ET0

1

phosphorylation

down-regulates

0.644

These results suggested that sik1 could phosphorylate all torcs and thereby repress their transactivation activities.

SIGNOR-147707

P28482

P08047

1

phosphorylation

up-regulates

0.644

Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. Mutation of these sites to alanines decreases by half the mapk-dependent transcriptional activity of sp1. Phosphorylated extracellular signal-regulated protein kinases 1 and 2 phosphorylate sp1 on serine 59 and regulate cellular senescence via transcription of p21sdi1/cip1/waf1.

SIGNOR-116158

Q9HCK8

P35222

1

binding

down-regulates

0.644

Duplin (axis duplication inhibitor) interacts with beta-catenin and prevents its binding to tcf, thereby inhibiting downstream wnt signaling

SIGNOR-128976

Q9HAU4

O15198

1

ubiquitination

down-regulates

0.644

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

SIGNOR-193390

P11309

O95644

1

phosphorylation

up-regulates activity

0.643

Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells.

SIGNOR-276775

Q13526

Q14653

1

binding

down-regulates quantity by destabilization

0.643

Here we report that activation of IRF3 is negatively regulated by the peptidyl-prolyl isomerase Pin1. After stimulation by double-stranded RNA, induced phosphorylation of the Ser339–Pro340 motif of IRF3 led to its interaction with Pin1 and finally polyubiquitination and then proteasome-dependent degradation of IRF3. Suppression of Pin1 by RNA interference or genetic deletion resulted in enhanced IRF-3-dependent production of interferon-beta, with consequent reduction of virus replication.

SIGNOR-252256

Q13535

P30307

1

phosphorylation

up-regulates activity

0.643

We also found that activated ATR phosphorylates CDC25C (Cell Division Cycle 25C) at serine 216, which in turn inactivates the cyclin B1/Cyclin-Dependent Kinase 1(CDK1) complex and induces G2-phase arrest.

SIGNOR-279008

P30556

P50148

1

binding

up-regulates activity

0.643

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-257017

Q9UQQ2

O60674

1

binding

down-regulates activity

0.643

we identified Lnk as a physiological negative regulator of JAK2 in stem cells and TPO/Mpl/JAK2/Lnk as a major regulatory pathway in controlling stem cell self-renewal and quiescence. we identify a direct interaction between Lnk and the Mpl/JAK2 complex that regulates various HSC functions.

SIGNOR-260075

P10082

Q15761

1

binding

up-regulates

0.643

Maml3 forms complexes in vivo with icn and csl and functiosn as transcriptional coactivators for notch signaling.

SIGNOR-114749

Q16825

P12931

1

dephosphorylation

up-regulates

0.643

Ptpd1 activates src tyrosine kinase and increases the magnitude and duration of epidermal growth factor (egf) signaling.

SIGNOR-124774

Q13535

P30304

1

phosphorylation

down-regulates activity

0.643

ATR and CHK1 mediated loss of CDC25A activity suspends CDKs, such as CDK2, in an inactive phosphorylated state, blocking initiation of DNA replication origins.|In the presence of replication stalling, activated CHK1 and ATR phosphorylates CDC25A and promotes its degradation.

SIGNOR-280183

Q00535

P46527

1

phosphorylation

down-regulates activity

0.643

CDK5 knockdown in HEY cells significantly prolonged the half-life of TP53 and p27 Kip1 proteins (XREF_FIG).|During neural stem cell differentiation, CDK5 can phosphorylate p27 at Thr187 and at Ser10, promoting neurite outgrowth as neurons differentiate .

SIGNOR-279681

O00238

Q15797

1

phosphorylation

up-regulates

0.643

Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression.

SIGNOR-187190

P06239

P51692

1

phosphorylation

up-regulates activity

0.643

A constitutively active Lck kinase promotes cell proliferation and resistance to apoptosis through signal transducer and activator of transcription 5b activation.|Expression of the active Lck kinase induces both tyrosine phosphorylation and DNA binding activity of signal transducer and activator of transcription 5b (STAT5b), a STAT family member activated in a variety of tumor cells.

