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
P49770	P05198	1	guanine nucleotide exchange factor	up-regulates activity	0.802	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.	SIGNOR-269125
P52797	Q15375	1	binding	up-regulates	0.802	The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion	SIGNOR-52384
P08069	Q9Y4H2	1	phosphorylation	up-regulates	0.802	Our results reveal that igf-1 receptors promote beta-cell development and survival through the irs-2 signalling pathway.	SIGNOR-70477
Q9NRD5	P17252	1	binding	up-regulates activity	0.802	We show that protein interacting with C-kinase 1 (PICK1) recruits activated protein kinase Cα (PKCα) to MycUNC5A at the plasma membrane, stimulating its endocytosis. We identify two PKCα phosphorylation sites at serines 408 and 587, as well as dileucine internalization motifs, which are required for this endocytosis.	SIGNOR-268178
Q15056	P60842	1	binding	up-regulates activity	0.802	Either eIF4B or eIF4H stimulated the initial rate and amplitude of eIF4A-dependent duplex unwinding, and the magnitude of stimulation is dependent on duplex stability	SIGNOR-261294
P15374	P62979	1	cleavage	up-regulates quantity	0.802	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270828
Q8WU20	P62993	1	binding	up-regulates activity	0.802	In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway.	SIGNOR-236953
P12757	Q15796	1	binding	down-regulates activity	0.801	The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway	SIGNOR-236099
P12931	Q14247	1	phosphorylation	down-regulates activity	0.801	Erk phosphorylation and a mimicking S405,418D double mutation enhanced cortactin binding and activation of N-WASP. In contrast, Src phosphorylation inhibited the ability of cortactin previously phosphorylated by Erk, and that of S405,418D double mutant cortactin, to bind and activate N-WASP. Furthermore, Y-->D mutation of three tyrosine residues targeted by Src (Y421, Y466, and Y482) inhibited the ability of S405,418D cortactin to activate N-WASP.	SIGNOR-246513
Q92934	P10415	1	relocalization	down-regulates activity	0.801	Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1.	SIGNOR-133756
P05230	P22607	1	binding	up-regulates	0.801	Reports also show that fgf/fgfr3 signals mediate some of the effects of tgf-beta on embryonic bone formation	SIGNOR-195585
P15374	P62987	1	cleavage	up-regulates quantity	0.801	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270827
P42345	P06730	1	phosphorylation	down-regulates activity	0.801	Mechanistic target of rapamycin complex 1 (mTORC1) phosphorylates and inhibits eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1).	SIGNOR-278963
Q9UKB1	P63208	1	binding	up-regulates	0.801	The scf is composed of skp1, cdc53/cul1, and a specificity-conferring f-box protein. F-box proteins contain two domains, an f-box motif that binds skp1 and allows assembly into skp1/cdc53 complexes, and a second proteinprotein interaction domain that interacts specifically with one or more target proteins. Cdc53/cul1, in turn, interacts with both the e2 and the skp1/f-box protein complex.	SIGNOR-64505
P35222	P24385	1	transcriptional regulation	up-regulates quantity by expression	0.801	One of the most well studied activators of CCND1 transcription is β-catenin, which could be actived by AKT signalling to inducing G1/S transition. When β-catenin is translocated from the cytoplasm to the nucleus, it forms a complex with the ternary complex factor (TCF) and/or lymphoid enhancer-binding factor (LEF) and stimulates cyclin D1 gene transcription (Fig. 4C).In agreement with the data described above, a chromatin immunoprecipitation (ChIP) assay confirmed that TNC regulates the binding of β-catenin to the TCF/LEF-binding site in the CCND1 promoter (Fig. 4C). Additionally, the β-cateninbinding activity with respect to the CCND1 promoter was much higher in TNC-overexpression PANC-1 cells than in the vector controls.	SIGNOR-277738
Q13535	P38398	1	phosphorylation	up-regulates activity	0.8	Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion.	SIGNOR-106432
Q9Y6H5	P37840	1	binding	up-regulates activity	0.8	Synphilin-1 interacts in vivo with α-synuclein, and their coexpression promotes the formation of Lewy body-like inclusions	SIGNOR-272597
Q7Z434	Q14653	1	binding	up-regulates activity	0.8	Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1.	SIGNOR-260143
P12643	Q13873	1	binding	up-regulates	0.8	Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor.	SIGNOR-33425
Q92993	Q13315	1	acetylation	up-regulates activity	0.8	Here, we report that sirtuin 7 (SIRT7)-mediated deacetylation is essential for dephosphorylation and deactivation of ATM. We show that SIRT7, a class III histone deacetylase, interacts with and deacetylates ATM in vitro and in vivo. \|Upon DNA damage, ATM is activated via a series of highly organized machineries, including acetylation by the histone acetyltransferase TIP60 at lysine 3016	SIGNOR-275891
P23458	P40763	1	binding	up-regulates activity	0.8	The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3).	SIGNOR-236369
Q13136	P10586	1	relocalization	up-regulates activity	0.8	We have identified a novel cytoplasmic 160 kDa phosphoserine protein termed LAR-interacting protein 1 (LIP.1), which binds to the LAR membrane-distal D2 protein tyrosine phosphatase domain and appears to localize LAR to focal adhesions.	SIGNOR-264141
P39905	P56159	1	binding	up-regulates	0.8	A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling	SIGNOR-49091
O95886	Q9Y566	1	relocalization	up-regulates activity	0.8	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264592
Q13261	P14784	1	binding	up-regulates	0.8	The il-15 receptor comprises a heterotrimeric complex consisting of the common ?cytokine Receptor (?c), the il-2 ? Receptor subunit (il-2r?), And an il-15-specific ? Receptor (il-15r?)	SIGNOR-157418
Q96EB6	Q9UBK2	1	deacetylation	up-regulates activity	0.799	SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3 SIRT1 activation has been reported to increase dramatically endurance exercise through the activation of PGC-1_ in muscle, which stimulates fatty acid oxidation	SIGNOR-217963
