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
O60566	Q12834	1	phosphorylation	up-regulates activity	0.993	Furthermore, BUBR1 phosphorylates p55CDC in vitro, and the phosphorylation of p55CDC by BUBR1 appears to be correlated with spindle checkpoint activation.	SIGNOR-279507
O43683	Q12834	1	phosphorylation	down-regulates activity	0.992	Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro.	SIGNOR-250606
O76094	Q9UHB9	1	binding	up-regulates activity	0.99	Taken together our data show that binding of the SRP68/72 heterodimer follows an ultrasensitive response dependent on the SRP72 C-terminus. Although the large solenoids of SRP68/72 have not been structurally characterized due to intrinsic flexibility, they serve as important contact sites in ribosome interaction.	SIGNOR-261164
P42345	Q8N122	1	phosphorylation	up-regulates activity	0.989	The phosphorylation of raptor is stimulated by insulin and inhibited by rapamycin. Importantly, the site-directed mutation of raptor at one phosphorylation site, Ser(863), reduced mTORC1 activity both in vitro and in vivo.	SIGNOR-184959
Q9HAU5	Q92900	1	binding	up-regulates activity	0.979	UPF2 and UPF3b increase UPF1 ATPase activity	SIGNOR-265246
P53350	Q12834	1	phosphorylation	down-regulates quantity by destabilization	0.977	Plk1 directly bound to Cdc20 and phosphorylates it on serine-170 located in CRY-box. Whereas wild-type Cdc20 was degraded according to progress cell cycle beyond mitosis, the phosphorylation-defective mutant, which serine-170 was changed into alanine, was not destroyed in early G1 phase.	SIGNOR-276493
P24941	P20248	1	phosphorylation	up-regulates	0.977	Here we present evidence from in vitro and in vivo assay systems that the degradation of human cyclin a can be inhibited by kinase-inactive mutants of cdk2 and cdc2cdk2 can phosphorylate cyclin a on ser-154	SIGNOR-74466
Q96GD4	Q9NQS7	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
Q9NQS7	Q96GD4	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
O75496	Q9H211	1	binding	down-regulates activity	0.972	Here we show that geminin interacts tightly with Cdt1, a recently identified replication initiation factor necessary for MCM loading.	SIGNOR-261680
Q96Q15	Q92900	1	phosphorylation	up-regulates	0.971	Smg-1 directly phosphorylates upf1 helicase, another key component of nmd, upon recognition of ptc on postspliced mrna during the initial round of translation. Phosphorylated-upf1 recruits the smg-5/smg-7 complex to induce ribosome dissociation and decapping-mediated decay. T28 and s1096 are responsible for phospho-specific recruitment of smg-6 to the n-terminal conserved region, and the smg-5/smg-7 heterodimer complex to the c-terminal sq-rich region of upf1, respectively	SIGNOR-200785
Q00987	P04637	1	ubiquitination	down-regulates quantity by destabilization	0.968	The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2.	SIGNOR-196116
Q12834	P14635	1	binding	down-regulates quantity by destabilization	0.968	These results suggested that cyclin A is a target of the Cdc20-associated APC/C in human cells.	SIGNOR-272578
Q92542	Q96BI3	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
Q96BI3	Q92542	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
P29353	P62993	1	binding	up-regulates	0.965	TGF-beta-induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well-characterised pathway linking receptor tyrosine kinases with Erk MAP kinases.	SIGNOR-236366
Q92542	P49768	1	binding	up-regulates	0.965	Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2.	SIGNOR-118852
O14965	Q9ULW0	1	phosphorylation	up-regulates activity	0.965	Here we show that TPX2, a microtubule-bundling protein and activator of Aurora A, plays an important role. TPX2 was phosphorylated by Aurora A during mitosis. Its phospho-null mutant caused short metaphase spindles coupled with low microtubule flux rate. Interestingly, phosphorylation of TPX2 regulated its interaction with CLASP1 but not Kif2a.\|This suggests that TPX2 phosphorylation positively regulates the function of CLASP1.\| This is in accord with a phosphoproteomics study that identified S121 and S125 as potential phosphorylation sites for Aurora A in mitotic HeLa cells	SIGNOR-265089
Q13418	Q9HBI1	1	phosphorylation	up-regulates activity	0.965	These results indicate that affixin directly associates with \u03b1-actinin only when its CH2 domain is phosphorylated by ILK.\|This may indicate that phosphorylation of the CH2 domain by ILK induces a conformational change of the CH2 domain of affixin, which enables affixin to interact with alpha-actinin to evoke the subsequent maturation of the FA complex.	SIGNOR-278259
Q8N3U4	O60216	1	binding	up-regulates quantity by stabilization	0.965	Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin	SIGNOR-261511
P24385	P11802	1	binding	up-regulates	0.964	D-type cyclins (cyclin d1, d2, or d3) and their associated cyclin-dependent kinases (cdk4, cdk6) connect signals from cytokines to the cell cycle machinery, and they propel cells through the g1 restriction point and into the s phase when activated by cyclin d1, cdk4 is able to phosphorylate prb,	SIGNOR-201666
O00311	P49736	1	phosphorylation	up-regulates	0.962	In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2	SIGNOR-143984
P09132	P61011	1	binding	up-regulates activity	0.962	Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure (Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54.	SIGNOR-261168
Q9Y6K9	O14920	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
O14920	Q9Y6K9	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
