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
Q05397	P07949	2	phosphorylation	up-regulates	0.639	Focal adhesion kinase (fak) binds ret kinase via its ferm domain, priming a direct and reciprocal ret-fak transactivation mechanism. following gdnf stimulation, increased phosphorylation of fak at tyr-576/577 as well as phosphorylation of ret at tyr-905 was observed.	SIGNOR-173009
P40189	O60674	1	phosphorylation	up-regulates activity	0.639	All IL-6-type cytokines recruit gp130to their receptot complexes They either signal via gp130 alone [8] or in combination with LIFR [9] or the recently cloned OSMR [10], which are all able to activate Jaks proteins. Two tyrosine residues at the corresponding positions of Jak2 (tyrosine-1007 and tyrosine-1008) were found to be phosphorylated, and a single mutation of tyrosine-1007 eliminated essentially all tyrosine kinase activity [59].	SIGNOR-238634
P07949	Q05397	2	phosphorylation	up-regulates	0.639	The identification of focal adhesion kinase (fak) as a direct substrate for ret kinase revealed (i) a ret-fak transactivation mechanism consisting of direct phosphorylation of fak tyr-576/577 by ret and a reciprocal phosphorylation of ret by fak, which crucially is able to rescue the kinase-impaired ret k758m mutant and (ii) that fak binds ret via its ferm domain. Interestingly, this interaction is abolished upon ret phosphorylation, indicating that ret binding to the ferm domain of fak is a priming step for ret-fak transactivation.	SIGNOR-173013
P28482	P00533	1	phosphorylation	down-regulates activity	0.639	A growth factor-stimulated protein kinase activity that phosphorylates the epidermal growth factor (EGF) receptor at Thr669 has been described Anion-exchange chromatography demonstrated that this protein kinase activity was accounted for by two enzymes. The first peak of activity eluted from the column corresponded to the microtubule-associated protein 2 (MAP2) kinase	SIGNOR-20545
Q9NX09	P49815	1	binding	up-regulates activity	0.639	Redd1 is a negative regulator of mTOR, mediating dissociation of 14-3-3 from tuberous sclerosis complex (TSC)2, which allows formation of a TSC-TSC2 complex.	SIGNOR-277469
P42574	P55211	2	cleavage	up-regulates activity	0.639	Active caspase-3 itself is able to process its upstream , caspase-8 and caspase-9, establishing a self-amplifying loop of caspase activation	SIGNOR-90397
P78504	Q04721	1	binding	up-regulates	0.639	Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch.	SIGNOR-81364
P12931	Q99961	1	phosphorylation	down-regulates	0.639	Further, we identified an interaction between fak's second pro-rich motif and endophilin a2's sh3 domain. This interaction served as an autophosphorylation-dependent scaffold to allow src phosphorylation of endophilin a2 at tyr315. Tyr315 phosphorylation inhibited endophilin/dynamin interactions, and blockade of tyr315 phosphorylation promoted endocytosis of mt1-mmp. Together, these results suggest a regulatory mechanism of cell invasion whereby fak promotes cell-surface presentation of mt1-mmp by inhibiting endophilin a2-dependent endocytosis.	SIGNOR-139150
Q8NCW0	O75581	1	binding	down-regulates	0.639	Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to block wnt/beta-catenin signalling. Kremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of the wnt receptor lrp6 from the plasma membrane.	SIGNOR-88894
P54727	P28715	1	binding	up-regulates activity	0.639	GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process\|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).\|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo	SIGNOR-275702
P42574	P06396	1	cleavage	down-regulates	0.639	Caspase-3 mediates cleavage of gelsolin, generating a fragment that severs actin filaments in an unregulated fashion. The cleavage of gelsolin causes cells to round up, detach and undergo nuclear fragmentation.	SIGNOR-51652
Q9Y6R4	P46734	1	phosphorylation	up-regulates activity	0.639	These results, therefore, suggest that mtk1 directly phosphorylates and activates mkk3, mkk6 and sek1.	SIGNOR-50891
P55211	P42574	2	cleavage	up-regulates activity	0.639	Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3.	SIGNOR-133267
Q04725	Q9UJU2	1	binding	down-regulates	0.638	Mapping studies reveal that groucho/tle binds two regions in lef-1.	SIGNOR-185736
P06493	Q13042	1	phosphorylation	up-regulates	0.638	Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation	SIGNOR-119762
Q13387	P45983	1	binding	up-regulates	0.638	These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins.	SIGNOR-70860