SIGNOR-279056

Q00987

P38936

1

binding

down-regulates quantity by destabilization

0.643

MDM2 facilitates p21 degradation independent of ubiquitination and the E3 ligase function of MDM2. Instead, MDM2 promotes p21 degradation by facilitating binding of p21 with the proteasomal C8 subunit. The physical interaction between p21 and MDM2 was demonstrated both in vitro and in vivo with the binding region in amino acids 180-298 of the MDM2 protein.

SIGNOR-272954

P15976

Q01196

1

binding

up-regulates activity

0.643

We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha. In particular, we will elaborate on recent data which suggest that GATA-1 targets RUNX1 for modification, in particular phosphorylation by cyclin-dependent kinases. Furthermore, targeting of RUNX1 by GATA-1 for phosphorylation may convert RUNX1 from a repressor to an activator. This is a potential mechanism of transcriptional cooperation and may be an essential step in megakaryocytic differentiation.

SIGNOR-254194

Q9P107

P61586

1

gtpase-activating protein

down-regulates activity

0.643

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-260505

P52945

P01308

1

transcriptional regulation

up-regulates quantity by expression

0.643

In conclusion, Pdx1 confers the expression of pancreatic β-cell-specific genes, such as genes encoding insulin, islet amyloid polypeptide, Glut2, and Nkx6.1.

SIGNOR-255541

Q00987

Q16665

1

ubiquitination

down-regulates quantity by destabilization

0.643

We find that p53 promotes Mdm2-mediated ubiquitination and proteasomal degradation of the HIF-1alpha subunit of hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that regulates cellular energy metabolism and angiogenesis in response to oxygen deprivation.

SIGNOR-271385

O14641

Q9NPB6

1

binding

up-regulates

0.643

In pcp , dvl binds to proteins such as pkc, atypical pkc (apkc), dvl-associated activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58.

SIGNOR-199500

Q16665

P01588

1

transcriptional regulation

up-regulates quantity by expression

0.643

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor that regulates hypoxia-inducible genes including the human erythropoietin (EPO) gene.

SIGNOR-253695

P04083

P25090

1

binding

up-regulates activity

0.643

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

SIGNOR-259437

P08311

P01019

1

cleavage

up-regulates activity

0.643

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

SIGNOR-256312

O14793

Q13705

1

binding

up-regulates activity

0.642

The purified C-terminal myostatin dimer was capable of binding the activin type II receptors, Act RIIB and, to a lesser extent, Act RIIA

SIGNOR-235153

O14920

Q92574

1

phosphorylation

down-regulates

0.642

Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression.

SIGNOR-157296

Q96S42

P36896

1

binding

up-regulates activity

0.642

Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors.

SIGNOR-251939

P31751

O60343

1

phosphorylation

down-regulates activity

0.642

AKT2 phosphorylation blocks AS160 function enhancing GLUT4 intracellular vesicular transport, and as such promotes glucose uptake following insulin release .|Notable mechanisms promoting this involves AKT2 mediated phosphorylation of the Rab-GTPase-activating protein TBC1D4, also known as AS160.

SIGNOR-280179

P53350

P30291

1

phosphorylation

down-regulates quantity by destabilization

0.642

In the present study, we show that phosphorylation of S123 (pS123) by CDK promoted the binding of Wee1A to beta-TrCP through three independent mechanisms. S123 phosphorylation creates a PBD-binding motif and accelerates S53 phosphorylation by Plk1.

SIGNOR-276040

Q13616

P46527

1

ubiquitination

down-regulates quantity by destabilization

0.642

Furthermore, c-myc activation can also promote the degradation of p27kip1 protein by directly activating the cul1 gene, which encodes a critical component of the ubiquitin ligase scfskp2

SIGNOR-102725

P13385

P27037

1

binding

down-regulates

0.642

Here we show that cripto can form a complex with activin and actrii/iib cripto inhibited crosslinking of activin to alk4 and the association of alk4 with actrii/iib.