O00444	Q9HC77	1	phosphorylation	up-regulates	0.799	Plk2 phosphorylates the s589 and s595 residues of cpap in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle. Plk4 also phosphorylates s595 of cpap	SIGNOR-166007
Q96SB4	Q07955	1	phosphorylation	up-regulates	0.799	These results suggest that the formation of complexes between sf2/asf and srpks, which is influenced by the phosphorylation state of sf2/asf, may have regulatory roles in the assembly and localization of this splicing factor.	SIGNOR-66465
Q6ZWJ1	Q12846	1	binding	up-regulates activity	0.799	Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4-containing vesicles. These data demonstrate that insulin activation of Akt2 specifically regulates the docking/fusion step of GLUT4-containing vesicles at the plasma membrane through the regulation of Synip phosphorylation and Synip-Syntaxin4 interaction.Thus, our data demonstrate that insulin-stimulated Akt2-dependent phosphorylation of Synip on serine residue 99 results in reduced binding interactions between Synip and Syntaxin4.	SIGNOR-262634
P24941	Q13309	1	phosphorylation	up-regulates quantity by stabilization	0.799	The activity of SCF(Skp2) is regulated by the Cyclin-dependent kinase (CDK)2-mediated phosphorylation of Skp2 on Ser64 allows its expression in mid-G1 phase, even in the presence of active APC(Cdh1). Reciprocally, dephosphorylation of Skp2 by the mitotic phosphatase Cdc14B at the M --> G1 transition promotes its degradation by APC(Cdh1).	SIGNOR-249173
P49023	Q13418	1	binding	up-regulates	0.799	Co-immunoprecipitation from fibroblasts confirmed that the association between paxillin and ilk occurs in vivo in both adherent cells and cells in suspension. [__] thus, paxillin binding is necessary for efficient focal adhesion targeting of ilk and may therefore impact the role of ilk in integrin-mediated signal transduction events.	SIGNOR-106824
Q9H0E2	P51617	1	binding	down-regulates activity	0.799	Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs)	SIGNOR-251980
O00187	P0C0L5	1	cleavage	up-regulates activity	0.798	MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a).	SIGNOR-263422
P62820	O60763	1	binding	up-regulates activity	0.798	Here, the tethering factor p115 was shown to be a Rab1 effector that binds directly to activated Rab1.	SIGNOR-261287
Q13547	P25490	1	deacetylation	down-regulates activity	0.798	Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs.	SIGNOR-268835
P49757	P46531	1	ubiquitination	down-regulates quantity by destabilization	0.798	Mammalian numb proteins promote notch1 receptor ubiquitination and degradation of the notch1 intracellular domain	SIGNOR-99762
P15976	Q8IX07	1	binding	up-regulates activity	0.798	GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1.	SIGNOR-256059
O00187	P0C0L4	1	cleavage	up-regulates activity	0.798	MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a).	SIGNOR-263431
Q15596	P19793	1	binding	up-regulates	0.798	Here, it is demonstrated that mutation of the h11 phenylalanine residues diminishes the ability of rxr to associate with the p160 coactivators tif2 and p/cip, but has little effect on ligand-dependent interactions of the receptor with the unrelated coactivator tif1.	SIGNOR-114847
Q86UR5	O14795	1	relocalization	up-regulates activity	0.798	N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle	SIGNOR-264385
P14138	P24530	1	binding	up-regulates	0.798	These results demonstrate that lys-161 of the receptor is important for high affinity binding with et-3 which, in part, confers the non-selective binding characteristics of the etb receptor for et isopeptides.	SIGNOR-36017
Q9Y490	P05556	1	binding	up-regulates activity	0.798	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257607
P08575	P06239	1	dephosphorylation	up-regulates activity	0.797	CD45 differentially regulates the negatively acting pTyr-505 and positively acting pTyr-394 p56(lck) tyrosine kinase phosphorylation sites. We propose that high wild-type CD45 expression is necessary to dephosphorylate p56(lck) pTyr-394, suppressing CD4 T+ cell lineage commitment and hyperactivity.	SIGNOR-259933
P56704	Q9H461	1	binding	up-regulates	0.797	Structural basis of wnt recognition by frizzled.	SIGNOR-197638
Q9H2X6	P04637	1	phosphorylation	up-regulates	0.797	Based on all these observations, it is legitimate to suggest that axin and daxx seem to adopt both parallel routes and a convergent means to activate p53. In either case, hipk2 seems to be the protein kinase that catalyzes the ser46 phosphorylation.	SIGNOR-151930
P18031	O60674	1	dephosphorylation	down-regulates activity	0.797	Immunoblots with phospho-specific antibodies confirmed that PTP1B suppresses phosphorylation of the Jak2 activation site tyrosines (Y1007/Y1008) and Stat3 in a dose-dependent manner	SIGNOR-248405
Q16829	P28482	1	dephosphorylation	down-regulates	0.797	Pyst2 preferentially dephosphorylates and inactivates p42 map kinase in vitro and in vivo	SIGNOR-60871
Q8IZQ8	P11831	1	binding	up-regulates	0.797	A coactivator of srf, myocd, interacts with srf and activates vsmc expression of contractile genes.	SIGNOR-174322
P49768	P46531	1	cleavage	up-regulates	0.797	Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains.	SIGNOR-72886
Q9H6Z9	Q16665	1	hydroxylation	down-regulates quantity by destabilization	0.797	There are three EglN family members in humans and mice (EglN1, EglN2, and EglN3). Their enzymatic activity requires oxygen, ascorbic acid, iron, and α-ketoglutarate (α-KG). Under hypoxic conditions, EglNs lose their activity and fail to hydroxylate HIFα, which leads to HIFα stabilization	SIGNOR-262000
P24941	P25205	1	phosphorylation	up-regulates	0.796	In this study, we demonstrate that mcm3 is a substrate of cyclin e/cdk2 and can be phosphorylated by cyclin e/cdk2 at thr-722.	SIGNOR-176656
O14965	Q8TEP8	2	phosphorylation	up-regulates activity	0.796	Thus, following their sequential activation in Cep192 complexes, both AurA and Plx1 phosphorylate Cep192.\|We found that Cep192 1\u20131000 -wt promoted AurA and Plx1 activation and itself underwent phosphorylation irrespective of whether it was bound to the endogenous or recombinant Plx1 (i.e. whether Plx1 was docked onto T46 or not) (lanes 6 and 8).	SIGNOR-279797