P53350	Q9H0H5	1	phosphorylation	up-regulates	0.638	Tandem mass spectrometry analysis of a purified hscyk-4 fragment (hscyk-4n) phosphorylated by plk1 in vitro identified four major sites (s157, s170, s214, and s260 plk1 phosphorylation of hscyk-4 localizes ect2 at the midzone and stimulates rhoa-dependent contractile ring assembly at the equatorial cortex.	SIGNOR-185758
P19474	Q02556	1	ubiquitination	down-regulates quantity	0.638	From these results, we concluded that TRIM21 down-regulated IRF8 and enhanced the secretion of IL-12/23p40 in BD monocytes.\|IRF8 is ubiquitinated by TRIM21, which promotes secretion of IL-12/23p40 after TLR/IFN-\u03b3 stimulation xref .	SIGNOR-278791
P32121	Q9Y496	1	binding	up-regulates	0.638	Betaarrestin 2 was subsequentialy shown to bridge smo to the kinestesin motor kif3 to promote ciliary accumulation of smo in mammalian cells	SIGNOR-199107
P06493	P52732	1	phosphorylation	up-regulates activity	0.638	Nek6 phosphorylated Eg5 at several sites in vitro and one of these sites, Ser1033, is phosphorylated in vivo during mitosis. Whereas CDK1 phosphorylates nearly all Eg5 at Thr926 during mitosis, Nek6 phosphorylates approximately 3% of Eg5, primarily at the spindle poles.	SIGNOR-273887
P09619	P16333	1	binding	up-regulates	0.638	Growth factor binding to receptor protein tyrosine kinases (r-ptks)1 induces their dimerization and trans-phosphorylation, creating docking sites for proteins containing sh2 and ptb protein interaction domains. Nck binds to the pdgf and egfr receptors (figure 3c).	SIGNOR-64737
Q14766	P01137	1	binding	up-regulates activity	0.638	Together these data form strong support for the hypothesis that the LTBP plays an essential role in the activation of latent TGF-b in heterotypic cultures.	SIGNOR-235754
O43815	P67775	1	binding	up-regulates activity	0.638	The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms	SIGNOR-261698
P16871	P23458	1	binding	up-regulates	0.638	For instance, jak1 is associated with the ? Subunits of ?c Cytokines such as il-7r? And IL-4R. jak3 is associated with the ?c20,21. Cytokine binding mediates the trans-phosphorylation of receptor associated jak kinases, which in turn phosphorylate tyrosine residues on the receptors themselves. The receptor phosphotyrosines serve as docking sites for sh2 domain proteins including the stat family of transcription factors which are activated by jak-mediated phosphorylation.	SIGNOR-178494
P42226	O15524	1	transcriptional regulation	up-regulates quantity by expression	0.638	We found that IL-4, like IFN-gamma, induces rapid de novo expression of SOCS-1 in primary macrophages. Induction of SOCS-1 gene expression by IL-4 is STAT6-dependent.	SIGNOR-249570
P40763	P01189	1	transcriptional regulation	up-regulates quantity by expression	0.638	We show that phospho-STAT3 activates POMC promoter in response to leptin signaling through a mechanism that requires an SP1-binding site in the POMC promoter.	SIGNOR-263497
P19474	Q9UJV9	1	ubiquitination	down-regulates quantity	0.638	Furthermore, overexpression of TRIM21 in mDCs led to lower expression of DDX41 in these mDCs and up to 70% less IFN-beta production by mDCs in response to intracellular DNA (XREF_FIG).\|Here we report that the E3 ligase TRIM21 negatively regulated the type I interferon response in myeloid dendritic cells (mDCs) and monocytes that had been induced by cytosolic double stranded DNA (dsDNA), mainly by promoting the ubiquitination and degradation of DDX41.	SIGNOR-278790
Q9NWZ3	Q9HAT8	1	phosphorylation	up-regulates	0.638	Pellino2 is one of the firstsubstrates identified for irak1 andirak4.	SIGNOR-103717
P45983	P04150	1	phosphorylation	down-regulates	0.638	Taken together, these findings suggest that jnk-mediated phosphorylation of the gr-ser226 enhances gr nuclear export and may contribute to termination of gr-mediated transcription.	SIGNOR-93558
P22681	P29317	1	binding	down-regulates quantity by destabilization	0.638	In our present study, we demonstrate that ligand-mediated stimulation causes EphA2 to be internalized and degraded. The mechanism of this response involves ligand-mediated autophosphorylation of EphA2, which promotes an association between EphA2 and the c-Cbl adaptor protein. We also show that c-Cbl promotes stimulation-dependent EphA2 degradation.	SIGNOR-272590
Q9UPN9	Q15796	1	binding	up-regulates activity	0.638	The ubiquitious nuclear protein transcriptional intermediary factor 1gamma (tif1gamma) selectively binds receptor-phosphorylated smad2/3 in competition with smad4. Rapid and robust binding of tif1gamma to smad2/3 occurs in hematopoietic, mesenchymal, and epithelial cell types in response to tgfbeta. Tif1gamma mediates the differentiation response while smad4 mediates the antiproliferative response with smad2/3 participating in both responses.	SIGNOR-236064
Q9NPH3	Q9H0E2	1	binding	down-regulates activity	0.638	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-251979
