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
Q15173	Q96M94	0	binding	down-regulates quantity by destabilization	0.2	Here, we report that KLHL15-Cul3 specifically targets B'β to promote turnover of the PP2A subunit by ubiquitylation and proteasomal degradation. We mapped KLHL15 residues critical for homodimerization as well as interaction with Cul3 and B'β.	SIGNOR-272017
P52907	P68400	0	phosphorylation	up-regulates	0.2	We demonstrate that ser9 of cpalpha is phosphorylated by protein kinase ck2 in vitro, that cpalpha is phosphorylated in vivo. Finally, we demonstrate that ckip-1 and ck2 inhibit the activity of actin capping protein at the barbed ends of actin filaments.	SIGNOR-135422
P18848	P67870	0	phosphorylation	down-regulates quantity by destabilization	0.2	By using mutants of ATF4 we identified serine 215 as the main CK2 phosphorylation site. The ATF4 S215A mutant turned out to be more stable than the wild-type form.	SIGNOR-276424
Q5TKA1	Q00526	0	phosphorylation	up-regulates	0.2	In this report, we demonstrate that cyclin e1/cdk3 phosphorylates lin-9 on thr-96. Mutating thr-96 to alanine inhibits activation of cyclins a2 and b1 promoters, whereas a phosphomimetic asp mutant strongly activates their promoters and triggers accelerated entry into g2/m phase in 293t cells.	SIGNOR-204529
P83916	Q5XPI4	0	polyubiquitination	down-regulates quantity by destabilization	0.2	In the present study, we report that HP1α and β undergo proteasomal degradation in lamin A/C knock-down cells and show by ectopic expression, RNAi and binding studies that the RING finger ubiquitin ligase RNF123 is directly involved in HP1 degradation.	SIGNOR-272034
O75807	P19484	0	transcriptional regulation	up-regulates quantity by expression	0.2	We found that the main regulator of the starvation-induced transcriptional program, TFEB, counteracts protein synthesis inhibition by directly activating expression of GADD34, a component of the protein phosphatase 1 complex that dephosphorylates eIF2α.	SIGNOR-276789
Q96RK0	Q15418	0	phosphorylation	down-regulates	0.2	Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3)	SIGNOR-169883
O60566	Q8NG31	0	binding	up-regulates	0.2	Association of the amino and middle domain of blinkin with the tpr domains in the amino termini of bubr1 and bub1 is essential for bubr1 and bub1 to execute their distinct mitotic functions	SIGNOR-158894
Q12834	Q9UHD2	0	phosphorylation	down-regulates activity	0.2	It was found that TBK1 phosphorylates both Cdc20 as well as Cdh1 (Figure 2F).	SIGNOR-279766
Q15746	P31260	0	transcriptional regulation	up-regulates quantity by expression	0.2	Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively	SIGNOR-261643
Q70Z35	P62136	0	dephosphorylation	up-regulates activity	0.2	PREX2 is dephosphorylated by PP1α and PP2A.PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ.	SIGNOR-277183
Q9BV40	Q86YJ5	0	ubiquitination	down-regulates quantity by destabilization	0.2	MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.	SIGNOR-271531
Q75N03	P08238	0	binding	up-regulates quantity	0.2	By immunoprecipitation, we present evidence that Hakai interacts with Hsp90 chaperone complex in several epithelial cells and demonstrate that is a novel Hsp90 client protein. Interestingly, by overexpressing and knocking-down experiments with Hakai, we identified Annexin A2 as a Hakai-regulated protein. Interestingly, geldanamycin-induced Hakai degradation is accompanied by an increased expression of E-cadherin and Annexin A2. Hsp90 participates in the correct folding of its client proteins, allowing them to maintain their stability and activity.	SIGNOR-271475
Q14676	P16104	0	binding	up-regulates	0.2	Here, we demonstrate that mammalian mdc1/nfbd1 directly binds to phospho-h2ax (gammah2ax) by specifically interacting with the phosphoepitope at the gammah2ax carboxyl terminus.	SIGNOR-143377
Q14141	Q8IYM1	0	binding	down-regulates	0.2	Sept12 interacts with sept6 and this interaction alters the filament structure of sept6 in hela cells.	SIGNOR-159537
P68431	Q9UPS6	0	methylation	down-regulates activity	0.2	SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks.	SIGNOR-265576
Q9NZQ7	Q13451	0	catalytic activity	up-regulates quantity by expression	0.2	FKBP51s upregulated PD-L1 expression on the plasma membrane by catalysing the protein folding required for subsequent glycosylation. Inhibition of FKBP51s isomerase activity by SAFit decreased PD-L1 levels	SIGNOR-274973
P63096	Q96LB1	0	binding	up-regulates activity	0.2	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257059
P16144	P17612	0	phosphorylation	down-regulates	0.2	Additionally, we show that s1360 and s1364 of beta4 are the only residues phosphorylated by pkc and pka in cells, respectivelywe have defined three regions on beta4 that together harbor all the serine and threonine phosphorylation sites and show that three serines (s1356, s1360, and s1364), previously implicated in hd regulation, prevent the interaction of beta4 with the plectin actin-binding domain when phosphorylated	SIGNOR-156873
Q05066	P19544	0	binding	up-regulates	0.2	Here we report that wt1 binds to and acts synergistically with sry to activate transcription from a promoter containing sry-binding sites	SIGNOR-100345
P32519	P62714	0	dephosphorylation	down-regulates activity	0.2	Elf-1 enhances the expression of CD3zeta, whereas it suppresses the expression of FcRgamma gene and lupus T cells have decreased amounts of DNA-binding 98 kDa form of Elf-1. We show that the aberrantly increased PP2A in lupus T cells dephosphorylates Elf-1 at Thr-231. Dephosphorylation results in limited expression and binding of the 98 kDa Elf-1 form to the CD3zeta and FcRgamma promoters. Suppression of the expression of the PP2A leads to increased expression of CD3zeta and decreased expression of FcRgamma genes and correction of the early signaling response	SIGNOR-248591
Q9UPP1	P68400	0	phosphorylation	up-regulates activity	0.2	The CK2 kinase is responsible for PHF8 phosphorylation at Ser854. PHF8 is phosphorylated by CK2, which regulates binding of PHF8 to TopBP1. The Ser854 residue of PHF8 is required for its interaction with TopBP1.	SIGNOR-273628
Q7Z6Z7	P43405	0	phosphorylation	up-regulates activity	0.2	Collectively, these data suggest that TNF induced tyrosine phosphorylation of Mule by Syk contributes to its E3 ligase activity.	SIGNOR-280150
P0C0S8	O76064	0	ubiquitination	up-regulates	0.2	Rnf8 and ubc13 ubiquitylate h2a and h2ax, but other substrates probably exist.	SIGNOR-166174
O15350	P05771	0	phosphorylation	up-regulates activity	0.2	Here, we report that p73 is able to induce cell cycle arrest independently of its amino-terminal transactivation domain, whereas this domain is crucial for p73 proapoptotic functions. its activity is regulated throughout the cell cycle and modified by protein kinase C-dependent phosphorylation at serine residue 388.	SIGNOR-276234
P08754	P21452	0	binding	up-regulates activity	0.2	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256879