P19525	O75569	1	phosphorylation	up-regulates activity	0.796	In stressed cells, this activation occurs when PACT, a PKR-binding protein, is phosphorylated and activates PKR.	SIGNOR-280003
Q92547	Q8WXE1	1	binding	up-regulates	0.796	Topbp1 directly activates atr/atrip and promotes atr-mediated chk1 phosphorylation.	SIGNOR-163214
P56704	Q9UP38	1	binding	up-regulates activity	0.796	Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.All the frizzled genes studied have a complex and partially overlapping pattern of expression in different regions of the embryo, and many of them (fz1, 3, 7, 8 and 9) have specific expression in the epithelial somites as well as in the newly formed myotomes.	SIGNOR-169651
Q96QT6	Q96ST3	1	binding	up-regulates activity	0.796	Pf1 interacts with mSin3A in vivo. Gal4-Pf1 repressed activity of the reporter gene fivefold relative to Gal4 alone (Fig. (Fig.5A),5A), suggesting that DNA-bound Pf1 was capable of recruiting functional mSin3A complexes.	SIGNOR-266995
Q9UPQ9	Q9UKV8	1	binding	up-regulates activity	0.796	The assay showed that full-length TNRC6B binds full-length human AGO2. We have identified and molecularly dissected important sequence and structure features in the conserved Ago hooks of S. pombe Tas3 and human TNRC6B. The effect of Ago hook peptides from the shuttling P-body component TNRC6B in our miRNA-mediated translational repression assay (Fig. 5b), in particular, hints at a novel regulatory role of Ago hooks in miRNA-mediated gene repression mechanisms.	SIGNOR-269680
Q8TEP8	O14965	2	binding	up-regulates activity	0.796	These findings demonstrated that Cep192 mediates the AurA-Plk1 interaction and that the formation of the Cep192-AurA-Plk1 complex could be important for activating AurA and Plk1.	SIGNOR-266406
P45983	P04637	1	phosphorylation	up-regulates	0.796	Activated jnk phosphorylates p53	SIGNOR-59812
P45983	P17535	1	phosphorylation	up-regulates	0.796	Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase.	SIGNOR-196038
O14543	O60674	1	binding	down-regulates activity	0.796	The ability of SOCS3 to simultaneously bind to JAK and to the cytokine receptor explains the specificity of the suppression. SOCS3 binds JAK and gp130 receptor simultaneously, using two opposing surfaces: while the phosphotyrosine-binding groove on the SOCS3 SH2 domain is occupied by the gp130 receptor, a subdomain in the SH2 domain of SOCS3 is also required for inhibition of JAK, binding in a phospho-independent manner to a non-canonical surface of JAK2 (58, 59). The KIR of SOCS3 occludes the substrate-binding groove on JAK2.	SIGNOR-255329
Q15389	Q02763	1	binding	up-regulates	0.796	Angiopoietin-1 (ang1) is an angiogenic factor that signals through the endothelial cell-specific tie2 receptor tyrosine kinase.	SIGNOR-49355
Q9BX63	P38398	1	binding	up-regulates activity	0.796	BRCA1 interacts in vivo with a novel protein, BACH1, a member of the DEAH helicase family. BACH1 binds directly to the BRCT repeats of BRCA1. Moreover, BACH1 likely contributes to the DNA repair function of BRCA1 [].	SIGNOR-259185
Q96GD4	O15392	1	phosphorylation	down-regulates	0.795	Phosphorylation by aurora-b negatively regulates survivin function . hat survivin is phosphorylated at t117 during mitosis, and once phosphorylated, dephosphorylation is crucial for chromosome congression and progression into anaphaseduring mitosis	SIGNOR-154569
Q9UNS1	O14757	1	binding	up-regulates activity	0.795	We performed a detailed molecular characterization of TIM interactions with the core clock protein CRY1 and the DNA damage signal transducer CHK1, and found that the N-terminus of TIM is required for association with both proteins, as well as for homodimerization.	SIGNOR-268054
Q99728	P38398	1	binding	up-regulates	0.795	Brac1 dimerizes with brca1?associated Ring domain protein 1 (bard1) to yield a functional e3 ligase.	SIGNOR-162499
O15524	O60674	1	ubiquitination	down-regulates quantity by destabilization	0.795	Shp-2 regulates socs-1-mediated janus kinase-2 ubiquitination/degradation downstream of the prolactin receptor	SIGNOR-118407
Q9UHD2	Q13137	1	phosphorylation	up-regulates activity	0.795	Furthermore, we found that TBC1D9-regulated TBK1 activation and recruitment of NDP52 and ULK1 complex to damaged mitochondria (Fig.\u00a0 xref ).\|TBK1 can phosphorylate p62, OPTN, and NDP52 to promote selective autophagy by facilitating their interaction with LC3, ubiquitin, and RAB35, respectively xref , xref , xref .	SIGNOR-280151
O75925	P42224	1	binding	down-regulates	0.795	Socs1 and socs3 target jak1 and gp130, respectively, near the plasma membrane to prevent cytoplasmic stats from being activated, whereas pias1 principally targets activated stat1 in the cell nucleus and prevents it from binding to dna.	SIGNOR-202039
Q15118	P08559	1	phosphorylation	down-regulates activity	0.794	Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293.	SIGNOR-109551
Q9HAW4	O14757	2	binding	up-regulates	0.794	Binding of claspin to xchk1 is highly elevated in the presence of dna templates that trigger a checkpoint arrest of the cell cycle in xenopus egg extracts	SIGNOR-84474
Q8WZA2	P62834	1	binding	up-regulates quantity	0.794	The SUR1 subunit of KATP channels recruits Epac2 to the plasma membrane where a signaling complex comprised of Epac2, Rap1 and PLC-ε is formed. Rap1 is activated by Epac2, and the activated form of Rap1 binds to and activates PLC-ε.	SIGNOR-278143
O14757	Q9HAW4	2	phosphorylation	up-regulates	0.794	We found that thr-916 on claspin is phosphorylated by chk1, suggesting that chk1 regulates claspin during checkpoint response.	SIGNOR-149411
Q13535	Q14191	1	phosphorylation	down-regulates quantity	0.794	Importantly, ATR-mediated phosphorylation targets Werner syndrome protein for ubiquitination and degradation.\|WRN is phosphorylated at serine 1141 by ATR in response to replication-associated DSBs A. WRN is heavily phosphorylated at S1141 in response to CPT treatment of cells.	SIGNOR-278159