P13984	P35269	1	binding	up-regulates activity	0.962	Direct Interaction Between the Subunit RAP30 of Transcription Factor IIF (TFIIF) and RNA Polymerase Subunit 5, Which Contributes to the Association Between TFIIF and RNA Polymerase II. we showed that RPB5 binds RAP30 but not RAP74 and associates to TFIIF through the binding to RAP30.	SIGNOR-261180
Q96BI3	Q9NZ42	1	binding	up-regulates	0.962	Furthermore, overexpression of aph-1 facilitates pen-2-mediated ps1 proteolysis, resulting in a significant increase in ps1 fragments. Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex.	SIGNOR-97104
P42345	P23443	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
Q9UGP8	Q99442	1	binding	up-regulates activity	0.96	Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62.	SIGNOR-265273
O43683	Q13257	1	relocalization	up-regulates activity	0.96	Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity	SIGNOR-252018
P12830	P35222	1	binding	up-regulates activity	0.96	At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin	SIGNOR-265863
Q8NCD3	P49450	1	binding	up-regulates activity	0.96	Here we demonstrate that prenucleosomal CENP-A is complexed with histone H4, nucleophosmin 1, and HJURP. Recruitment of new CENP-A into nucleosomes at replicated centromeres is dependent on HJURP. Recognition by HJURP is mediated through the centromere targeting domain (CATD) of CENP-A, a region that we demonstrated previously to induce a unique conformational rigidity to both the subnucleosomal CENP-A heterotetramer and the corresponding assembled nucleosome. We propose HJURP to be a cell-cycle-regulated CENP-A-specific histone chaperone required for centromeric chromatin assembly.	SIGNOR-263707
P23443	P42345	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
Q9NZ42	P49768	1	cleavage	up-regulates	0.959	Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex.	SIGNOR-97113
Q9BSB4	O75143	1	binding	up-regulates	0.959	Furthermore, atg101 is important for the stability and basal phosphorylation of atg13 and ulk1	SIGNOR-186989
P30153	P67775	1	binding	up-regulates	0.959	Pr65/a acts as a scaffold protein for binding pp2ac and regulatory b subunits in a heterotrimeric holoenzyme	SIGNOR-138883
P63208	Q13616	1	binding	up-regulates	0.959	The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin.	SIGNOR-64511
P06850	P34998	1	binding	up-regulates	0.958	Crf and ucn bind and activate crf-r1 with similarly high affinities.	SIGNOR-108713
O00311	P33991	1	phosphorylation	up-regulates	0.958	Activation of the eukaryotic replicative dna helicase, the mcm2-7 complex, requires phosphorylation by cdc7/dbf4 (dbf4-dependent kinase or ddk), which, in turn, depends on prior phosphorylation of mcm2-7 by an unknown kinase (or kinases).we propose that the resulting mec1 modification of mcm4 and mcm6 further activates ddk phosphorylation of mcm2-7 ( fig. 7aii ).	SIGNOR-169453
Q9BZI7	Q92900	1	binding	up-regulates activity	0.957	UPF2 and UPF3b increase UPF1 ATPase activity	SIGNOR-265247
P60953	P42768	1	binding	up-regulates activity	0.957	Cdc42 can induce Arp2/3-mediated filopodia formation through the activation of WASp (Wiskott-Aldrich syndrome proteins) and neuronal N-WASp (Rohatgi et al., 1999). Similarly, Rac1-enhanced lamellipodia formation is related to Arp2/3 activation by the WAVE (WASP-family verprolin-homologous) complex	SIGNOR-261869
O43521	Q07817	1	binding	down-regulates activity	0.956	Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.Bim binds bcl-2, bcl2l1, bcl2l2, mcl1 and a1 tightly.	SIGNOR-178679
P05019	P08069	1	binding	up-regulates activity	0.956	Binding of IGF1 to its receptor leads to activation of its intrinsic tyrosine kinase and autophosphorylation, thus generating docking sites for insulin receptor substrate (IRS), which is also phosphorylated by the IGF1 receptor.	SIGNOR-175662
P18074	P19447	1	binding	up-regulates	0.955	Xpd helps xpb in promoter opening and as such participates in the transcription reaction.	SIGNOR-64672
P24941	P24864	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
P24864	P24941	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
P01138	P04629	1	binding	up-regulates	0.955	Ngf is the preferred ligand for trka, bdnf and nt4/5 are preferred for trkb, and nt3 for trkc (barbacid 1994). These specificities are not absolute, and nt3 is also a ligand for trka and trkb.	SIGNOR-85114
Q9UKL0	O60341	1	binding	up-regulates activity	0.955	CoREST protects LSD1 from proteasomal degradation and also plays an indispensable role in LSD1-mediated demethylation of nucleosomal substrates in vitro. in contrast to CoREST, which is a positive regulator of LSD1 activity, the in vitro evidence presented above suggests that BHC80 may function to inhibit LSD1 activity.	SIGNOR-264506
P24941	P38936	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
O14727	P55211	1	binding	up-regulates activity	0.954	Caspase-9 and Apaf-1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome c and dATP, an event that leads to caspase-9 activation.	SIGNOR-53576
P38936	P24941	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
P56589	P40855	1	binding	up-regulates activity	0.954	PEX3 is required for PEX19 to dock at peroxisomes, interacts specifically with the docking domain of PEX19, and is required for recruitment of the PEX19 docking domain to peroxisomes.	SIGNOR-253026
P01100	P05412	1	binding	up-regulates activity	0.953	The cFos proto-oncoprotein associates with cJun to form a heterodimer with increased DNA binding and transcriptional activities.	SIGNOR-252087