Q7Z434	P0DTC5	0	binding	down-regulates activity	0.1	Here, we identified SARS-CoV-2 membrane glycoprotein M as a negative regulator of the innate immune response. We found that the M protein interacted with the central adaptor protein MAVS in the innate immune response pathways. This interaction impaired MAVS aggregation and its recruitment of downstream TRAF3, TBK1, and IRF3, leading to attenuation of the innate antiviral response. Our findings reveal a mechanism by which SARS-CoV-2 evades the innate immune response and suggest that the M protein of SARS-CoV-2 is a potential target for the development of SARS-CoV-2 interventions.	SIGNOR-262515
P17844	P0C6X7	0	binding	up-regulates activity	null	To our knowledge, this is the first report to show that SARS-CoV helicase can interact directly with multifunctional protein Ddx5 in cell culture and that inhibition of Ddx5 results in the suppression of viral replication. We speculate that Ddx5 may act as a coactivator by direct binding to the SARS-CoV helicase, resulting in enhanced viral genome transcription and virus proliferation.	SIGNOR-260250
P03206	Q02548	0	binding	down-regulates activity	null	... we demonstrate that Pax5 inhibits Z-mediated lytic viral gene expression and the release of infectious viral particles in latently infected epithelial cell lines. Conversely, we found that shRNA-mediated knockdown of endogenous Pax5 in a Burkitt lymphoma B-cell line leads to viral reactivation. Furthermore, we show that Pax5 reduces Z activation of early lytic viral promoters in reporter gene assays and inhibits Z binding to lytic viral promoters in vivo. We confirm that Pax5 and Z directly interact	SIGNOR-269082
Q13283	P0DTC9	0	binding	down-regulates activity	null	N targets stress granule protein G3BP1, an essential antiviral protein which is known to induce innate immune response through multiple mechanisms	SIGNOR-260749
Q9NQS7	Q96GD4	2	phosphorylation	up-regulates	0.974	Human incenp was a substrate of aurora b and mass spectrometry identified three consecutive residues (threonine 893, serine 894, and serine 895) containing at least two phosphorylation sites.	SIGNOR-118015
Q96GD4	Q9NQS7	2	binding	up-regulates	0.974	Using recombinant proteins, we found that aurora b kinase activity was stimulated by incenp and that the c-terminal region of incenp was sufficient for activation.	SIGNOR-86218
Q96BI3	Q92542	2	binding	up-regulates	0.967	We show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. Similar to the loss of presenilin or nicastrin, the inactivation of endogenous maph-1 using small interfering rnas results in the decrease of presenilin levels, accumulation of gamma-secretase substrates (app carboxyl-terminal fragments), and reduction of gamma-secretase products (amyloid-beta peptides and the intracellular domains of app and notch).	SIGNOR-103611
Q92542	Q96BI3	2	binding	up-regulates	0.967	By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain.	SIGNOR-93259
O14920	Q9Y6K9	2	binding	up-regulates activity	0.962	The n-terminal domain of ikkgamma is required both for the binding of ikkalfa and ikkbeta and their assembly into a high-molecular-weight complex essential for activation	SIGNOR-91705
Q9Y6K9	O14920	2	phosphorylation	down-regulates activity	0.962	In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I	SIGNOR-158659
P23443	P42345	2	phosphorylation	up-regulates activity	0.96	S6K1 is a positive regulator of protein synthesis, and its activity is induced by mTOR-mediated phosphorylation.	SIGNOR-101328
P42345	P23443	2	phosphorylation	down-regulates activity	0.96	Importantly, phosphorylation of mTOR by S6K1 occurs at threonine 2446/serine 2448. This region has been shown previously to be part of a regulatory repressor domain. These sites are also constitutively phosphorylated in the breast cancer cell line MCF7 carrying an amplification of the S6K1 geneit has been proposed that other inputs, in addition to phosphorylation of Thr-2446/Ser-2448 by S6K1, are part of the mechanism involved in inhibiting this repressor domain	SIGNOR-102051
P24864	P24941	2	phosphorylation	down-regulates	0.955	Phosphorylation-triggered ubiquitination has been proposed to be the major pathway regulating cyclin e protein abundance. Cdk2 activity is required for cyclin e turnover in vivo because it phosphorylates s384. Mutation of ser384 to alanine also rendered cyclin e resistant to degradation	SIGNOR-118555
P24941	P24864	2	binding	up-regulates	0.955	Our results suggest that ad-induced cyclin e activates cdk2 that targets the transcriptional repressor prb/cyclin e activates the cdk2 kinase necessary for the actual initiation of dna replication	SIGNOR-201506
P38936	P24941	2	phosphorylation	down-regulates quantity by destabilization	0.954	Cdk2 destabilizes p21 via the cy2 cyclin-binding motif and p21 phosphorylation at ser-130.	SIGNOR-149416
P24941	P38936	2	binding	down-regulates	0.954	Considering that akt1 phosphorylates p21, this dissociation likely results from phosphorylation of p21 and release of cdk2.	SIGNOR-149711
P24941	P46527	2	binding	down-regulates	0.95	P27, an important cell cycle regulator, blocks the g(1)/s transition in cells by binding and inhibiting cdk2/cyclin a and cdk2/cyclin e complexes (cdk2/e).	SIGNOR-154191
P46527	P24941	2	phosphorylation	down-regulates	0.95	Ubiquitination and subsequent degradation play a critical role in regulating the levels of p27 during cell cycle progression. Here we provide evidence suggesting that both cdk2/e and phosphorylation of thr(187) on p27 are essential for the recognition of p27 by the scf(skp2/cks1) complex, the ubiquitin-protein isopeptide ligase (e3).	SIGNOR-154188
Q00535	Q15078	2	binding	up-regulates activity	0.943	Cyclin-dependent kinase 5 (Cdk5) is required for proper development of the mammalian central nervous system. To be activated, Cdk5 has to associate with its regulatory subunit, p35. We have found that p25, a truncated form of p35, accumulates in neurons in the brains of patients with Alzheimer's disease. This accumulation correlates with an increase in Cdk5 kinase activity. Unlike p35, p25 is not readily degraded, and binding of p25 to Cdk5 constitutively activates Cdk5, changes its cellular location and alters its substrate specificity.	SIGNOR-268153
Q15078	Q00535	2	phosphorylation	down-regulates	0.943	P35 phosphorylation by cdk5 interferes with the microtubule-binding and polymerizing activities of p35. Using a mutational approach, we found that only phosphorylation at thr-138, one of the two residues primarily phosphorylated in vivo, inhibits the polymerizing activity	SIGNOR-177967
P59768	P62873	2	binding	up-regulates activity	0.94	GNB1 dissociates from the receptor, bound with GNG2 as stable dimer	SIGNOR-251105
P78527	P12956	2	relocalization	up-regulates	0.94	Ku and dna-pkcs only interact in the presence of dna and recruitment of dna-pkcs to sites of dna damage in vivo is ku-dependent. Inward translocation of ku allows dna-pkcs to interact with the extreme termini of the dna, allowing two dna-pkcs molecules to interact across the dsb in a so-called synaptic complex . This interaction stimulates the kinase activity of dna-pkcs, promoting phosphorylation in trans across the dsb (discussed in more detail below). Once assembled at the dna ends, the dna-pkcs-ku-dsb complex serves to tether the ends of the dsb together and protects the dna ends from nuclease attack.	SIGNOR-183276