Q13158	Q92851	1	binding	up-regulates	0.794	The death-effector domains ofcasp8and -10 bothinteractwith the death-effector domain offadd. Therefore, caspase-10 is recruited into the fas signaling complex and becomes activated like caspase-8	SIGNOR-112058
P56817	P05067	1	cleavage	up-regulates activity	0.794	Beta-secretase 1 (BACE1) cleaves the type-I transmembrane protein APP to form the N-terminus of Aβ.	SIGNOR-255480
O00141	O43524	1	phosphorylation	down-regulates activity	0.794	We show here that sgk1, like akt, promotes cell survival and that it does so in part by phosphorylating and inactivating fkhrl1. However, sgk and akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on fkhrl1. While both kinases can phosphorylate thr-32, sgk displays a marked preference for ser-315 whereas akt favors ser-253.	SIGNOR-236607
P49841	O75581	1	phosphorylation	up-regulates activity	0.794	Glycogen synthase kinase 3 (gsk3), which is known for its inhibitory role in wnt through the promotion of beta-catenin phosphorylation and degradation, mediates the phosphorylation and activation of lrp6. We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin.	SIGNOR-143041
Q9Y490	P05106	1	binding	up-regulates activity	0.793	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257625
Q16539	P15336	1	phosphorylation	up-regulates	0.793	On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38.	SIGNOR-65597
O60674	Q06124	2	phosphorylation	up-regulates activity	0.793	Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2	SIGNOR-236266
Q06124	O60674	2	dephosphorylation	up-regulates quantity by stabilization	0.793	We report that SHP-2 dephosphorylates tyrosine (Tyr-1007) of Jak2 kinase, a critical recruitment site for the ubiquitin ligase-associated inhibitory protein suppressor of cytokine signaling-1 (SOCS-1), thereby contributing to Jak2 stability. Inactivation of SHP-2 function by blocking receptor/SHP-2 association or by using a catalytically inactive mutant of SHP-2 led to a marked increase in Jak2 ubiquitination/degradation, Jak2 phosphorylation on Tyr-1007, and Jak2/SOCS-1 association	SIGNOR-248665
P55157	P04114	1	lipidation	up-regulates activity	0.793	As ApoB is translated, it is lipidated by microsomal triglyceride transfer protein (MTP). MTP adds triglycerides to the nascent ApoB during its co-translational translocation into the lumen of the endoplasmic reticulum.	SIGNOR-252118
P08100	P11488	1	binding	up-regulates activity	0.793	We report that his affected descendants carry a missense mutation in the gene encoding the a subunit of rod transducin — the G-protein that couples rhodopsin to cGMP-phosphodiesterase in the phototransduction cascade.	SIGNOR-260007
P13725	Q99650	1	binding	up-regulates	0.793	The oncostatin m receptor (osmr) is part of receptor complexes for oncostatin m and interleukin-31.	SIGNOR-141588
P43034	P30622	1	binding	up-regulates activity	0.793	Here we demonstrate colocalization and direct interaction between CLIP-170 and LIS1. In mammalian cells, LIS1 recruitment to kinetochores is dynein/dynactin dependent, and recruitment there of CLIP-170 is dependent on its site of binding to LIS1, located in the distal zinc finger motif.	SIGNOR-252166
P78527	P04637	1	phosphorylation	up-regulates	0.793	We demonstrate that phosphorylation of p53 at serines 15 and 37 impairs the ability of mdm2 to inhibit p53-dependent transactivation. We present evidence that these effects are most likely due to a conformational change induced upon phosphorylation of p53. Our studies provide a plausible mechanism by which the induction of p53 can be modulated by dna-pk (or other protein kinases with similar specificity) in response to dna damage.	SIGNOR-53030
P51617	Q92985	1	phosphorylation	up-regulates activity	0.792	These data indicate that IRAK-1, but not IRAK-4, phosphorylates IRF7 in vitro.	SIGNOR-278235
P99999	O14727	1	binding	up-regulates activity	0.792	During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9.	SIGNOR-135384
Q13489	Q9NR28	2	ubiquitination	down-regulates quantity by destabilization	0.792	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-271391
P60953	Q5VT25	1	binding	up-regulates activity	0.792	Myotonic dystrophy kinase-related Cdc42-binding kinase acts as a Cdc42 effector in promoting cytoskeletal reorganization\|MRCK alpha and Cdc42V12 colocalize, particularly at the cell periphery in transfected HeLa cells. Microinjection of plasmid encoding MRCK alpha resulted in actin and myosin reorganization.	SIGNOR-262593
P28482	P01100	1	phosphorylation	up-regulates activity	0.792	We have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. ERK2 phosphorylated c-Fos TADs that included Thr- 325, Thr-331, or Ser-374 as unique phospho-acceptor sites, thus indicating that these residues can serve as in vitro targets for the enzymatic activity of ERK2.	SIGNOR-236010
P31749	P49841	1	phosphorylation	down-regulates activity	0.792	Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3beta (GSK3B). The AKT-mediated phosphorylation of glycogen synthase kinase 3b on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1	SIGNOR-245416
Q02297	P04626	1	binding	up-regulates	0.792	Direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3.	SIGNOR-26875
P52333	P40763	1	phosphorylation	up-regulates	0.792	Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated	SIGNOR-256254
Q9NR28	Q13489	2	binding	down-regulates quantity	0.792	Smac/diablo selectively causes the rapid degradation of c-iap1 and c-iap2 in hela cells. Smac binding to c-iap via its n-terminal iap-binding motif is the prerequisite for this effect	SIGNOR-121886
Q9UJQ4	Q9H9S0	1	transcriptional regulation	up-regulates quantity by expression	0.792	We conclude that the Nanog enhancer activity is regulated by both Sall4 and Nanog.	SIGNOR-266079
O96017	P04637	1	phosphorylation	up-regulates quantity by stabilization	0.791	Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53.	SIGNOR-74831
Q9NYF0	O14641	1	binding	down-regulates	0.791	Dapper 1 antagonizes wnt signaling by promoting dishevelled degradation	SIGNOR-144053
O15111	Q00653	1	phosphorylation	up-regulates activity	0.791	Ikkalfa phosphorylates p100, leading to its proteasomal processing to p52.	SIGNOR-124230