P06493	Q13415	1	phosphorylation	up-regulates	0.637	Horc1p contains three (s/t)px(k/r) consensus sites for cdk phosphorylation (ser258, ser273, and thr375). These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability.	SIGNOR-116329
P27361	P04049	1	phosphorylation	down-regulates activity	0.637	Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. \| Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.\|FLAG-Raf-1 phosphorylated by activated ERK2	SIGNOR-143688
P18031	P08581	1	dephosphorylation	down-regulates activity	0.637	It has been reported that the protein tyrosine phosphatase PTP1B could inactivate MET by direct dephosphorylation of Tyr 1234 and 1235 in its activation loop, and that this dephosphorylation takes place in peri-nuclear region of the cell [ xref ].	SIGNOR-277001
Q05655	Q15717	1	phosphorylation	up-regulates	0.637	Tandem phosphorylation of serines 221 and 318 by protein kinase cdelta coordinates mrna binding and nucleocytoplasmic shuttling of hurstabilization of mrna by the ubiquitous rna binding protein human antigen r (hur), a member of the embryonic lethal abnormal vision (elav) protein family, requires canonical binding to au-rich element (are)-bearing target mrna and export of nuclear hur-mrna complexes to the cytoplasm. In human mesangial cells (hmc) both processes are induced by angiotensin ii (angii) via protein kinase cdelta (pkcdelta)-triggered serine phosphorylation of hur.	SIGNOR-163524
O60890	P60953	1	gtpase-activating protein	up-regulates activity	0.637	OPHN-1 colocalized with the actin cytoskeleton in neuronal and glial cells. We have previously shown that OPHN1 stimulates GTPases activity of RhoA, Cdc42, and Rac1 in vitro	SIGNOR-268398
O14733	P45984	1	phosphorylation	up-regulates	0.637	Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1). These results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway.	SIGNOR-83744
Q8N2W9	Q12888	1	sumoylation	up-regulates	0.637	Pias1 and pias4 are recruited to dna-damage sites and mediate 53bp1 recruitment and sumoylation	SIGNOR-162167
P27361	P17302	1	phosphorylation	down-regulates activity	0.637	These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication.	SIGNOR-249466
P42229	O14543	1	transcriptional regulation	up-regulates quantity by expression	0.637	We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling	SIGNOR-261548
P00533	O14964	1	phosphorylation	up-regulates activity	0.637	We have analysed hrs phosphorylation in response to epidermal growth factor (egf) stimulation and show that the evolutionary conserved tyrosines y329 and y334 provide the principal phosphorylation sitesover-expression of wild-type hrs or a double mutant, y329/334f, defective in egf-dependent phosphorylation, substantially retard egf receptor (egfr) degradation	SIGNOR-100246
P12931	Q05193	1	phosphorylation	up-regulates activity	0.637	Endocytosis of ligand-activated receptors requires dynamin-mediated GTP hydrolysis, which is regulated by dynamin self-assembly. Here, we demonstrate that phosphorylation of dynamin I by c-Src induces its self-assembly and increases its GTPase activity. Electron microscopic analyses reveal that tyrosine-phosphorylated dynamin I spontaneously self-assembles into large stacks of rings. Tyrosine 597 was identified as being phosphorylated both in vitro and in cultured cells following epidermal growth factor receptor stimulation.	SIGNOR-247129
Q16539	Q8IW41	1	phosphorylation	up-regulates activity	0.637	In hela cells, prak was activated in response to cellular stress and proinflammatory cytokines. Prak activity was regulated by p38alpha and p38beta both in vitro and in vivo and thr182 was shown to be the regulatory phosphorylation site.	SIGNOR-58135
Q08881	P19174	1	phosphorylation	up-regulates	0.637	In t cells, the predominant tec kinase is itk, which functions downstream of the t-cell receptor to regulate phospholipase c-gamma.	SIGNOR-165803
P45984	O43521	1	phosphorylation	up-regulates activity	0.637	JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity.	SIGNOR-250134
O75385	O95166	1	binding	up-regulates	0.637	N-terminal proline/serine rich (ps) domain of ulk1 (amino acid 287-416) is required for ulk1-gate-16 and ulk1-gabarap protein interactions	SIGNOR-85614
P49674	O14640	1	phosphorylation	up-regulates activity	0.637	Phenotypic analysis of mutant mDvl-1 indicates that phosphorylation of these sites stimulates the Dvl-activated beta-catenin-dependent Wnt signaling pathway in both cell culture and in Xenopus development.	SIGNOR-217849