P62873	P59768	2	binding	up-regulates activity	0.94	GNG2 dissociates from the activated receptor, bound with GNB1 as stable dimer.	SIGNOR-251106
P12956	P78527	2	phosphorylation	up-regulates activity	0.94	Ku70 phosphorylation occurs within minutes of genotoxic stress and involves DNA-PKcs and/or ATM kinase activities.By using specific vectors enabling the simultaneous shRNA-mediated inhibition of endogenous Ku70 and the expression of exogenous Ku70 resistant to shRNA (i.e. S27-S33-Ku70 and A27-A33-Ku70 expressing cells), we showed that phospho-Ku70 contributes to faster but error-prone DNA repair resulting in higher levels of chromosomal breaks.	SIGNOR-274023
Q15831	Q7RTN6	2	phosphorylation	up-regulates quantity	0.939	Furthermore, interaction of STRAD with LKB1 promoted LKB1 phosphorylation at a PKA site S431 and elevated the LKB1 level, and overexpressing LKB1 with a serine-to-alanine mutation at S431 (LKB1 (S431A)) prevented axon differentiation.	SIGNOR-280149
Q7RTN6	Q15831	2	phosphorylation	up-regulates activity	0.939	Endogenous LKB1 and STRAD form a complex in which STRAD activates LKB1, resulting in phosphorylation of both partners.LKB1 phosphorylates STRAD at Thr329 and Thr419	SIGNOR-261950
P27986	P42336	2	phosphorylation	up-regulates activity	0.936	We find that p110 alpha phosphorylates p85 alpha Ser608 in vivo with significant stoichiometry. However, p110 beta is far less efficient at phosphorylating p85 alpha Ser608, identifying a potential difference in the mechanisms by which these two isoforms are regulated. The p85 alpha Ser608 phosphorylation was increased by treatment with insulin, platelet-derived growth factor, and the phosphatase inhibitor okadaic acid. The functional effects of this phosphorylation are highlighted by mutation of Ser608, which results in reduced lipid kinase activity and reduced association of the p110 alpha catalytic subunit with p85 alpha.	SIGNOR-276004
P42336	P27986	2	binding	up-regulates activity	0.936	Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival	SIGNOR-242637
O14490	P78352	2	relocalization	up-regulates activity	0.932	Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b).	SIGNOR-264196
P78352	O14490	2	binding	up-regulates activity	0.932	SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area.	SIGNOR-264209
Q15750	O43318	2	phosphorylation	up-regulates activity	0.929	We identified amino acids (aa) 452/453 and 456/457 of TAB1 as novel sites phosphorylated by TAK1 as well as by p38 MAPK in intact cells as well as in vitro.	SIGNOR-276365
P31749	P42345	2	phosphorylation	up-regulates activity	0.929	The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1	SIGNOR-252599
O43318	Q15750	2	binding	up-regulates activity	0.929	The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. Tab1 activates the kinase activity of tak1 by directly binding to its catalytic domain. Tab1 overexpression increase the kinase activity of tak1 in mammalian cells.	SIGNOR-153031
P42345	P31749	2	phosphorylation	up-regulates	0.929	Once phosphorylated, Akt can act on a broad spectrum of substrates that can influence cell survival and proliferation and protein synthesis (65). Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K	SIGNOR-255107
P01019	P00797	2	cleavage	up-regulates activity	0.928	Angiotensinogen, an _-glycoprotein, is released from the liver (152, 250, 444) and is cleaved in the circulation by the enzyme renin that is secreted from the juxtaglomerular apparatus of the kidney (245, 250, 540, 631) to form the decapeptide angiotensin (ANG) I	SIGNOR-252297
P00797	P01019	2	binding	up-regulates activity	0.928	Renin is an aspartic protease that enzymatically cleaves its substrate angiotensinogen, which is produced by the liver, to form an inactive peptide: angiotensin (Ang)I or Ang (1–10).	SIGNOR-260224
P43405	P15498	2	binding	up-regulates	0.92	Vav interacts with the tyrosine kinase syk	SIGNOR-107049
P15498	P43405	2	phosphorylation	up-regulates	0.92	Vav interacts with the tyrosine kinase syk. inhibition of syk kinase activity prevents tyrosine phosphorylation of vav and its interaction with pi 3-k.	SIGNOR-107046
Q9NR28	P98170	2	ubiquitination	down-regulates quantity by destabilization	0.914	Xiap functions as ubiquitin ligase toward smac to inhibit apoptosis.	SIGNOR-134504
P98170	Q9NR28	2	binding	down-regulates activity	0.914	Smac/diablo, an inhibitor of xiap, is released from mitochondria upon receiving apoptotic stimuli and binds to the bir2 and bir3 domains of xiap, thereby inhibiting its caspase-inhibitory activity	SIGNOR-110831
Q9Y4K3	P51617	2	binding	up-regulates activity	0.913	Il-1 treatment of 293 cells induces the association of traf6 with irak.	SIGNOR-44234
P51617	Q9Y4K3	2	ubiquitination	up-regulates activity	0.913	K63-linked polyubiquitination of proximal signaling proteins is a common mechanism used by diverse innate immune receptors for recruiting IKK and activating NF-_B	SIGNOR-252252
Q13546	Q14790	2	cleavage	down-regulates activity	0.909	These results suggested that the aspartic acid at position 324 is the cleavage site of ripk1. In this study we found that receptor-interacting protein (ripk1) is cleaved by casp8 when cells undergo tnf-induced apoptosis. The cleavage of ripk1 abolished its nf-kb inducing ability.	SIGNOR-71265
Q14790	Q13546	2	binding	up-regulates activity	0.909	Tradd and rip1 associate with fadd and caspase-8, forming a cytoplasmic complex	SIGNOR-104255
P28482	Q16828	2	dephosphorylation	down-regulates activity	0.904	Dual-specificity phosphatase six (DUSP6, MKP3, or PYST1) dephosphorylates phosphotyrosine and phosphothreonine residues on ERK-2 (MAPK1) to inactivate the ERK-2 kinase.	SIGNOR-277006
Q16828	P28482	2	phosphorylation	down-regulates quantity by destabilization	0.904	In vitro phosphorylation assays using glutathione S-transferase (GST)-MKP-3 fusion proteins indicated that ERK2 could phosphorylate MKP-3 on serines 159 and 197Double serine mutants of MKP-3 or MKP-3-GFP were more efficiently protected from degradation than single mutants or wild-type MKP-3, indicating that phosphorylation of either serine by ERK1/2 enhances proteasomal degradation of MKP-3.	SIGNOR-132971
Q9NPD8	Q9NW38	2	ubiquitination	down-regulates quantity	0.901	Monoubiquitination of UBE2T was enhanced by FANCL introduction, suggesting that FANCL feeds back to UBE2T and can downregulate its activity.Although the FA pathway has been extensively studied, the E2 enzyme cooperating with the FA core complex for monoubiquitination of FANCD2 has not been discovered.\|This monoubiquitination is stimulated by the presence of the FANCL protein and inactivates UBE2T.	SIGNOR-278809
Q9NW38	Q9NPD8	2	ubiquitination	up-regulates activity	0.901	Using the Fanconi Anemia pathway exclusive E3-E2 pair, FANCL-Ube2T, we report the atomic structure of the FANCL RING-Ube2T complex\|Our structural and biochemical analyses suggest that, in a cellular environment with multiple E2s present, FANCL will preferentially select Ube2T.	SIGNOR-263263