P49770

P05198

1

guanine nucleotide exchange factor

up-regulates activity

0.802

EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.

SIGNOR-269125

P52797

Q15375

1

binding

up-regulates

0.802

The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion

SIGNOR-52384

P08069

Q9Y4H2

1

phosphorylation

up-regulates

0.802

Our results reveal that igf-1 receptors promote beta-cell development and survival through the irs-2 signalling pathway.

SIGNOR-70477

Q9NRD5

P17252

1

binding

up-regulates activity

0.802

We show that protein interacting with C-kinase 1 (PICK1) recruits activated protein kinase Cα (PKCα) to MycUNC5A at the plasma membrane, stimulating its endocytosis. We identify two PKCα phosphorylation sites at serines 408 and 587, as well as dileucine internalization motifs, which are required for this endocytosis.

SIGNOR-268178

Q15056

P60842

1

binding

up-regulates activity

0.802

Either eIF4B or eIF4H stimulated the initial rate and amplitude of eIF4A-dependent duplex unwinding, and the magnitude of stimulation is dependent on duplex stability

SIGNOR-261294

P15374

P62979

1

cleavage

up-regulates quantity

0.802

Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.

SIGNOR-270828

Q8WU20

P62993

1

binding

up-regulates activity

0.802

In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway.

SIGNOR-236953

P12757

Q15796

1

binding

down-regulates activity

0.801

The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway

SIGNOR-236099

P12931

Q14247

1

phosphorylation

down-regulates activity

0.801

Erk phosphorylation and a mimicking S405,418D double mutation enhanced cortactin binding and activation of N-WASP. In contrast, Src phosphorylation inhibited the ability of cortactin previously phosphorylated by Erk, and that of S405,418D double mutant cortactin, to bind and activate N-WASP. Furthermore, Y-->D mutation of three tyrosine residues targeted by Src (Y421, Y466, and Y482) inhibited the ability of S405,418D cortactin to activate N-WASP.

SIGNOR-246513

Q92934

P10415

1

relocalization

down-regulates activity

0.801

Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1.

SIGNOR-133756

P05230

P22607

1

binding

up-regulates

0.801

Reports also show that fgf/fgfr3 signals mediate some of the effects of tgf-beta on embryonic bone formation

SIGNOR-195585

P15374

P62987

1

cleavage

up-regulates quantity

0.801

Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.

SIGNOR-270827

P42345

P06730

1

phosphorylation

down-regulates activity

0.801

Mechanistic target of rapamycin complex 1 (mTORC1) phosphorylates and inhibits eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1).

SIGNOR-278963

Q9UKB1

P63208

1

binding

up-regulates

0.801

The scf is composed of skp1, cdc53/cul1, and a specificity-conferring f-box protein. F-box proteins contain two domains, an f-box motif that binds skp1 and allows assembly into skp1/cdc53 complexes, and a second proteinprotein interaction domain that interacts specifically with one or more target proteins. Cdc53/cul1, in turn, interacts with both the e2 and the skp1/f-box protein complex.

SIGNOR-64505

P35222

P24385

1

transcriptional regulation

up-regulates quantity by expression

0.801

One of the most well studied activators of CCND1 transcription is β-catenin, which could be actived by AKT signalling to inducing G1/S transition. When β-catenin is translocated from the cytoplasm to the nucleus, it forms a complex with the ternary complex factor (TCF) and/or lymphoid enhancer-binding factor (LEF) and stimulates cyclin D1 gene transcription (Fig. 4C).In agreement with the data described above, a chromatin immunoprecipitation (ChIP) assay confirmed that TNC regulates the binding of β-catenin to the TCF/LEF-binding site in the CCND1 promoter (Fig. 4C). Additionally, the β-cateninbinding activity with respect to the CCND1 promoter was much higher in TNC-overexpression PANC-1 cells than in the vector controls.

SIGNOR-277738

Q13535

P38398

1

phosphorylation

up-regulates activity

0.8

Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion.

SIGNOR-106432

Q9Y6H5

P37840

1

binding

up-regulates activity

0.8

Synphilin-1 interacts in vivo with α-synuclein, and their coexpression promotes the formation of Lewy body-like inclusions

SIGNOR-272597

Q7Z434

Q14653

1

binding

up-regulates activity

0.8

Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1.

SIGNOR-260143

P12643

Q13873

1

binding

up-regulates

0.8

Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor.

SIGNOR-33425

Q92993

Q13315

1

acetylation

up-regulates activity

0.8

Here, we report that sirtuin 7 (SIRT7)-mediated deacetylation is essential for dephosphorylation and deactivation of ATM. We show that SIRT7, a class III histone deacetylase, interacts with and deacetylates ATM in vitro and in vivo. |Upon DNA damage, ATM is activated via a series of highly organized machineries, including acetylation by the histone acetyltransferase TIP60 at lysine 3016

SIGNOR-275891

P23458

P40763

1

binding

up-regulates activity

0.8

The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3).

SIGNOR-236369

Q13136

P10586

1

relocalization

up-regulates activity

0.8

We have identified a novel cytoplasmic 160 kDa phosphoserine protein termed LAR-interacting protein 1 (LIP.1), which binds to the LAR membrane-distal D2 protein tyrosine phosphatase domain and appears to localize LAR to focal adhesions.

SIGNOR-264141

P39905

P56159

1

binding

up-regulates

0.8

A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling

SIGNOR-49091

O95886

Q9Y566

1

relocalization

up-regulates activity

0.8

SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).

SIGNOR-264592

Q13261

P14784

1

binding

up-regulates

0.8

The il-15 receptor comprises a heterotrimeric complex consisting of the common ?cytokine Receptor (?c), the il-2 ? Receptor subunit (il-2r?), And an il-15-specific ? Receptor (il-15r?)

SIGNOR-157418

Q96EB6

Q9UBK2

1

deacetylation

up-regulates activity

0.799

SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3 SIRT1 activation has been reported to increase dramatically endurance exercise through the activation of PGC-1_ in muscle, which stimulates fatty acid oxidation

SIGNOR-217963

O00444

Q9HC77

1

phosphorylation

up-regulates

0.799

Plk2 phosphorylates the s589 and s595 residues of cpap in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle. Plk4 also phosphorylates s595 of cpap

SIGNOR-166007

Q96SB4

Q07955

1

phosphorylation

up-regulates

0.799

These results suggest that the formation of complexes between sf2/asf and srpks, which is influenced by the phosphorylation state of sf2/asf, may have regulatory roles in the assembly and localization of this splicing factor.