Q06124	Q13480	1	dephosphorylation	down-regulates activity	0.952	These results suggest that Tyr(P)-627 and Tyr(P)-659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) that binds and activates SHP2.\|Thus, physical association of activated SHP2 with Gab1 is necessary and sufficient to mediate the ERK mitogen-activated protein kinase activation. Phosphopeptides derived from Gab1 were dephosphorylated by active SHP2 in vitro.	SIGNOR-248674
P46527	P24941	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
Q15382	P42345	1	binding	up-regulates activity	0.95	Rheb stimulates the phosphorylation of mtor and plays an essential role in regulation of s6k and 4ebp1 in response to nutrients and cellular energy status.	SIGNOR-162006
P24941	P46527	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
P09132	Q9UHB9	1	binding	up-regulates activity	0.95	Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure (Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54.	SIGNOR-261167
Q14145	Q13618	1	binding	up-regulates activity	0.95	Keap1 is a BTB-Kelch protein that functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex. Keap1 targets its substrate, the Nrf2 transcription factor, for ubiquitination and subsequent degradation by the 26 S proteasome. The N-terminal BTB domain and central linker region of Keap1 bind Cul3, whereas the C-terminal Kelch domain of Keap1 binds Nrf2 via residues located within loops that extend out from the bottom of the Kelch domain	SIGNOR-268925
P21579	P60880	1	binding	up-regulates activity	0.95	Because synaptotagmins bind SNAP-25 and Ca2+, SNAP-25 has also been linked to the Ca2+ dependence of exocytosis (42). One model suggests that synaptotagmin blocks full SNARE fusion pore formation by binding to t-SNAREs.This interaction prevents fusion from occurring in the absence of calcium. When Ca2+ is present, synaptotagmin releases the t-SNAREs so they can fully zipper with the v-SNARE, leading to fusion	SIGNOR-263975
P51532	Q92922	1	binding	up-regulates	0.95	The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added.	SIGNOR-65441
P46531	Q06330	1	binding	up-regulates	0.95	The intracellular part of the notch receptor is cleaved off and translocates to the nucleus, where it binds to the transcription factor rbp-j.	SIGNOR-183510
Q9UMX1	P08151	1	binding	down-regulates activity	0.949	Here we characterize structural and functional determinants of Su(fu) required for Gli regulation and show that Su(fu) contains at least two distinct domains: a highly conserved carboxy-terminal region required for binding to the amino-terminal ends of the Gli proteins and a unique amino-terminal domain that binds the carboxy-terminal tail of Gli1. While each domain is capable of binding to different Gli1 regions independently, interactions between Su(fu) and Gli1 at both sites are required for cytoplasmic tethering and repression of Gli1	SIGNOR-249591
P01133	P00533	1	binding	up-regulates activity	0.949	Epidermal growth factor (egf) regulates cell proliferation and differentiation by binding to the egf receptor (egfr) extracellular region, comprising domains i-iv, with the resultant dimerization of the receptor tyrosine kinase.	SIGNOR-186159
P01008	P00734	1	cleavage	down-regulates activity	0.948	Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1	SIGNOR-264136
O15151	P04637	1	ubiquitination	down-regulates quantity by destabilization	0.948	Here we demonstrate that MdmX acts as a ubiquitin ligase in vitro, being capable of autoubiquitination, as well as mediating the ubiquitination of p53.	SIGNOR-271389
P51587	Q06609	1	binding	up-regulates activity	0.947	We suggest that interactions of the BRCA2 C-terminal region with RAD51 may facilitate efficient nucleation of RAD51 multimers on DNA and thereby stimulate recombination-mediated repair.	SIGNOR-259905
P28715	P18074	1	binding	up-regulates quantity by stabilization	0.947	The NER protein XPG was also found to associate with the TFIIH complex by interacting directly with XPD stabilizing the interaction between TFIIH and the CAK-XPD complex	SIGNOR-251974
O60716	P12830	1	binding	up-regulates quantity by stabilization	0.947	P120 regulates E-cadherin turnover at the cell membrane. Because direct binding of p120 to E-cadherin is required, it is possible that p120 binding blocks the interaction of an unknown binding partner (or event) that targets E-cadherin for degradation	SIGNOR-252123
Q96BI3	P49768	1	binding	up-regulates	0.947	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-93262
P55072	Q8TAT6	1	binding	up-regulates activity	0.946	These findings ascribe specific functions to each of the components of the VCP-UFD1L-NPL4 complex in Vpu-mediated CD4 degradation: VCP energizes the process through ATP binding and hydrolysis, UFD1L binds ubiquitinated CD4 through recognition of K48 Ub chains, and NPL4 stabilizes UFD1L. VCP is thus likely to provide the energy required for extraction of CD4 from membranes.	SIGNOR-252423
P05305	P24530	1	binding	up-regulates	0.946	Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors.	SIGNOR-145762
Q99836	Q9NWZ3	1	binding	up-regulates activity	0.946	Signaling between MyD88 and TRAF6 is mediated by members of the IL-1R-associated kinase (IRAK) family; however, the exact function of each IRAK protein remains controversial. IRAK-1 is required for the optimal transduction of IL-1R- and TLR-mediated signals, but IRAK-1 can be replaced by other IRAKs. Surprisingly, gene targeting studies show that the newest IRAK protein, IRAK-4, has an essential role in mediating signals initiated by IL-1R and TLR engagement.	SIGNOR-252097
Q8TAF3	O94782	1	binding	up-regulates activity	0.946	In vitro reconstitution of USP1 deubiquitinating enzyme activity, using either ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) or purified monoubiquitinated FANCD2 protein as substrates, demonstrates that UAF1 functions as an activator of USP1. UAF1 binding increases the catalytic turnover (kcat) but does not increase the affinity of the USP1 enzyme for the substrate (KM).	SIGNOR-263274