Q9NR28	Q13490	2	ubiquitination	down-regulates quantity by destabilization	0.895	Here we show that cIAP1 and cIAP2 are E3 ubiquitin-protein isopeptide ligases (ubiquitin ligases) for Smac. cIAPs stimulate Smac ubiquitination both in vivo and in vitro, leading to Smac degradation. cIAP1 and cIAP2 associate with overlapping but distinct subsets of E2 (ubiquitin carrier protein) ubiquitin-conjugating enzymes. The substrate-dependent E3 activity of cIAPs is mediated by their RING domains and is dependent on the specific interactions between cIAPs and Smac.	SIGNOR-271392
Q13490	Q9NR28	2	binding	down-regulates quantity	0.895	Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, IAPs, and removing their inhibitory activity. Smac is normally a mitochondrial protein but is released into the cytosol when cells undergo apoptosis.	SIGNOR-80206
Q13489	Q12933	2	binding	up-regulates	0.892	A traf2 trimer interacts with one ciap2 both in the crystal and in solution through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2 (13). Traf2 recruit ciap1 and ciap2. A traf2 trimer interacts with one ciap2 both in the crystal and in solution.	SIGNOR-182124
Q12933	Q13489	2	ubiquitination	down-regulates quantity by destabilization	0.892	Traf3-binding receptors stabilize nik by activating ciap-dependent degradation of traf2 and traf3.	SIGNOR-182131
P22681	P00533	2	relocalization	up-regulates	0.886	Likewise, cbl is recruited to erbb1 either directly (tyr1045), or indirectly, trough grb2	SIGNOR-147826
P00533	P22681	2	ubiquitination	down-regulates quantity by destabilization	0.886	Ligand binding to EGFR also leads to rapid internalization and proteosomal/lysosomal degradation of the receptors. This process results in a dramatic downregulation of both total and cell surface receptors. EGF-induced degradation of EGFR is thought to be initiated by phosphorylation of tyrosine 1045 of the receptor followed by binding of Cbl adaptor proteins and ubiquitination of the receptor. Internalized EGFR is transported to early endosomes where receptor-ligand complexes are sorted for either degradation or recycling to the cell surface.	SIGNOR-65642
Q13043	Q9H4B6	2	binding	up-regulates quantity by stabilization	0.886	Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation.	SIGNOR-261958
Q9H4B6	Q13043	2	null	up-regulates	0.886	In vitro phosphorylation experiments indicate that the phosphorylation of Sav by Mst is direct. The stabilizing effect of Mst was much greater on N-terminally truncated hSav mutants, as long as they retained the ability to bind Mst. Mst mutants that lacked the C-terminal coiled-coil domain and were unable to bind to hSav, also failed to stabilize or phosphorylate hSav	SIGNOR-217833
Q9HCE7	O15105	2	relocalization	up-regulates activity	0.882	One of the major mechanisms underlying the inhibitory effect of Smad7 on TGF-_ signaling operates through accelerating T_RI turnover by recruiting ubiquitin E3 ligases such as Smurf1 and Smurf2	SIGNOR-175269
O15105	Q9HCE7	2	ubiquitination	down-regulates activity	0.882	Smad ubiquitin regulatory factor 1 (Smurf1), a HECT type E3 ubiquitin ligase, interacts with inhibitory Smad7 and induces translocation of Smad7 to the cytoplasm	SIGNOR-97064
P31323	P17612	2	phosphorylation	up-regulates activity	0.881	Serine 114 phosphorylation is required for both nuclear localization and down-regulation of il-2 production by riibeta.	SIGNOR-125545
P17612	P31323	2	binding	down-regulates activity	0.881	Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets	SIGNOR-258754
P40818	Q9H4P4	2	ubiquitination	down-regulates quantity by destabilization	0.88	RNF41 redistributes and ubiquitylates USP8, and reduces USP8 levels.	SIGNOR-259106
Q8IZP0	P00519	2	phosphorylation	up-regulates	0.88	Abi-1 is an adaptor protein for abelson kinase (c-abl). Here, we identified a new phosphorylation site (y398) in the sh3 domain of abi1, and disruption of y398, combined with the previously identified phosphorylation site y213, significantly weakens the binding of abi-1 to c-abl. Phosphorylation of abi-1 is dependent on c-abl kinase	SIGNOR-172017
P00519	Q8IZP0	2	binding	up-regulates	0.88	Our results are in agreement with previous report showing that abi-1, the putative mouse homologue of e3b1, is a abl binding protein	SIGNOR-45994
Q9H4P4	P40818	2	deubiquitination	up-regulates quantity by stabilization	0.88	Ubiquitin-specific protease 8 (USP8), an RNF41-interacting deubiquitylating enzyme (DUB) stabilizes RNF41 and is involved in trafficking of various transmembrane proteins.	SIGNOR-259105
P45983	Q9UQF2	2	binding	down-regulates	0.879	The jip proteins function by aggregating components of a map kinase module (including mlk, mkk7, and jnk) and facilitate signal transmission by the protein kinase cascade. Overexpression of jip1 deactivates the jnk pathway selectively by cytoplasmic retention of jnk and thereby inhibits gene expression mediated by jnk, which occurs in the nucleus	SIGNOR-124727
Q9UQF2	P45983	2	phosphorylation	up-regulates activity	0.879	After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1.	SIGNOR-250128
Q92793	Q04206	2	binding	up-regulates	0.879	Both p53 and rela(p65) interact with the transcriptional coactivator proteins p300 and creb-binding protein (cbp), and we demonstrate that these results are consistent with competition for a limiting pool of p300/cbp complexes in vivo.	SIGNOR-66953
Q04206	Q92793	2	acetylation	up-regulates	0.879	Rela is also acetylated at several sites by p300 and cbp	SIGNOR-143396
Q12933	Q13490	2	ubiquitination	down-regulates quantity by destabilization	0.873	Traf3-binding receptors stabilize nik by activating ciap-dependent degradation of traf2 and traf3.	SIGNOR-182128
Q13490	Q12933	2	binding	up-regulates activity	0.873	The c-iaps associate with traf1 and traf3	SIGNOR-39527
P00533	Q06124	2	dephosphorylation	down-regulates activity	0.87	Given that substrate trapping occurred in intact cells and that the interaction was very specific, it is highly likely that egfr and gab1 represent physiological shp2 substrates.To further confirm that phosphotyrosyl proteins trapped by SHP2 are target substrates, we carried out an immunocomplex in vitrophosphatase assay.The WT protein partially dephosphorylated both the EGFR and Gab1, whereas the DM protein did not	SIGNOR-236424
O15105	Q9HAU4	2	polyubiquitination	down-regulates quantity by destabilization	0.87	Smad7 Recruits Smurf2 to the TGFβ Receptor Complex. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways.	SIGNOR-272940
Q9HAU4	O15105	2	relocalization	up-regulates activity	0.87	Smurf2 is nuclear, but binding to smad7 induces export and recruitment to the activated tgf beta receptor, where it causes degradation of receptors and smad7 via proteasomal and lysosomal pathways.	SIGNOR-104996
Q06124	P00533	2	phosphorylation	up-regulates activity	0.87	EGFRvIII transformation may be due to the enhanced PTPase activity from higher basal SHP-2 Tyr542 phosphorylation induced by EGFRvIII ( xref ).\|These results suggest that EGFRvIII expression recruits SHP-2 to an activated complex and induces SHP-2 Tyr542 and its PTPase activity in GBM cells.	SIGNOR-279460