SIGNOR-66465

Q6ZWJ1

Q12846

1

binding

up-regulates activity

0.799

Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4-containing vesicles. These data demonstrate that insulin activation of Akt2 specifically regulates the docking/fusion step of GLUT4-containing vesicles at the plasma membrane through the regulation of Synip phosphorylation and Synip-Syntaxin4 interaction.Thus, our data demonstrate that insulin-stimulated Akt2-dependent phosphorylation of Synip on serine residue 99 results in reduced binding interactions between Synip and Syntaxin4.

SIGNOR-262634

P24941

Q13309

1

phosphorylation

up-regulates quantity by stabilization

0.799

The activity of SCF(Skp2) is regulated by the Cyclin-dependent kinase (CDK)2-mediated phosphorylation of Skp2 on Ser64 allows its expression in mid-G1 phase, even in the presence of active APC(Cdh1). Reciprocally, dephosphorylation of Skp2 by the mitotic phosphatase Cdc14B at the M --> G1 transition promotes its degradation by APC(Cdh1).

SIGNOR-249173

P49023

Q13418

1

binding

up-regulates

0.799

Co-immunoprecipitation from fibroblasts confirmed that the association between paxillin and ilk occurs in vivo in both adherent cells and cells in suspension. [__] thus, paxillin binding is necessary for efficient focal adhesion targeting of ilk and may therefore impact the role of ilk in integrin-mediated signal transduction events.

SIGNOR-106824

Q9H0E2

P51617

1

binding

down-regulates activity

0.799

Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs)

SIGNOR-251980

O00187

P0C0L5

1

cleavage

up-regulates activity

0.798

MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a).

SIGNOR-263422

P62820

O60763

1

binding

up-regulates activity

0.798

Here, the tethering factor p115 was shown to be a Rab1 effector that binds directly to activated Rab1.

SIGNOR-261287

Q13547

P25490

1

deacetylation

down-regulates activity

0.798

Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs.

SIGNOR-268835

P49757

P46531

1

ubiquitination

down-regulates quantity by destabilization

0.798

Mammalian numb proteins promote notch1 receptor ubiquitination and degradation of the notch1 intracellular domain

SIGNOR-99762

P15976

Q8IX07

1

binding

up-regulates activity

0.798

GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1.

SIGNOR-256059

O00187

P0C0L4

1

cleavage

up-regulates activity

0.798

MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a).

SIGNOR-263431

Q15596

P19793

1

binding

up-regulates

0.798

Here, it is demonstrated that mutation of the h11 phenylalanine residues diminishes the ability of rxr to associate with the p160 coactivators tif2 and p/cip, but has little effect on ligand-dependent interactions of the receptor with the unrelated coactivator tif1.

SIGNOR-114847

Q86UR5

O14795

1

relocalization

up-regulates activity

0.798

N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle

SIGNOR-264385

P14138

P24530

1

binding

up-regulates

0.798

These results demonstrate that lys-161 of the receptor is important for high affinity binding with et-3 which, in part, confers the non-selective binding characteristics of the etb receptor for et isopeptides.

SIGNOR-36017

Q9Y490

P05556

1

binding

up-regulates activity

0.798

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

SIGNOR-257607

P08575

P06239

1

dephosphorylation

up-regulates activity

0.797

CD45 differentially regulates the negatively acting pTyr-505 and positively acting pTyr-394 p56(lck) tyrosine kinase phosphorylation sites. We propose that high wild-type CD45 expression is necessary to dephosphorylate p56(lck) pTyr-394, suppressing CD4 T+ cell lineage commitment and hyperactivity.

SIGNOR-259933

P56704

Q9H461

1

binding

up-regulates

0.797

Structural basis of wnt recognition by frizzled.

SIGNOR-197638

Q9H2X6

P04637

1

phosphorylation

up-regulates

0.797

Based on all these observations, it is legitimate to suggest that axin and daxx seem to adopt both parallel routes and a convergent means to activate p53. In either case, hipk2 seems to be the protein kinase that catalyzes the ser46 phosphorylation.

SIGNOR-151930

P18031

O60674

1

dephosphorylation

down-regulates activity

0.797

Immunoblots with phospho-specific antibodies confirmed that PTP1B suppresses phosphorylation of the Jak2 activation site tyrosines (Y1007/Y1008) and Stat3 in a dose-dependent manner

SIGNOR-248405

Q16829

P28482

1

dephosphorylation

down-regulates

0.797

Pyst2 preferentially dephosphorylates and inactivates p42 map kinase in vitro and in vivo

SIGNOR-60871

Q8IZQ8

P11831

1

binding

up-regulates

0.797

A coactivator of srf, myocd, interacts with srf and activates vsmc expression of contractile genes.

SIGNOR-174322

P49768

P46531

1

cleavage

up-regulates

0.797

Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains.

SIGNOR-72886

Q9H6Z9

Q16665

1

hydroxylation

down-regulates quantity by destabilization

0.797

There are three EglN family members in humans and mice (EglN1, EglN2, and EglN3). Their enzymatic activity requires oxygen, ascorbic acid, iron, and α-ketoglutarate (α-KG). Under hypoxic conditions, EglNs lose their activity and fail to hydroxylate HIFα, which leads to HIFα stabilization

SIGNOR-262000

P24941

P25205

1

phosphorylation

up-regulates

0.796

In this study, we demonstrate that mcm3 is a substrate of cyclin e/cdk2 and can be phosphorylated by cyclin e/cdk2 at thr-722.

SIGNOR-176656

O14965

Q8TEP8

2

phosphorylation

up-regulates activity

0.796

Thus, following their sequential activation in Cep192 complexes, both AurA and Plx1 phosphorylate Cep192.|We found that Cep192 1\u20131000 -wt promoted AurA and Plx1 activation and itself underwent phosphorylation irrespective of whether it was bound to the endogenous or recombinant Plx1 (i.e. whether Plx1 was docked onto T46 or not) (lanes 6 and 8).