SIGNOR-100052

Q9BY41

Q9UPR3

1

binding

up-regulates quantity by stabilization

0.642

Here, we report that the human ortholog of the yeast ever-shorter telomeres 1B (EST1B) binds HDAC8. This interaction is regulated by protein kinase A-mediated HDAC8 phosphorylation and protects human EST1B (hEST1B) from ubiquitin-mediated degradation.

SIGNOR-272650

O15169

Q6ZNA4

1

binding

up-regulates

0.642

Here, we show that axin activates tgf-beta signaling by forming a multimeric complex consisting of smad7 and ubiquitin e3 ligase arkadia. Axin is a scaffold protein in tgf-beta signaling that promotes degradation of smad7 by arkadia.

SIGNOR-119660

P78504

P46531

1

binding

up-regulates activity

0.642

We identify functional fragments of human notch-1 (n-1) and jagged-1 (j-1) which interact in a calcium-dependent manner.

SIGNOR-219253

Q92734

O15027

1

binding

up-regulates

0.642

We identify tfg-1, a new conserved regulator of protein secretion that interacts directly with sec-16 and controls the export of cargoes from the endoplasmic reticulum in caenorhabditis elegans. Hydrodynamic studies indicate that tfg-1 forms hexamers that facilitate the co-assembly of sec-16 with copii subunits.

SIGNOR-173242

P27448

Q8IVT5

1

phosphorylation

down-regulates activity

0.642

C-TAK1 phosphorylates KSR1 at S392, forming a 14-3-3 binding site.|In mammalian cells, C-TAK1 has been shown to negatively regulate KSR1 by phosphorylation of Ser392.

SIGNOR-279225

Q92973

P35637

1

relocalization

up-regulates activity

0.642

The C-terminal nuclear localization sequence of FUsed in Sarcoma (FUS-NLS) is critical for its nuclear import mediated by transportin (Trn1).

SIGNOR-262101

Q9UJM3

P00533

2

binding

down-regulates activity

0.641

The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2

SIGNOR-252076

Q9UNH5

Q16659

1

dephosphorylation

down-regulates

0.641

Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.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.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis.

SIGNOR-164412

P06493

P16949

1

phosphorylation

up-regulates activity

0.641

null

SIGNOR-279803

P00533

Q9UJM3

2

phosphorylation

up-regulates activity

0.641

here we found that the epidermal growth factor receptor (EGFR) phosphorylates Mig6 on Y394 and that this phosphorylation is primed by prior phosphorylation of an adjacent residue, Y395, by Src.

SIGNOR-252091

Q76N89

O14640

1

ubiquitination

down-regulates quantity by destabilization

0.641

We have also found that NEDL1 targets Dishevelled-1 (Dvl1) for ubiquitination-mediated degradation and that mutant (but not wild-type) SOD1 affects the function of Dvl1.

SIGNOR-271499

Q9Y283

O14640

1

ubiquitination

down-regulates

0.641

Inversin inhibits the canonical wnt pathway by targeting cytoplasmic dishevelled (dsh or dvl1) for degradation

SIGNOR-135766

P50148

P01112

1

binding

up-regulates

0.641

Galfaq/11 subunits also activate p21ras

SIGNOR-50104

Q15746

Q05682

1

phosphorylation

down-regulates

0.641

Phosphorylation of caldesmon by myosin light chain kinase increases its binding affinity for phosphorylated myosin filaments.

SIGNOR-166049

P38405

O60266

1

binding

up-regulates activity

0.641

Subsequently, the Gaolf subunit activates the integral membrane protein adenylyl cyclase type III (AC3), leading to the conversion of adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP)

SIGNOR-278072

P78527

Q14191

1

phosphorylation

up-regulates

0.641

Here, we identify ser-440 and -467 in wrn as major phosphorylation sites mediated by dna-pk our findings indicate that phosphorylation of ser-440 and -467 in wrn are important for relocalization of wrn to nucleoli, and that it is required for efficient dsb repair.

SIGNOR-203737

Q14332

Q92997

1

binding

up-regulates activity

0.641

Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.