Q15173

Q96M94

0

binding

down-regulates quantity by destabilization

0.2

Here, we report that KLHL15-Cul3 specifically targets B'β to promote turnover of the PP2A subunit by ubiquitylation and proteasomal degradation. We mapped KLHL15 residues critical for homodimerization as well as interaction with Cul3 and B'β.

SIGNOR-272017

P52907

P68400

0

phosphorylation

up-regulates

0.2

We demonstrate that ser9 of cpalpha is phosphorylated by protein kinase ck2 in vitro, that cpalpha is phosphorylated in vivo. Finally, we demonstrate that ckip-1 and ck2 inhibit the activity of actin capping protein at the barbed ends of actin filaments.

SIGNOR-135422

P18848

P67870

0

phosphorylation

down-regulates quantity by destabilization

0.2

By using mutants of ATF4 we identified serine 215 as the main CK2 phosphorylation site. The ATF4 S215A mutant turned out to be more stable than the wild-type form.

SIGNOR-276424

Q5TKA1

Q00526

0

phosphorylation

up-regulates

0.2

In this report, we demonstrate that cyclin e1/cdk3 phosphorylates lin-9 on thr-96. Mutating thr-96 to alanine inhibits activation of cyclins a2 and b1 promoters, whereas a phosphomimetic asp mutant strongly activates their promoters and triggers accelerated entry into g2/m phase in 293t cells.

SIGNOR-204529

P83916

Q5XPI4

0

polyubiquitination

down-regulates quantity by destabilization

0.2

In the present study, we report that HP1α and β undergo proteasomal degradation in lamin A/C knock-down cells and show by ectopic expression, RNAi and binding studies that the RING finger ubiquitin ligase RNF123 is directly involved in HP1 degradation.

SIGNOR-272034

O75807

P19484

0

transcriptional regulation

up-regulates quantity by expression

0.2

We found that the main regulator of the starvation-induced transcriptional program, TFEB, counteracts protein synthesis inhibition by directly activating expression of GADD34, a component of the protein phosphatase 1 complex that dephosphorylates eIF2α.

SIGNOR-276789

Q96RK0

Q15418

0

phosphorylation

down-regulates

0.2

Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3)

SIGNOR-169883

O60566

Q8NG31

0

binding

up-regulates

0.2

Association of the amino and middle domain of blinkin with the tpr domains in the amino termini of bubr1 and bub1 is essential for bubr1 and bub1 to execute their distinct mitotic functions

SIGNOR-158894

Q12834

Q9UHD2

0

phosphorylation

down-regulates activity

0.2

It was found that TBK1 phosphorylates both Cdc20 as well as Cdh1 (Figure 2F).

SIGNOR-279766

Q15746

P31260

0

transcriptional regulation

up-regulates quantity by expression

0.2

Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively

SIGNOR-261643

Q70Z35

P62136

0

dephosphorylation

up-regulates activity

0.2

PREX2 is dephosphorylated by PP1α and PP2A.PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ.

SIGNOR-277183

Q9BV40

Q86YJ5

0

ubiquitination

down-regulates quantity by destabilization

0.2

MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.

SIGNOR-271531

Q75N03

P08238

0

binding

up-regulates quantity

0.2

By immunoprecipitation, we present evidence that Hakai interacts with Hsp90 chaperone complex in several epithelial cells and demonstrate that is a novel Hsp90 client protein. Interestingly, by overexpressing and knocking-down experiments with Hakai, we identified Annexin A2 as a Hakai-regulated protein. Interestingly, geldanamycin-induced Hakai degradation is accompanied by an increased expression of E-cadherin and Annexin A2. Hsp90 participates in the correct folding of its client proteins, allowing them to maintain their stability and activity.

SIGNOR-271475

Q14676

P16104

0

binding

up-regulates

0.2

Here, we demonstrate that mammalian mdc1/nfbd1 directly binds to phospho-h2ax (gammah2ax) by specifically interacting with the phosphoepitope at the gammah2ax carboxyl terminus.

SIGNOR-143377

Q14141

Q8IYM1

0

binding

down-regulates

0.2

Sept12 interacts with sept6 and this interaction alters the filament structure of sept6 in hela cells.

SIGNOR-159537

P68431

Q9UPS6

0

methylation

down-regulates activity

0.2

SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks.

SIGNOR-265576

Q9NZQ7

Q13451

0

catalytic activity

up-regulates quantity by expression

0.2

FKBP51s upregulated PD-L1 expression on the plasma membrane by catalysing the protein folding required for subsequent glycosylation. Inhibition of FKBP51s isomerase activity by SAFit decreased PD-L1 levels

SIGNOR-274973

P63096

Q96LB1

0

binding

up-regulates activity

0.2

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

SIGNOR-257059

P16144

P17612

0

phosphorylation

down-regulates

0.2

Additionally, we show that s1360 and s1364 of beta4 are the only residues phosphorylated by pkc and pka in cells, respectivelywe have defined three regions on beta4 that together harbor all the serine and threonine phosphorylation sites and show that three serines (s1356, s1360, and s1364), previously implicated in hd regulation, prevent the interaction of beta4 with the plectin actin-binding domain when phosphorylated

SIGNOR-156873

Q05066

P19544

0

binding

up-regulates

0.2

Here we report that wt1 binds to and acts synergistically with sry to activate transcription from a promoter containing sry-binding sites

SIGNOR-100345

P32519

P62714

0

dephosphorylation

down-regulates activity

0.2

Elf-1 enhances the expression of CD3zeta, whereas it suppresses the expression of FcRgamma gene and lupus T cells have decreased amounts of DNA-binding 98 kDa form of Elf-1. We show that the aberrantly increased PP2A in lupus T cells dephosphorylates Elf-1 at Thr-231. Dephosphorylation results in limited expression and binding of the 98 kDa Elf-1 form to the CD3zeta and FcRgamma promoters. Suppression of the expression of the PP2A leads to increased expression of CD3zeta and decreased expression of FcRgamma genes and correction of the early signaling response

SIGNOR-248591

Q9UPP1

P68400

0

phosphorylation

up-regulates activity

0.2

The CK2 kinase is responsible for PHF8 phosphorylation at Ser854. PHF8 is phosphorylated by CK2, which regulates binding of PHF8 to TopBP1. The Ser854 residue of PHF8 is required for its interaction with TopBP1.

SIGNOR-273628

Q7Z6Z7

P43405

0

phosphorylation

up-regulates activity

0.2

Collectively, these data suggest that TNF induced tyrosine phosphorylation of Mule by Syk contributes to its E3 ligase activity.

SIGNOR-280150

P0C0S8

O76064

0

ubiquitination

up-regulates

0.2

Rnf8 and ubc13 ubiquitylate h2a and h2ax, but other substrates probably exist.

SIGNOR-166174

O15350

P05771

0

phosphorylation

up-regulates activity

0.2

Here, we report that p73 is able to induce cell cycle arrest independently of its amino-terminal transactivation domain, whereas this domain is crucial for p73 proapoptotic functions. its activity is regulated throughout the cell cycle and modified by protein kinase C-dependent phosphorylation at serine residue 388.