P51955	Q12834	1	phosphorylation	up-regulates activity	0.945	In summary, we have demonstrated that Nek2 can associate with and phosphorylate Mad2 and Cdc20.\|The results presented here support a model in which Nek2 modulates the functions of Mad2 and Cdc20 in the mitotic checkpoint and elevation of Nek2 levels may contribute to chromosome instability by interfering with the control of the checkpoint.	SIGNOR-278366
P14778	Q99836	1	binding	up-regulates activity	0.945	Interleukin-1 (il-1) stimulates the association of the il-1 receptor-associated protein kinase (irak) with the heterodimer of il-iri and il-iracp via the adapter protein myd88.	SIGNOR-67140
O95997	Q14674	1	binding	down-regulates activity	0.945	Prior to anaphase, separase is kept inactive by its inhibitor securin	SIGNOR-275538
P52803	P54764	1	binding	up-regulates	0.945	Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor	SIGNOR-52473
O15169	P25054	1	binding	up-regulates activity	0.944	Axin, an inhibitor of the wnt pathway, interacts with beta-catenin, gsk-3beta and apc and reduces the beta-catenin level.	SIGNOR-60043
Q15078	Q00535	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
O43683	O43684	1	relocalization	up-regulates activity	0.943	Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity	SIGNOR-252019
Q00535	Q15078	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
P52803	P29320	1	binding	up-regulates	0.943	Highly promiscuous for ephrin-a ligands it binds preferentially efna5 and became active.	SIGNOR-52470
Q12824	P51532	1	binding	up-regulates activity	0.943	The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added.	SIGNOR-65438
P30154	P67775	1	binding	up-regulates activity	0.943	Since B_ suppresses the association of the catalytic C and regulatory A subunits of protein phosphatase 2A [94], the B_ interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity	SIGNOR-217872
Q96S52	Q92643	1	binding	up-regulates activity	0.943	To determine roles for PIG-S and PIG-T, we disrupted these genes in mouse F9 cells by homologous recombination. PIG-S and PIG-T knockout cells were defective in transfer of GPI to proteins, particularly in formation of the carbonyl intermediates. We also demonstrate that PIG-S and PIG-T form a protein complex with GAA1 and GPI8, and that PIG-T maintains the complex by stabilizing the expression of GAA1 and GPI8.	SIGNOR-261362
P05112	P24394	1	binding	up-regulates	0.942	IL-4R Is a 140-kd protein that binds il-4 with high affinity	SIGNOR-100762
Q15465	Q13635	1	binding	down-regulates activity	0.942	In the responding cell, active Hedgehog binds to its receptor Patched, a 12-pass transmembrane protein, which frees Smoothened, an adjacent 7-pass transmembrane protein, for downstream signaling.Thus, a balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other.	SIGNOR-118615
Q86YC2	P51587	1	binding	up-regulates	0.942	Palb2 colocalizes with brca2 in nuclear foci, promotes its localization and stability in key nuclear structures (e.g., chromatin and nuclear matrix), and enables its recombinational repair and checkpoint functions.	SIGNOR-147217
Q8WW43	Q9NZ42	1	binding	up-regulates	0.942	Furthermore, overexpression of aph-1 facilitates pen-2-mediated ps1 proteolysis, resulting in a significant increase in ps1 fragments. Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex.	SIGNOR-97110
P24941	Q99741	1	phosphorylation	down-regulates activity	0.942	Hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)\|An HsCdc6A1A2A3 mutant, which mimics unphosphorylated HsCdc6, is exclusively nuclear, and its expression inhibits initiation of DNA replication. An HsCdc6E1E2E3 mutant, which mimics phosphorylated HsCdc6, is exclusively cytoplasmic and is not associated with the chromatin/nuclear matrix fraction.	SIGNOR-67544
P09132	O76094	1	binding	up-regulates activity	0.942	Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure (Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54.	SIGNOR-261166
P60953	Q13153	1	binding	up-regulates activity	0.942	A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways.	SIGNOR-248243
O00311	P33993	1	phosphorylation	up-regulates	0.942	We propose that phosphorylation of mcm4/6 s/tp sites, which are already phosphorylated in g1, allows initial mcm2-7 phosphorylation by ddk and initiation from the first origins of replication ( fig. 7ai ).	SIGNOR-169506
O14788	O00300	1	binding	up-regulates	0.942	Receptor activator of nf-kappa b ligand (rankl, also known as odf and opgl), a member of the tumor necrosis factor (tnf) family, triggers osteoclastogenesis by forming a complex with its receptor, rank.	SIGNOR-112539
Q15276	Q9UJ41	1	binding	up-regulates	0.942	We show that rabaptin-5 increases the exchange activity of rabex-5 on rab5.	SIGNOR-109395
Q9HB90	Q8N122	1	binding	up-regulates	0.941	Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor.	SIGNOR-162054
P38936	P11802	1	binding	down-regulates	0.941	P21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage.We Have explored the interaction of p21 with the currently known cdks. p21 effectively inhibits cdk2, cdk3, cdk4, and cdk6 kinases.	SIGNOR-29957
Q92793	P16220	1	binding	up-regulates	0.941	When overexpressed in serum-stimulated cells, akt/pkb potently induced ser-133 phosphorylation of creb and promoted recruitment of cbp.	SIGNOR-62260
Q9H8S9	O95835	1	binding	up-regulates	0.941	Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1	SIGNOR-169752