SIGNOR-279797

P19525

O75569

1

phosphorylation

up-regulates activity

0.796

In stressed cells, this activation occurs when PACT, a PKR-binding protein, is phosphorylated and activates PKR.

SIGNOR-280003

Q92547

Q8WXE1

1

binding

up-regulates

0.796

Topbp1 directly activates atr/atrip and promotes atr-mediated chk1 phosphorylation.

SIGNOR-163214

P56704

Q9UP38

1

binding

up-regulates activity

0.796

Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.All the frizzled genes studied have a complex and partially overlapping pattern of expression in different regions of the embryo, and many of them (fz1, 3, 7, 8 and 9) have specific expression in the epithelial somites as well as in the newly formed myotomes.

SIGNOR-169651

Q96QT6

Q96ST3

1

binding

up-regulates activity

0.796

Pf1 interacts with mSin3A in vivo. Gal4-Pf1 repressed activity of the reporter gene fivefold relative to Gal4 alone (Fig. (Fig.5A),5A), suggesting that DNA-bound Pf1 was capable of recruiting functional mSin3A complexes.

SIGNOR-266995

Q9UPQ9

Q9UKV8

1

binding

up-regulates activity

0.796

The assay showed that full-length TNRC6B binds full-length human AGO2. We have identified and molecularly dissected important sequence and structure features in the conserved Ago hooks of S. pombe Tas3 and human TNRC6B. The effect of Ago hook peptides from the shuttling P-body component TNRC6B in our miRNA-mediated translational repression assay (Fig. 5b), in particular, hints at a novel regulatory role of Ago hooks in miRNA-mediated gene repression mechanisms.

SIGNOR-269680

Q8TEP8

O14965

2

binding

up-regulates activity

0.796

These findings demonstrated that Cep192 mediates the AurA-Plk1 interaction and that the formation of the Cep192-AurA-Plk1 complex could be important for activating AurA and Plk1.

SIGNOR-266406

P45983

P04637

1

phosphorylation

up-regulates

0.796

Activated jnk phosphorylates p53

SIGNOR-59812

P45983

P17535

1

phosphorylation

up-regulates

0.796

Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase.

SIGNOR-196038

O14543

O60674

1

binding

down-regulates activity

0.796

The ability of SOCS3 to simultaneously bind to JAK and to the cytokine receptor explains the specificity of the suppression. SOCS3 binds JAK and gp130 receptor simultaneously, using two opposing surfaces: while the phosphotyrosine-binding groove on the SOCS3 SH2 domain is occupied by the gp130 receptor, a subdomain in the SH2 domain of SOCS3 is also required for inhibition of JAK, binding in a phospho-independent manner to a non-canonical surface of JAK2 (58, 59). The KIR of SOCS3 occludes the substrate-binding groove on JAK2.

SIGNOR-255329

Q15389

Q02763

1

binding

up-regulates

0.796

Angiopoietin-1 (ang1) is an angiogenic factor that signals through the endothelial cell-specific tie2 receptor tyrosine kinase.

SIGNOR-49355

Q9BX63

P38398

1

binding

up-regulates activity

0.796

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

SIGNOR-259185

Q96GD4

O15392

1

phosphorylation

down-regulates

0.795

Phosphorylation by aurora-b negatively regulates survivin function . hat survivin is phosphorylated at t117 during mitosis, and once phosphorylated, dephosphorylation is crucial for chromosome congression and progression into anaphaseduring mitosis

SIGNOR-154569

Q9UNS1

O14757

1

binding

up-regulates activity

0.795

We performed a detailed molecular characterization of TIM interactions with the core clock protein CRY1 and the DNA damage signal transducer CHK1, and found that the N-terminus of TIM is required for association with both proteins, as well as for homodimerization.

SIGNOR-268054

Q99728

P38398

1

binding

up-regulates

0.795

Brac1 dimerizes with brca1?associated Ring domain protein 1 (bard1) to yield a functional e3 ligase.

SIGNOR-162499

O15524

O60674

1

ubiquitination

down-regulates quantity by destabilization

0.795

Shp-2 regulates socs-1-mediated janus kinase-2 ubiquitination/degradation downstream of the prolactin receptor

SIGNOR-118407

Q9UHD2

Q13137

1

phosphorylation

up-regulates activity

0.795

Furthermore, we found that TBC1D9-regulated TBK1 activation and recruitment of NDP52 and ULK1 complex to damaged mitochondria (Fig.\u00a0 xref ).|TBK1 can phosphorylate p62, OPTN, and NDP52 to promote selective autophagy by facilitating their interaction with LC3, ubiquitin, and RAB35, respectively xref , xref , xref .

SIGNOR-280151

O75925

P42224

1

binding

down-regulates

0.795

Socs1 and socs3 target jak1 and gp130, respectively, near the plasma membrane to prevent cytoplasmic stats from being activated, whereas pias1 principally targets activated stat1 in the cell nucleus and prevents it from binding to dna.

SIGNOR-202039

Q15118

P08559

1

phosphorylation

down-regulates activity

0.794

Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293.

SIGNOR-109551

Q9HAW4

O14757

2

binding

up-regulates

0.794

Binding of claspin to xchk1 is highly elevated in the presence of dna templates that trigger a checkpoint arrest of the cell cycle in xenopus egg extracts

SIGNOR-84474

Q8WZA2

P62834

1

binding

up-regulates quantity

0.794

The SUR1 subunit of KATP channels recruits Epac2 to the plasma membrane where a signaling complex comprised of Epac2, Rap1 and PLC-ε is formed. Rap1 is activated by Epac2, and the activated form of Rap1 binds to and activates PLC-ε.

SIGNOR-278143

O14757

Q9HAW4

2

phosphorylation

up-regulates

0.794

We found that thr-916 on claspin is phosphorylated by chk1, suggesting that chk1 regulates claspin during checkpoint response.

SIGNOR-149411

Q13535

Q14191

1

phosphorylation

down-regulates quantity

0.794

Importantly, ATR-mediated phosphorylation targets Werner syndrome protein for ubiquitination and degradation.|WRN is phosphorylated at serine 1141 by ATR in response to replication-associated DSBs A. WRN is heavily phosphorylated at S1141 in response to CPT treatment of cells.