SIGNOR-276234

P08754

P21452

0

binding

up-regulates activity

0.2

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

SIGNOR-256879

Q7Z434

P0DTC5

0

binding

down-regulates activity

0.1

Here, we identified SARS-CoV-2 membrane glycoprotein M as a negative regulator of the innate immune response. We found that the M protein interacted with the central adaptor protein MAVS in the innate immune response pathways. This interaction impaired MAVS aggregation and its recruitment of downstream TRAF3, TBK1, and IRF3, leading to attenuation of the innate antiviral response. Our findings reveal a mechanism by which SARS-CoV-2 evades the innate immune response and suggest that the M protein of SARS-CoV-2 is a potential target for the development of SARS-CoV-2 interventions.

SIGNOR-262515

P17844

P0C6X7

0

binding

up-regulates activity

null

To our knowledge, this is the first report to show that SARS-CoV helicase can interact directly with multifunctional protein Ddx5 in cell culture and that inhibition of Ddx5 results in the suppression of viral replication. We speculate that Ddx5 may act as a coactivator by direct binding to the SARS-CoV helicase, resulting in enhanced viral genome transcription and virus proliferation.

SIGNOR-260250

P03206

Q02548

0

binding

down-regulates activity

null

... we demonstrate that Pax5 inhibits Z-mediated lytic viral gene expression and the release of infectious viral particles in latently infected epithelial cell lines. Conversely, we found that shRNA-mediated knockdown of endogenous Pax5 in a Burkitt lymphoma B-cell line leads to viral reactivation. Furthermore, we show that Pax5 reduces Z activation of early lytic viral promoters in reporter gene assays and inhibits Z binding to lytic viral promoters in vivo. We confirm that Pax5 and Z directly interact

SIGNOR-269082

Q13283

P0DTC9

0

binding

down-regulates activity

null

N targets stress granule protein G3BP1, an essential antiviral protein which is known to induce innate immune response through multiple mechanisms

SIGNOR-260749

Q9NQS7

Q96GD4

2

phosphorylation

up-regulates

0.974

Human incenp was a substrate of aurora b and mass spectrometry identified three consecutive residues (threonine 893, serine 894, and serine 895) containing at least two phosphorylation sites.

SIGNOR-118015

Q96GD4

Q9NQS7

2

binding

up-regulates

0.974

Using recombinant proteins, we found that aurora b kinase activity was stimulated by incenp and that the c-terminal region of incenp was sufficient for activation.

SIGNOR-86218

Q96BI3

Q92542

2

binding

up-regulates

0.967

We show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. Similar to the loss of presenilin or nicastrin, the inactivation of endogenous maph-1 using small interfering rnas results in the decrease of presenilin levels, accumulation of gamma-secretase substrates (app carboxyl-terminal fragments), and reduction of gamma-secretase products (amyloid-beta peptides and the intracellular domains of app and notch).

SIGNOR-103611

Q92542

Q96BI3

2

binding

up-regulates

0.967

By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain.

SIGNOR-93259

O14920

Q9Y6K9

2

binding

up-regulates activity

0.962

The n-terminal domain of ikkgamma is required both for the binding of ikkalfa and ikkbeta and their assembly into a high-molecular-weight complex essential for activation

SIGNOR-91705

Q9Y6K9

O14920

2

phosphorylation

down-regulates activity

0.962

In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I

SIGNOR-158659

P23443

P42345

2

phosphorylation

up-regulates activity

0.96

S6K1 is a positive regulator of protein synthesis, and its activity is induced by mTOR-mediated phosphorylation.

SIGNOR-101328

P42345

P23443

2

phosphorylation

down-regulates activity

0.96

Importantly, phosphorylation of mTOR by S6K1 occurs at threonine 2446/serine 2448. This region has been shown previously to be part of a regulatory repressor domain. These sites are also constitutively phosphorylated in the breast cancer cell line MCF7 carrying an amplification of the S6K1 geneit has been proposed that other inputs, in addition to phosphorylation of Thr-2446/Ser-2448 by S6K1, are part of the mechanism involved in inhibiting this repressor domain

SIGNOR-102051

P24864

P24941

2

phosphorylation

down-regulates

0.955

Phosphorylation-triggered ubiquitination has been proposed to be the major pathway regulating cyclin e protein abundance. Cdk2 activity is required for cyclin e turnover in vivo because it phosphorylates s384. Mutation of ser384 to alanine also rendered cyclin e resistant to degradation

SIGNOR-118555

P24941

P24864

2

binding

up-regulates

0.955

Our results suggest that ad-induced cyclin e activates cdk2 that targets the transcriptional repressor prb/cyclin e activates the cdk2 kinase necessary for the actual initiation of dna replication

SIGNOR-201506

P38936

P24941

2

phosphorylation

down-regulates quantity by destabilization

0.954

Cdk2 destabilizes p21 via the cy2 cyclin-binding motif and p21 phosphorylation at ser-130.

SIGNOR-149416

P24941

P38936

2

binding

down-regulates

0.954

Considering that akt1 phosphorylates p21, this dissociation likely results from phosphorylation of p21 and release of cdk2.

SIGNOR-149711

P24941

P46527

2

binding

down-regulates

0.95

P27, an important cell cycle regulator, blocks the g(1)/s transition in cells by binding and inhibiting cdk2/cyclin a and cdk2/cyclin e complexes (cdk2/e).

SIGNOR-154191

P46527

P24941

2

phosphorylation

down-regulates

0.95

Ubiquitination and subsequent degradation play a critical role in regulating the levels of p27 during cell cycle progression. Here we provide evidence suggesting that both cdk2/e and phosphorylation of thr(187) on p27 are essential for the recognition of p27 by the scf(skp2/cks1) complex, the ubiquitin-protein isopeptide ligase (e3).

SIGNOR-154188

Q00535

Q15078

2

binding

up-regulates activity

0.943

Cyclin-dependent kinase 5 (Cdk5) is required for proper development of the mammalian central nervous system. To be activated, Cdk5 has to associate with its regulatory subunit, p35. We have found that p25, a truncated form of p35, accumulates in neurons in the brains of patients with Alzheimer's disease. This accumulation correlates with an increase in Cdk5 kinase activity. Unlike p35, p25 is not readily degraded, and binding of p25 to Cdk5 constitutively activates Cdk5, changes its cellular location and alters its substrate specificity.

SIGNOR-268153

Q15078

Q00535

2

phosphorylation

down-regulates

0.943

P35 phosphorylation by cdk5 interferes with the microtubule-binding and polymerizing activities of p35. Using a mutational approach, we found that only phosphorylation at thr-138, one of the two residues primarily phosphorylated in vivo, inhibits the polymerizing activity

SIGNOR-177967

P59768

P62873

2

binding

up-regulates activity

0.94

GNB1 dissociates from the receptor, bound with GNG2 as stable dimer

SIGNOR-251105

P78527

P12956

2

relocalization

up-regulates

0.94

Ku and dna-pkcs only interact in the presence of dna and recruitment of dna-pkcs to sites of dna damage in vivo is ku-dependent. Inward translocation of ku allows dna-pkcs to interact with the extreme termini of the dna, allowing two dna-pkcs molecules to interact across the dsb in a so-called synaptic complex . This interaction stimulates the kinase activity of dna-pkcs, promoting phosphorylation in trans across the dsb (discussed in more detail below). Once assembled at the dna ends, the dna-pkcs-ku-dsb complex serves to tether the ends of the dsb together and protects the dna ends from nuclease attack.

SIGNOR-183276

P62873

P59768

2

binding

up-regulates activity

0.94

GNG2 dissociates from the activated receptor, bound with GNB1 as stable dimer.