O60566

Q12834

1

phosphorylation

up-regulates activity

0.993

Furthermore, BUBR1 phosphorylates p55CDC in vitro, and the phosphorylation of p55CDC by BUBR1 appears to be correlated with spindle checkpoint activation.

SIGNOR-279507

O43683

Q12834

1

phosphorylation

down-regulates activity

0.992

Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro.

SIGNOR-250606

O76094

Q9UHB9

1

binding

up-regulates activity

0.99

Taken together our data show that binding of the SRP68/72 heterodimer follows an ultrasensitive response dependent on the SRP72 C-terminus. Although the large solenoids of SRP68/72 have not been structurally characterized due to intrinsic flexibility, they serve as important contact sites in ribosome interaction.

SIGNOR-261164

P42345

Q8N122

1

phosphorylation

up-regulates activity

0.989

The phosphorylation of raptor is stimulated by insulin and inhibited by rapamycin. Importantly, the site-directed mutation of raptor at one phosphorylation site, Ser(863), reduced mTORC1 activity both in vitro and in vivo.

SIGNOR-184959

Q9HAU5

Q92900

1

binding

up-regulates activity

0.979

UPF2 and UPF3b increase UPF1 ATPase activity

SIGNOR-265246

P53350

Q12834

1

phosphorylation

down-regulates quantity by destabilization

0.977

Plk1 directly bound to Cdc20 and phosphorylates it on serine-170 located in CRY-box. Whereas wild-type Cdc20 was degraded according to progress cell cycle beyond mitosis, the phosphorylation-defective mutant, which serine-170 was changed into alanine, was not destroyed in early G1 phase.

SIGNOR-276493

P24941

P20248

1

phosphorylation

up-regulates

0.977

Here we present evidence from in vitro and in vivo assay systems that the degradation of human cyclin a can be inhibited by kinase-inactive mutants of cdk2 and cdc2cdk2 can phosphorylate cyclin a on ser-154

SIGNOR-74466

Q96GD4

Q9NQS7

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

Q9NQS7

Q96GD4

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

O75496

Q9H211

1

binding

down-regulates activity

0.972

Here we show that geminin interacts tightly with Cdt1, a recently identified replication initiation factor necessary for MCM loading.

SIGNOR-261680

Q96Q15

Q92900

1

phosphorylation

up-regulates

0.971

Smg-1 directly phosphorylates upf1 helicase, another key component of nmd, upon recognition of ptc on postspliced mrna during the initial round of translation. Phosphorylated-upf1 recruits the smg-5/smg-7 complex to induce ribosome dissociation and decapping-mediated decay. T28 and s1096 are responsible for phospho-specific recruitment of smg-6 to the n-terminal conserved region, and the smg-5/smg-7 heterodimer complex to the c-terminal sq-rich region of upf1, respectively

SIGNOR-200785

Q00987

P04637

1

ubiquitination

down-regulates quantity by destabilization

0.968

The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2.

SIGNOR-196116

Q12834

P14635

1

binding

down-regulates quantity by destabilization

0.968

These results suggested that cyclin A is a target of the Cdc20-associated APC/C in human cells.

SIGNOR-272578

Q92542

Q96BI3

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

Q96BI3

Q92542

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

P29353

P62993

1

binding

up-regulates

0.965

TGF-beta-induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well-characterised pathway linking receptor tyrosine kinases with Erk MAP kinases.

SIGNOR-236366

Q92542

P49768

1

binding

up-regulates

0.965

Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2.

SIGNOR-118852

O14965

Q9ULW0

1

phosphorylation

up-regulates activity

0.965

Here we show that TPX2, a microtubule-bundling protein and activator of Aurora A, plays an important role. TPX2 was phosphorylated by Aurora A during mitosis. Its phospho-null mutant caused short metaphase spindles coupled with low microtubule flux rate. Interestingly, phosphorylation of TPX2 regulated its interaction with CLASP1 but not Kif2a.|This suggests that TPX2 phosphorylation positively regulates the function of CLASP1.| This is in accord with a phosphoproteomics study that identified S121 and S125 as potential phosphorylation sites for Aurora A in mitotic HeLa cells

SIGNOR-265089

Q13418

Q9HBI1

1

phosphorylation

up-regulates activity

0.965

These results indicate that affixin directly associates with \u03b1-actinin only when its CH2 domain is phosphorylated by ILK.|This may indicate that phosphorylation of the CH2 domain by ILK induces a conformational change of the CH2 domain of affixin, which enables affixin to interact with alpha-actinin to evoke the subsequent maturation of the FA complex.

SIGNOR-278259

Q8N3U4

O60216

1

binding

up-regulates quantity by stabilization

0.965

Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin

SIGNOR-261511

P24385

P11802

1

binding

up-regulates

0.964

D-type cyclins (cyclin d1, d2, or d3) and their associated cyclin-dependent kinases (cdk4, cdk6) connect signals from cytokines to the cell cycle machinery, and they propel cells through the g1 restriction point and into the s phase when activated by cyclin d1, cdk4 is able to phosphorylate prb,

SIGNOR-201666

O00311

P49736

1

phosphorylation

up-regulates

0.962

In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2

SIGNOR-143984

P09132

P61011

1

binding

up-regulates activity

0.962

Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure (Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54.

SIGNOR-261168

Q9Y6K9

O14920

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

O14920

Q9Y6K9

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

P13984

P35269

1

binding

up-regulates activity

0.962

Direct Interaction Between the Subunit RAP30 of Transcription Factor IIF (TFIIF) and RNA Polymerase Subunit 5, Which Contributes to the Association Between TFIIF and RNA Polymerase II. we showed that RPB5 binds RAP30 but not RAP74 and associates to TFIIF through the binding to RAP30.