SIGNOR-278159

Q13158

Q92851

1

binding

up-regulates

0.794

The death-effector domains ofcasp8and -10 bothinteractwith the death-effector domain offadd. Therefore, caspase-10 is recruited into the fas signaling complex and becomes activated like caspase-8

SIGNOR-112058

P56817

P05067

1

cleavage

up-regulates activity

0.794

Beta-secretase 1 (BACE1) cleaves the type-I transmembrane protein APP to form the N-terminus of Aβ.

SIGNOR-255480

O00141

O43524

1

phosphorylation

down-regulates activity

0.794

We show here that sgk1, like akt, promotes cell survival and that it does so in part by phosphorylating and inactivating fkhrl1. However, sgk and akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on fkhrl1. While both kinases can phosphorylate thr-32, sgk displays a marked preference for ser-315 whereas akt favors ser-253.

SIGNOR-236607

P49841

O75581

1

phosphorylation

up-regulates activity

0.794

Glycogen synthase kinase 3 (gsk3), which is known for its inhibitory role in wnt through the promotion of beta-catenin phosphorylation and degradation, mediates the phosphorylation and activation of lrp6. We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin.

SIGNOR-143041

Q9Y490

P05106

1

binding

up-regulates activity

0.793

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

SIGNOR-257625

Q16539

P15336

1

phosphorylation

up-regulates

0.793

On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38.

SIGNOR-65597

O60674

Q06124

2

phosphorylation

up-regulates activity

0.793

Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2

SIGNOR-236266

Q06124

O60674

2

dephosphorylation

up-regulates quantity by stabilization

0.793

We report that SHP-2 dephosphorylates tyrosine (Tyr-1007) of Jak2 kinase, a critical recruitment site for the ubiquitin ligase-associated inhibitory protein suppressor of cytokine signaling-1 (SOCS-1), thereby contributing to Jak2 stability. Inactivation of SHP-2 function by blocking receptor/SHP-2 association or by using a catalytically inactive mutant of SHP-2 led to a marked increase in Jak2 ubiquitination/degradation, Jak2 phosphorylation on Tyr-1007, and Jak2/SOCS-1 association

SIGNOR-248665

P55157

P04114

1

lipidation

up-regulates activity

0.793

As ApoB is translated, it is lipidated by microsomal triglyceride transfer protein (MTP). MTP adds triglycerides to the nascent ApoB during its co-translational translocation into the lumen of the endoplasmic reticulum.

SIGNOR-252118

P08100

P11488

1

binding

up-regulates activity

0.793

We report that his affected descendants carry a missense mutation in the gene encoding the a subunit of rod transducin — the G-protein that couples rhodopsin to cGMP-phosphodiesterase in the phototransduction cascade.

SIGNOR-260007

P13725

Q99650

1

binding

up-regulates

0.793

The oncostatin m receptor (osmr) is part of receptor complexes for oncostatin m and interleukin-31.

SIGNOR-141588

P43034

P30622

1

binding

up-regulates activity

0.793

Here we demonstrate colocalization and direct interaction between CLIP-170 and LIS1. In mammalian cells, LIS1 recruitment to kinetochores is dynein/dynactin dependent, and recruitment there of CLIP-170 is dependent on its site of binding to LIS1, located in the distal zinc finger motif.

SIGNOR-252166

P78527

P04637

1

phosphorylation

up-regulates

0.793

We demonstrate that phosphorylation of p53 at serines 15 and 37 impairs the ability of mdm2 to inhibit p53-dependent transactivation. We present evidence that these effects are most likely due to a conformational change induced upon phosphorylation of p53. Our studies provide a plausible mechanism by which the induction of p53 can be modulated by dna-pk (or other protein kinases with similar specificity) in response to dna damage.

SIGNOR-53030

P51617

Q92985

1

phosphorylation

up-regulates activity

0.792

These data indicate that IRAK-1, but not IRAK-4, phosphorylates IRF7 in vitro.

SIGNOR-278235

P99999

O14727

1

binding

up-regulates activity

0.792

During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9.

SIGNOR-135384

Q13489

Q9NR28

2

ubiquitination

down-regulates quantity by destabilization

0.792

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-271391

P60953

Q5VT25

1

binding

up-regulates activity

0.792

Myotonic dystrophy kinase-related Cdc42-binding kinase acts as a Cdc42 effector in promoting cytoskeletal reorganization|MRCK alpha and Cdc42V12 colocalize, particularly at the cell periphery in transfected HeLa cells. Microinjection of plasmid encoding MRCK alpha resulted in actin and myosin reorganization.

SIGNOR-262593

P28482

P01100

1

phosphorylation

up-regulates activity

0.792

We have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. ERK2 phosphorylated c-Fos TADs that included Thr- 325, Thr-331, or Ser-374 as unique phospho-acceptor sites, thus indicating that these residues can serve as in vitro targets for the enzymatic activity of ERK2.

SIGNOR-236010

P31749

P49841

1

phosphorylation

down-regulates activity

0.792

Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3beta (GSK3B). The AKT-mediated phosphorylation of glycogen synthase kinase 3b on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1

SIGNOR-245416

Q02297

P04626

1

binding

up-regulates

0.792

Direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3.

SIGNOR-26875

P52333

P40763

1

phosphorylation

up-regulates

0.792

Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated

SIGNOR-256254

Q9NR28

Q13489

2

binding

down-regulates quantity

0.792

Smac/diablo selectively causes the rapid degradation of c-iap1 and c-iap2 in hela cells. Smac binding to c-iap via its n-terminal iap-binding motif is the prerequisite for this effect

SIGNOR-121886

Q9UJQ4

Q9H9S0

1

transcriptional regulation

up-regulates quantity by expression

0.792

We conclude that the Nanog enhancer activity is regulated by both Sall4 and Nanog.

SIGNOR-266079

O96017

P04637

1

phosphorylation

up-regulates quantity by stabilization

0.791

Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53.

SIGNOR-74831

Q9NYF0

O14641

1

binding

down-regulates

0.791

Dapper 1 antagonizes wnt signaling by promoting dishevelled degradation

SIGNOR-144053

O15111

Q00653

1

phosphorylation

up-regulates activity

0.791

Ikkalfa phosphorylates p100, leading to its proteasomal processing to p52.

SIGNOR-124230