SIGNOR-251106

P12956

P78527

2

phosphorylation

up-regulates activity

0.94

Ku70 phosphorylation occurs within minutes of genotoxic stress and involves DNA-PKcs and/or ATM kinase activities.By using specific vectors enabling the simultaneous shRNA-mediated inhibition of endogenous Ku70 and the expression of exogenous Ku70 resistant to shRNA (i.e. S27-S33-Ku70 and A27-A33-Ku70 expressing cells), we showed that phospho-Ku70 contributes to faster but error-prone DNA repair resulting in higher levels of chromosomal breaks.

SIGNOR-274023

Q15831

Q7RTN6

2

phosphorylation

up-regulates quantity

0.939

Furthermore, interaction of STRAD with LKB1 promoted LKB1 phosphorylation at a PKA site S431 and elevated the LKB1 level, and overexpressing LKB1 with a serine-to-alanine mutation at S431 (LKB1 (S431A)) prevented axon differentiation.

SIGNOR-280149

Q7RTN6

Q15831

2

phosphorylation

up-regulates activity

0.939

Endogenous LKB1 and STRAD form a complex in which STRAD activates LKB1, resulting in phosphorylation of both partners.LKB1 phosphorylates STRAD at Thr329 and Thr419

SIGNOR-261950

P27986

P42336

2

phosphorylation

up-regulates activity

0.936

We find that p110 alpha phosphorylates p85 alpha Ser608 in vivo with significant stoichiometry. However, p110 beta is far less efficient at phosphorylating p85 alpha Ser608, identifying a potential difference in the mechanisms by which these two isoforms are regulated. The p85 alpha Ser608 phosphorylation was increased by treatment with insulin, platelet-derived growth factor, and the phosphatase inhibitor okadaic acid. The functional effects of this phosphorylation are highlighted by mutation of Ser608, which results in reduced lipid kinase activity and reduced association of the p110 alpha catalytic subunit with p85 alpha.

SIGNOR-276004

P42336

P27986

2

binding

up-regulates activity

0.936

Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival

SIGNOR-242637

O14490

P78352

2

relocalization

up-regulates activity

0.932

Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b).

SIGNOR-264196

P78352

O14490

2

binding

up-regulates activity

0.932

SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area.

SIGNOR-264209

Q15750

O43318

2

phosphorylation

up-regulates activity

0.929

We identified amino acids (aa) 452/453 and 456/457 of TAB1 as novel sites phosphorylated by TAK1 as well as by p38 MAPK in intact cells as well as in vitro.

SIGNOR-276365

P31749

P42345

2

phosphorylation

up-regulates activity

0.929

The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1

SIGNOR-252599

O43318

Q15750

2

binding

up-regulates activity

0.929

The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. Tab1 activates the kinase activity of tak1 by directly binding to its catalytic domain. Tab1 overexpression increase the kinase activity of tak1 in mammalian cells.

SIGNOR-153031

P42345

P31749

2

phosphorylation

up-regulates

0.929

Once phosphorylated, Akt can act on a broad spectrum of substrates that can influence cell survival and proliferation and protein synthesis (65). Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K

SIGNOR-255107

P01019

P00797

2

cleavage

up-regulates activity

0.928

Angiotensinogen, an _-glycoprotein, is released from the liver (152, 250, 444) and is cleaved in the circulation by the enzyme renin that is secreted from the juxtaglomerular apparatus of the kidney (245, 250, 540, 631) to form the decapeptide angiotensin (ANG) I

SIGNOR-252297

P00797

P01019

2

binding

up-regulates activity

0.928

Renin is an aspartic protease that enzymatically cleaves its substrate angiotensinogen, which is produced by the liver, to form an inactive peptide: angiotensin (Ang)I or Ang (1–10).

SIGNOR-260224

P43405

P15498

2

binding

up-regulates

0.92

Vav interacts with the tyrosine kinase syk

SIGNOR-107049

P15498

P43405

2

phosphorylation

up-regulates

0.92

Vav interacts with the tyrosine kinase syk. inhibition of syk kinase activity prevents tyrosine phosphorylation of vav and its interaction with pi 3-k.

SIGNOR-107046

Q9NR28

P98170

2

ubiquitination

down-regulates quantity by destabilization

0.914

Xiap functions as ubiquitin ligase toward smac to inhibit apoptosis.

SIGNOR-134504

P98170

Q9NR28

2

binding

down-regulates activity

0.914

Smac/diablo, an inhibitor of xiap, is released from mitochondria upon receiving apoptotic stimuli and binds to the bir2 and bir3 domains of xiap, thereby inhibiting its caspase-inhibitory activity

SIGNOR-110831

Q9Y4K3

P51617

2

binding

up-regulates activity

0.913

Il-1 treatment of 293 cells induces the association of traf6 with irak.

SIGNOR-44234

P51617

Q9Y4K3

2

ubiquitination

up-regulates activity

0.913

K63-linked polyubiquitination of proximal signaling proteins is a common mechanism used by diverse innate immune receptors for recruiting IKK and activating NF-_B

SIGNOR-252252

Q13546

Q14790

2

cleavage

down-regulates activity

0.909

These results suggested that the aspartic acid at position 324 is the cleavage site of ripk1. In this study we found that receptor-interacting protein (ripk1) is cleaved by casp8 when cells undergo tnf-induced apoptosis. The cleavage of ripk1 abolished its nf-kb inducing ability.

SIGNOR-71265

Q14790

Q13546

2

binding

up-regulates activity

0.909

Tradd and rip1 associate with fadd and caspase-8, forming a cytoplasmic complex

SIGNOR-104255

P28482

Q16828

2

dephosphorylation

down-regulates activity

0.904

Dual-specificity phosphatase six (DUSP6, MKP3, or PYST1) dephosphorylates phosphotyrosine and phosphothreonine residues on ERK-2 (MAPK1) to inactivate the ERK-2 kinase.

SIGNOR-277006

Q16828

P28482

2

phosphorylation

down-regulates quantity by destabilization

0.904

In vitro phosphorylation assays using glutathione S-transferase (GST)-MKP-3 fusion proteins indicated that ERK2 could phosphorylate MKP-3 on serines 159 and 197Double serine mutants of MKP-3 or MKP-3-GFP were more efficiently protected from degradation than single mutants or wild-type MKP-3, indicating that phosphorylation of either serine by ERK1/2 enhances proteasomal degradation of MKP-3.

SIGNOR-132971

Q9NPD8

Q9NW38

2

ubiquitination

down-regulates quantity

0.901

Monoubiquitination of UBE2T was enhanced by FANCL introduction, suggesting that FANCL feeds back to UBE2T and can downregulate its activity.Although the FA pathway has been extensively studied, the E2 enzyme cooperating with the FA core complex for monoubiquitination of FANCD2 has not been discovered.|This monoubiquitination is stimulated by the presence of the FANCL protein and inactivates UBE2T.

SIGNOR-278809

Q9NW38

Q9NPD8

2

ubiquitination

up-regulates activity

0.901

Using the Fanconi Anemia pathway exclusive E3-E2 pair, FANCL-Ube2T, we report the atomic structure of the FANCL RING-Ube2T complex|Our structural and biochemical analyses suggest that, in a cellular environment with multiple E2s present, FANCL will preferentially select Ube2T.