SIGNOR-261180

Q96BI3

Q9NZ42

1

binding

up-regulates

0.962

Furthermore, overexpression of aph-1 facilitates pen-2-mediated ps1 proteolysis, resulting in a significant increase in ps1 fragments. Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex.

SIGNOR-97104

P42345

P23443

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

Q9UGP8

Q99442

1

binding

up-regulates activity

0.96

Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62.

SIGNOR-265273

O43683

Q13257

1

relocalization

up-regulates activity

0.96

Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity

SIGNOR-252018

P12830

P35222

1

binding

up-regulates activity

0.96

At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin

SIGNOR-265863

Q8NCD3

P49450

1

binding

up-regulates activity

0.96

Here we demonstrate that prenucleosomal CENP-A is complexed with histone H4, nucleophosmin 1, and HJURP. Recruitment of new CENP-A into nucleosomes at replicated centromeres is dependent on HJURP. Recognition by HJURP is mediated through the centromere targeting domain (CATD) of CENP-A, a region that we demonstrated previously to induce a unique conformational rigidity to both the subnucleosomal CENP-A heterotetramer and the corresponding assembled nucleosome. We propose HJURP to be a cell-cycle-regulated CENP-A-specific histone chaperone required for centromeric chromatin assembly.

SIGNOR-263707

P23443

P42345

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

Q9NZ42

P49768

1

cleavage

up-regulates

0.959

Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex.

SIGNOR-97113

Q9BSB4

O75143

1

binding

up-regulates

0.959

Furthermore, atg101 is important for the stability and basal phosphorylation of atg13 and ulk1

SIGNOR-186989

P30153

P67775

1

binding

up-regulates

0.959

Pr65/a acts as a scaffold protein for binding pp2ac and regulatory b subunits in a heterotrimeric holoenzyme

SIGNOR-138883

P63208

Q13616

1

binding

up-regulates

0.959

The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin.

SIGNOR-64511

P06850

P34998

1

binding

up-regulates

0.958

Crf and ucn bind and activate crf-r1 with similarly high affinities.

SIGNOR-108713

O00311

P33991

1

phosphorylation

up-regulates

0.958

Activation of the eukaryotic replicative dna helicase, the mcm2-7 complex, requires phosphorylation by cdc7/dbf4 (dbf4-dependent kinase or ddk), which, in turn, depends on prior phosphorylation of mcm2-7 by an unknown kinase (or kinases).we propose that the resulting mec1 modification of mcm4 and mcm6 further activates ddk phosphorylation of mcm2-7 ( fig. 7aii ).

SIGNOR-169453

Q9BZI7

Q92900

1

binding

up-regulates activity

0.957

UPF2 and UPF3b increase UPF1 ATPase activity

SIGNOR-265247

P60953

P42768

1

binding

up-regulates activity

0.957

Cdc42 can induce Arp2/3-mediated filopodia formation through the activation of WASp (Wiskott-Aldrich syndrome proteins) and neuronal N-WASp (Rohatgi et al., 1999). Similarly, Rac1-enhanced lamellipodia formation is related to Arp2/3 activation by the WAVE (WASP-family verprolin-homologous) complex

SIGNOR-261869

O43521

Q07817

1

binding

down-regulates activity

0.956

Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.Bim binds bcl-2, bcl2l1, bcl2l2, mcl1 and a1 tightly.

SIGNOR-178679

P05019

P08069

1

binding

up-regulates activity

0.956

Binding of IGF1 to its receptor leads to activation of its intrinsic tyrosine kinase and autophosphorylation, thus generating docking sites for insulin receptor substrate (IRS), which is also phosphorylated by the IGF1 receptor.

SIGNOR-175662

P18074

P19447

1

binding

up-regulates

0.955

Xpd helps xpb in promoter opening and as such participates in the transcription reaction.

SIGNOR-64672

P24941

P24864

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

P24864

P24941

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

P01138

P04629

1

binding

up-regulates

0.955

Ngf is the preferred ligand for trka, bdnf and nt4/5 are preferred for trkb, and nt3 for trkc (barbacid 1994). These specificities are not absolute, and nt3 is also a ligand for trka and trkb.

SIGNOR-85114

Q9UKL0

O60341

1

binding

up-regulates activity

0.955

CoREST protects LSD1 from proteasomal degradation and also plays an indispensable role in LSD1-mediated demethylation of nucleosomal substrates in vitro. in contrast to CoREST, which is a positive regulator of LSD1 activity, the in vitro evidence presented above suggests that BHC80 may function to inhibit LSD1 activity.

SIGNOR-264506

P24941

P38936

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

O14727

P55211

1

binding

up-regulates activity

0.954

Caspase-9 and Apaf-1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome c and dATP, an event that leads to caspase-9 activation.

SIGNOR-53576

P38936

P24941

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

P56589

P40855

1

binding

up-regulates activity

0.954

PEX3 is required for PEX19 to dock at peroxisomes, interacts specifically with the docking domain of PEX19, and is required for recruitment of the PEX19 docking domain to peroxisomes.

SIGNOR-253026

P01100

P05412

1

binding

up-regulates activity

0.953

The cFos proto-oncoprotein associates with cJun to form a heterodimer with increased DNA binding and transcriptional activities.