SIGNOR-258962

Q5T9L3

P56704

1

relocalization

up-regulates activity

0.641

WNT secretion requires its binding to the carrier protein wntless (WLS);

SIGNOR-256599

Q13467

Q92997

1

binding

up-regulates activity

0.641

Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.

SIGNOR-258963

P43403

Q9UJU6

1

phosphorylation

up-regulates

0.64

We found an interaction between the tyrosine kinase zap-70 and hip-55, which was induced by tcr stimulation. Zap-70 phosphorylated hip-55 at tyr-334 and tyr-344, which were shown to be the tyrosine phosphorylation sites of hip-55 in stimulated t cells.Our results demonstrate for the first time that hip-55 is an important adaptor protein for the jnk kinase cascade in tcr signaling.

SIGNOR-118695

O00744

Q14332

1

binding

up-regulates

0.64

Inhibition of adipogenesis by wnt10b is likely mediated by wnt receptors, frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 7

SIGNOR-89137

P35372

P09471

1

binding

up-regulates activity

0.64

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-256990

P12931

Q5TCZ1

1

phosphorylation

up-regulates activity

0.64

First, we observed that the co-expression of both activated Src and wild-type Tks5 stimulated gelatin degradation beyond that of Tks5 overexpression alone ( ).|In melanoma cells Src dependent phosphorylation of Tks5 at tyrosine 557 is important for binding to Nck, for Nck recruitment to invadopodia, and for invadopodia associated matrix degradation activity .

SIGNOR-280134

Q13485

P01106

1

transcriptional regulation

down-regulates quantity by repression

0.64

Down-regulation of c-Myc is a critical event for growth inhibition induced by transforming growth factor-β (TGF-β) and is frequently impaired in cancer cells. We determined a Smad-responsive element in the c-mycpromoter.

SIGNOR-251493

P36897

P61586

1

null

up-regulates activity

0.64

Thus, TGF-_1 rapidly stimulates activity of both RhoA and Rac1 and this activation requires ALK5/T_RI kinase activity.

SIGNOR-227499

Q8IXL6

Q9GZV9

1

phosphorylation

down-regulates activity

0.64

Here we show that Fam20C directly phosphorylates FGF23 on Ser(180) | Our above results support, phosphorylation of FGF23 at Ser180 inhibits O-glycosylation and would therefore promote hormone proteolysis and thus inactivation.

SIGNOR-260925

P52757

P63000

1

gtpase-activating protein

down-regulates activity

0.64

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-260500

P56704

Q9NPG1

1

binding

up-regulates activity

0.64

Here we focus on the role of Wnts, their putative receptors Frizzled and the soluble antagonist Frzb1 in regulating mammalian myogenesis. Although it is becoming evident that the signaling downstream of Frizzled receptors is much more complex than anticipated, it is conceivable that it may lead to transcriptional activation of Myf5 and MyoD and to initiation of myogenesis.

SIGNOR-73039

Q99835

Q9UMX1

1

binding

down-regulates activity

0.64

In addition to activating g(i), smo signals through its c-terminal tail to inhibit suppressor of fused, resulting in stabilization and activation of the gli family of transcription factors, which execute a transcriptional response to so-called canonical hh signaling.

SIGNOR-177656

P04637

O43819

1

transcriptional regulation

up-regulates quantity by expression

0.64

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-267463

P05198

P18848

1

transcriptional regulation

down-regulates quantity

0.64

ER stress, viral infection, and other cellular stress signals activate PERK, PKR, HRI, and GCN2 kinases that converge on phosphorylation of eIF2alpha, the core of ISR. This leads to global attenuation of Cap Âdependent translation while concomitantly initiates the preferential translation of ISR Âspecific mRNAs, such as ATF4. ATF4 is the main effector of the ISR. eIF2alpha phosphorylation causes a reduction in global protein synthesis while allowing the translation of selected genes including activating transcription factor 4 (ATF4), aiding cell survival and recovery

SIGNOR-260169

O14904

O75581

1

binding

up-regulates

0.64

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-132076