SIGNOR-263263

Q9NR28

Q13490

2

ubiquitination

down-regulates quantity by destabilization

0.895

Here we show that cIAP1 and cIAP2 are E3 ubiquitin-protein isopeptide ligases (ubiquitin ligases) for Smac. cIAPs stimulate Smac ubiquitination both in vivo and in vitro, leading to Smac degradation. cIAP1 and cIAP2 associate with overlapping but distinct subsets of E2 (ubiquitin carrier protein) ubiquitin-conjugating enzymes. The substrate-dependent E3 activity of cIAPs is mediated by their RING domains and is dependent on the specific interactions between cIAPs and Smac.

SIGNOR-271392

Q13490

Q9NR28

2

binding

down-regulates quantity

0.895

Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, IAPs, and removing their inhibitory activity. Smac is normally a mitochondrial protein but is released into the cytosol when cells undergo apoptosis.

SIGNOR-80206

Q13489

Q12933

2

binding

up-regulates

0.892

A traf2 trimer interacts with one ciap2 both in the crystal and in solution through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2 (13). Traf2 recruit ciap1 and ciap2. A traf2 trimer interacts with one ciap2 both in the crystal and in solution.

SIGNOR-182124

Q12933

Q13489

2

ubiquitination

down-regulates quantity by destabilization

0.892

Traf3-binding receptors stabilize nik by activating ciap-dependent degradation of traf2 and traf3.

SIGNOR-182131

P22681

P00533

2

relocalization

up-regulates

0.886

Likewise, cbl is recruited to erbb1 either directly (tyr1045), or indirectly, trough grb2

SIGNOR-147826

P00533

P22681

2

ubiquitination

down-regulates quantity by destabilization

0.886

Ligand binding to EGFR also leads to rapid internalization and proteosomal/lysosomal degradation of the receptors. This process results in a dramatic downregulation of both total and cell surface receptors. EGF-induced degradation of EGFR is thought to be initiated by phosphorylation of tyrosine 1045 of the receptor followed by binding of Cbl adaptor proteins and ubiquitination of the receptor. Internalized EGFR is transported to early endosomes where receptor-ligand complexes are sorted for either degradation or recycling to the cell surface.

SIGNOR-65642

Q13043

Q9H4B6

2

binding

up-regulates quantity by stabilization

0.886

Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation.

SIGNOR-261958

Q9H4B6

Q13043

2

null

up-regulates

0.886

In vitro phosphorylation experiments indicate that the phosphorylation of Sav by Mst is direct. The stabilizing effect of Mst was much greater on N-terminally truncated hSav mutants, as long as they retained the ability to bind Mst. Mst mutants that lacked the C-terminal coiled-coil domain and were unable to bind to hSav, also failed to stabilize or phosphorylate hSav

SIGNOR-217833

Q9HCE7

O15105

2

relocalization

up-regulates activity

0.882

One of the major mechanisms underlying the inhibitory effect of Smad7 on TGF-_ signaling operates through accelerating T_RI turnover by recruiting ubiquitin E3 ligases such as Smurf1 and Smurf2

SIGNOR-175269

O15105

Q9HCE7

2

ubiquitination

down-regulates activity

0.882

Smad ubiquitin regulatory factor 1 (Smurf1), a HECT type E3 ubiquitin ligase, interacts with inhibitory Smad7 and induces translocation of Smad7 to the cytoplasm

SIGNOR-97064

P31323

P17612

2

phosphorylation

up-regulates activity

0.881

Serine 114 phosphorylation is required for both nuclear localization and down-regulation of il-2 production by riibeta.

SIGNOR-125545

P17612

P31323

2

binding

down-regulates activity

0.881

Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets

SIGNOR-258754

P40818

Q9H4P4

2

ubiquitination

down-regulates quantity by destabilization

0.88

RNF41 redistributes and ubiquitylates USP8, and reduces USP8 levels.

SIGNOR-259106

Q8IZP0

P00519

2

phosphorylation

up-regulates

0.88

Abi-1 is an adaptor protein for abelson kinase (c-abl). Here, we identified a new phosphorylation site (y398) in the sh3 domain of abi1, and disruption of y398, combined with the previously identified phosphorylation site y213, significantly weakens the binding of abi-1 to c-abl. Phosphorylation of abi-1 is dependent on c-abl kinase

SIGNOR-172017

P00519

Q8IZP0

2

binding

up-regulates

0.88

Our results are in agreement with previous report showing that abi-1, the putative mouse homologue of e3b1, is a abl binding protein

SIGNOR-45994

Q9H4P4

P40818

2

deubiquitination

up-regulates quantity by stabilization

0.88

Ubiquitin-specific protease 8 (USP8), an RNF41-interacting deubiquitylating enzyme (DUB) stabilizes RNF41 and is involved in trafficking of various transmembrane proteins.

SIGNOR-259105

P45983

Q9UQF2

2

binding

down-regulates

0.879

The jip proteins function by aggregating components of a map kinase module (including mlk, mkk7, and jnk) and facilitate signal transmission by the protein kinase cascade. Overexpression of jip1 deactivates the jnk pathway selectively by cytoplasmic retention of jnk and thereby inhibits gene expression mediated by jnk, which occurs in the nucleus

SIGNOR-124727

Q9UQF2

P45983

2

phosphorylation

up-regulates activity

0.879

After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1.

SIGNOR-250128

Q92793

Q04206

2

binding

up-regulates

0.879

Both p53 and rela(p65) interact with the transcriptional coactivator proteins p300 and creb-binding protein (cbp), and we demonstrate that these results are consistent with competition for a limiting pool of p300/cbp complexes in vivo.

SIGNOR-66953

Q04206

Q92793

2

acetylation

up-regulates

0.879

Rela is also acetylated at several sites by p300 and cbp

SIGNOR-143396

Q12933

Q13490

2

ubiquitination

down-regulates quantity by destabilization

0.873

Traf3-binding receptors stabilize nik by activating ciap-dependent degradation of traf2 and traf3.

SIGNOR-182128

Q13490

Q12933

2

binding

up-regulates activity

0.873

The c-iaps associate with traf1 and traf3

SIGNOR-39527

P00533

Q06124

2

dephosphorylation

down-regulates activity

0.87

Given that substrate trapping occurred in intact cells and that the interaction was very specific, it is highly likely that egfr and gab1 represent physiological shp2 substrates.To further confirm that phosphotyrosyl proteins trapped by SHP2 are target substrates, we carried out an immunocomplex in vitrophosphatase assay.The WT protein partially dephosphorylated both the EGFR and Gab1, whereas the DM protein did not

SIGNOR-236424

O15105

Q9HAU4

2

polyubiquitination

down-regulates quantity by destabilization

0.87

Smad7 Recruits Smurf2 to the TGFβ Receptor Complex. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways.

SIGNOR-272940

Q9HAU4

O15105

2

relocalization

up-regulates activity

0.87

Smurf2 is nuclear, but binding to smad7 induces export and recruitment to the activated tgf beta receptor, where it causes degradation of receptors and smad7 via proteasomal and lysosomal pathways.

SIGNOR-104996

Q06124

P00533

2

phosphorylation

up-regulates activity

0.87

EGFRvIII transformation may be due to the enhanced PTPase activity from higher basal SHP-2 Tyr542 phosphorylation induced by EGFRvIII ( xref ).|These results suggest that EGFRvIII expression recruits SHP-2 to an activated complex and induces SHP-2 Tyr542 and its PTPase activity in GBM cells.

SIGNOR-279460