SIGNOR-252087

Q06124

Q13480

1

dephosphorylation

down-regulates activity

0.952

These results suggest that Tyr(P)-627 and Tyr(P)-659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) that binds and activates SHP2.|Thus, physical association of activated SHP2 with Gab1 is necessary and sufficient to mediate the ERK mitogen-activated protein kinase activation. Phosphopeptides derived from Gab1 were dephosphorylated by active SHP2 in vitro.

SIGNOR-248674

P46527

P24941

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

Q15382

P42345

1

binding

up-regulates activity

0.95

Rheb stimulates the phosphorylation of mtor and plays an essential role in regulation of s6k and 4ebp1 in response to nutrients and cellular energy status.

SIGNOR-162006

P24941

P46527

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

P09132

Q9UHB9

1

binding

up-regulates activity

0.95

Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure (Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54.

SIGNOR-261167

Q14145

Q13618

1

binding

up-regulates activity

0.95

Keap1 is a BTB-Kelch protein that functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex. Keap1 targets its substrate, the Nrf2 transcription factor, for ubiquitination and subsequent degradation by the 26 S proteasome. The N-terminal BTB domain and central linker region of Keap1 bind Cul3, whereas the C-terminal Kelch domain of Keap1 binds Nrf2 via residues located within loops that extend out from the bottom of the Kelch domain

SIGNOR-268925

P21579

P60880

1

binding

up-regulates activity

0.95

Because synaptotagmins bind SNAP-25 and Ca2+, SNAP-25 has also been linked to the Ca2+ dependence of exocytosis (42). One model suggests that synaptotagmin blocks full SNARE fusion pore formation by binding to t-SNAREs.This interaction prevents fusion from occurring in the absence of calcium. When Ca2+ is present, synaptotagmin releases the t-SNAREs so they can fully zipper with the v-SNARE, leading to fusion

SIGNOR-263975

P51532

Q92922

1

binding

up-regulates

0.95

The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added.

SIGNOR-65441

P46531

Q06330

1

binding

up-regulates

0.95

The intracellular part of the notch receptor is cleaved off and translocates to the nucleus, where it binds to the transcription factor rbp-j.

SIGNOR-183510

Q9UMX1

P08151

1

binding

down-regulates activity

0.949

Here we characterize structural and functional determinants of Su(fu) required for Gli regulation and show that Su(fu) contains at least two distinct domains: a highly conserved carboxy-terminal region required for binding to the amino-terminal ends of the Gli proteins and a unique amino-terminal domain that binds the carboxy-terminal tail of Gli1. While each domain is capable of binding to different Gli1 regions independently, interactions between Su(fu) and Gli1 at both sites are required for cytoplasmic tethering and repression of Gli1

SIGNOR-249591

P01133

P00533

1

binding

up-regulates activity

0.949

Epidermal growth factor (egf) regulates cell proliferation and differentiation by binding to the egf receptor (egfr) extracellular region, comprising domains i-iv, with the resultant dimerization of the receptor tyrosine kinase.

SIGNOR-186159

P01008

P00734

1

cleavage

down-regulates activity

0.948

Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1

SIGNOR-264136

O15151

P04637

1

ubiquitination

down-regulates quantity by destabilization

0.948

Here we demonstrate that MdmX acts as a ubiquitin ligase in vitro, being capable of autoubiquitination, as well as mediating the ubiquitination of p53.

SIGNOR-271389

P51587

Q06609

1

binding

up-regulates activity

0.947

We suggest that interactions of the BRCA2 C-terminal region with RAD51 may facilitate efficient nucleation of RAD51 multimers on DNA and thereby stimulate recombination-mediated repair.

SIGNOR-259905

P28715

P18074

1

binding

up-regulates quantity by stabilization

0.947

The NER protein XPG was also found to associate with the TFIIH complex by interacting directly with XPD stabilizing the interaction between TFIIH and the CAK-XPD complex

SIGNOR-251974

O60716

P12830

1

binding

up-regulates quantity by stabilization

0.947

P120 regulates E-cadherin turnover at the cell membrane. Because direct binding of p120 to E-cadherin is required, it is possible that p120 binding blocks the interaction of an unknown binding partner (or event) that targets E-cadherin for degradation

SIGNOR-252123

Q96BI3

P49768

1

binding

up-regulates

0.947

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-93262

P55072

Q8TAT6

1

binding

up-regulates activity

0.946

These findings ascribe specific functions to each of the components of the VCP-UFD1L-NPL4 complex in Vpu-mediated CD4 degradation: VCP energizes the process through ATP binding and hydrolysis, UFD1L binds ubiquitinated CD4 through recognition of K48 Ub chains, and NPL4 stabilizes UFD1L. VCP is thus likely to provide the energy required for extraction of CD4 from membranes.

SIGNOR-252423

P05305

P24530

1

binding

up-regulates

0.946

Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors.

SIGNOR-145762

Q99836

Q9NWZ3

1

binding

up-regulates activity

0.946

Signaling between MyD88 and TRAF6 is mediated by members of the IL-1R-associated kinase (IRAK) family; however, the exact function of each IRAK protein remains controversial. IRAK-1 is required for the optimal transduction of IL-1R- and TLR-mediated signals, but IRAK-1 can be replaced by other IRAKs. Surprisingly, gene targeting studies show that the newest IRAK protein, IRAK-4, has an essential role in mediating signals initiated by IL-1R and TLR engagement.

SIGNOR-252097

Q8TAF3

O94782

1

binding

up-regulates activity

0.946

In vitro reconstitution of USP1 deubiquitinating enzyme activity, using either ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) or purified monoubiquitinated FANCD2 protein as substrates, demonstrates that UAF1 functions as an activator of USP1. UAF1 binding increases the catalytic turnover (kcat) but does not increase the affinity of the USP1 enzyme for the substrate (KM).

SIGNOR-263274

P51955

Q12834

1

phosphorylation

up-regulates activity

0.945

In summary, we have demonstrated that Nek2 can associate with and phosphorylate Mad2 and Cdc20.|The results presented here support a model in which Nek2 modulates the functions of Mad2 and Cdc20 in the mitotic checkpoint and elevation of Nek2 levels may contribute to chromosome instability by interfering with the control of the checkpoint.

SIGNOR-278366

P14778

Q99836

1

binding

up-regulates activity

0.945

Interleukin-1 (il-1) stimulates the association of the il-1 receptor-associated protein kinase (irak) with the heterodimer of il-iri and il-iracp via the adapter protein myd88.

SIGNOR-67140

O95997

Q14674

1

binding

down-regulates activity

0.945

Prior to anaphase, separase is kept inactive by its inhibitor securin

SIGNOR-275538

P52803

P54764

1

binding

up-regulates

0.945

Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor

SIGNOR-52473

O15169

P25054

1

binding

up-regulates activity

0.944

Axin, an inhibitor of the wnt pathway, interacts with beta-catenin, gsk-3beta and apc and reduces the beta-catenin level.

SIGNOR-60043

Q15078

Q00535

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

O43683

O43684

1

relocalization

up-regulates activity

0.943

Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity

SIGNOR-252019

Q00535

Q15078

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

P52803

P29320

1

binding

up-regulates

0.943

Highly promiscuous for ephrin-a ligands it binds preferentially efna5 and became active.

SIGNOR-52470

Q12824

P51532

1

binding

up-regulates activity

0.943

The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added.

SIGNOR-65438

P30154

P67775

1

binding

up-regulates activity

0.943

Since B_ suppresses the association of the catalytic C and regulatory A subunits of protein phosphatase 2A [94], the B_ interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity

SIGNOR-217872

Q96S52

Q92643

1

binding

up-regulates activity

0.943

To determine roles for PIG-S and PIG-T, we disrupted these genes in mouse F9 cells by homologous recombination. PIG-S and PIG-T knockout cells were defective in transfer of GPI to proteins, particularly in formation of the carbonyl intermediates. We also demonstrate that PIG-S and PIG-T form a protein complex with GAA1 and GPI8, and that PIG-T maintains the complex by stabilizing the expression of GAA1 and GPI8.

SIGNOR-261362

P05112

P24394

1

binding

up-regulates

0.942

IL-4R Is a 140-kd protein that binds il-4 with high affinity

SIGNOR-100762

Q15465

Q13635

1

binding

down-regulates activity

0.942

In the responding cell, active Hedgehog binds to its receptor Patched, a 12-pass transmembrane protein, which frees Smoothened, an adjacent 7-pass transmembrane protein, for downstream signaling.Thus, a balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other.

SIGNOR-118615

Q86YC2

P51587

1

binding

up-regulates

0.942

Palb2 colocalizes with brca2 in nuclear foci, promotes its localization and stability in key nuclear structures (e.g., chromatin and nuclear matrix), and enables its recombinational repair and checkpoint functions.

SIGNOR-147217

Q8WW43

Q9NZ42

1

binding

up-regulates

0.942

Furthermore, overexpression of aph-1 facilitates pen-2-mediated ps1 proteolysis, resulting in a significant increase in ps1 fragments. Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex.

SIGNOR-97110

P24941

Q99741

1

phosphorylation

down-regulates activity

0.942

Hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)|An HsCdc6A1A2A3 mutant, which mimics unphosphorylated HsCdc6, is exclusively nuclear, and its expression inhibits initiation of DNA replication. An HsCdc6E1E2E3 mutant, which mimics phosphorylated HsCdc6, is exclusively cytoplasmic and is not associated with the chromatin/nuclear matrix fraction.

SIGNOR-67544

P09132

O76094

1

binding

up-regulates activity

0.942

Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure (Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54.

SIGNOR-261166

P60953

Q13153

1

binding

up-regulates activity

0.942

A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways.

SIGNOR-248243

O00311

P33993

1

phosphorylation

up-regulates

0.942

We propose that phosphorylation of mcm4/6 s/tp sites, which are already phosphorylated in g1, allows initial mcm2-7 phosphorylation by ddk and initiation from the first origins of replication ( fig. 7ai ).

SIGNOR-169506

O14788

O00300

1

binding

up-regulates

0.942

Receptor activator of nf-kappa b ligand (rankl, also known as odf and opgl), a member of the tumor necrosis factor (tnf) family, triggers osteoclastogenesis by forming a complex with its receptor, rank.

SIGNOR-112539

Q15276

Q9UJ41

1

binding

up-regulates

0.942

We show that rabaptin-5 increases the exchange activity of rabex-5 on rab5.

SIGNOR-109395

Q9HB90

Q8N122

1

binding

up-regulates

0.941

Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor.

SIGNOR-162054

P38936

P11802

1

binding

down-regulates

0.941

P21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage.We Have explored the interaction of p21 with the currently known cdks. p21 effectively inhibits cdk2, cdk3, cdk4, and cdk6 kinases.

SIGNOR-29957

Q92793

P16220

1

binding

up-regulates

0.941

When overexpressed in serum-stimulated cells, akt/pkb potently induced ser-133 phosphorylation of creb and promoted recruitment of cbp.

SIGNOR-62260

Q9H8S9

O95835

1

binding

up-regulates

0.941

Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1

SIGNOR-169752