P06493	Q9ULW0	1	phosphorylation	down-regulates activity	0.637	In this study, we characterize the phosphorylation of threonine 72 (Thr(72)) in human TPX2, a residue highly conserved across species. We find that Cdk1/2 phosphorylate TPX2 in vitro and in vivo. \|Endogenous TPX2 phosphorylated at Thr(72) does not associate with the mitotic spindle. Furthermore, ectopic GFP-TPX2 T72A preferentially concentrates on the spindle	SIGNOR-265096
O14625	P25106	1	binding	up-regulates activity	0.637	This paper characterizes an alternate receptor, CXCR7, which binds with high affinity to SDF-1 and to a second chemokine, interferon-inducible T cell alpha chemoattractant (I-TAC; also known as CXCL11)	SIGNOR-268415
Q9H171	Q9Y572	1	binding	up-regulates activity	0.637	ZBP1 initiates RIPK3-driven cell death by sensing IAV RNA and activating RIPK3. Here, we show that replicating IAV generates Z-RNAs, which activate ZBP1 in the nucleus of infected cells. ZBP1 then initiates RIPK3-mediated MLKL activation in the nucleus, resulting in nuclear envelope disruption, leakage of DNA into the cytosol, and eventual necroptosis.	SIGNOR-266430
Q9H1J7	Q9NPG1	1	binding	up-regulates	0.636	Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors.	SIGNOR-141440
Q12913	P12931	2	phosphorylation	up-regulates activity	0.636	CK2-dependent phosphorylation of DEP-1 T1318 promotes Y1320 phosphorylation and Src activation upon VEGF stimulation.	SIGNOR-277877
Q8IW93	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.636	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260543
P06493	Q9UJX2	1	phosphorylation	up-regulates	0.636	Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation	SIGNOR-119821
P17081	Q9UPT5	1	binding	up-regulates	0.636	Here we show that tc10 interacts with one of the components of the exocyst complex, exo70.	SIGNOR-100486
Q12933	Q13077	2	binding	up-regulates	0.636	Our analysis indicates that traf1 and traf2 are associated with the cytoplasmic domain of tnf-r2 in a heterodimeric complex in which traf2 contacts the receptor directly. Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2.	SIGNOR-35881
P01023	P08253	2	binding	down-regulates activity	0.636	Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity\| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.	SIGNOR-261803
P27361	Q07889	1	phosphorylation	down-regulates	0.636	For example, inactivation of sos through phosphorylation by the downstream mapk	SIGNOR-26338
Q96S42	Q8NER5	1	binding	up-regulates activity	0.636	Human activin receptor-like kinase 7 (ALK7), a type I receptor for Nodal. activation of the Nodal-ALK7 signaling pathway leads to induction of apoptosis and inhibition of cell proliferation.	SIGNOR-251936
Q13315	Q9HB75	1	phosphorylation	up-regulates activity	0.636	ATM phosphorylates PIDD on Thr788 within the DD. This phosphorylation is necessary and sufficient for RAIDD binding and caspase-2 activation. Conversely, nonphosphorylatable PIDD fails to bind RAIDD or activate caspase-2, and engages prosurvival RIP1 instead. Thus, ATM phosphorylation of the PIDD DD enables a binary switch through which cells elect to survive or die upon DNA injury.	SIGNOR-262640
Q7Z699	P21359	1	binding	up-regulates quantity	0.636	Sprouty-related, EVH1 domain-containing (SPRED) proteins negatively regulate RAS/mitogen-activated protein kinase (MAPK) signaling following growth factor stimulation. This inhibition of RAS is thought to occur primarily through SPRED1 binding and recruitment of neurofibromin, a RasGAP, to the plasma membrane. Here, we report the structure of neurofibromin (GTPase-activating protein [GAP]-related domain) complexed with SPRED1 (EVH1 domain) and KRAS. The structure provides insight into how the membrane targeting of neurofibromin by SPRED1 allows simultaneous interaction with activated KRAS.	SIGNOR-273660
P08253	P01023	2	cleavage	down-regulates quantity by destabilization	0.636	The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.\|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.	SIGNOR-261739
P31749	P49840	2	phosphorylation	down-regulates	0.636	In response to insulin, gsk3a inhibited by phosphorylation at ser-21 by pkb/akt1;phosphorylation at this site causes a conformational change, preventing access of substrates to the active site.	SIGNOR-252589
P06241	P15498	1	phosphorylation	up-regulates	0.636	Study of t cells from a fyn-deficient tcr transgenic mouse also showed that fyn was required for tyrosine phosphorylation and activation of vav induced by both antagonist and agonist peptides.	SIGNOR-82287
P12931	P19174	1	phosphorylation	up-regulates activity	0.636	The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.	SIGNOR-247316
O00548	Q04721	1	binding	up-regulates	0.636	In this study, we demonstrate that dll1 can activate notch signaling mostly through notch2 receptor and can contribute to drug resistance to bortezomib, both in murine and human mm cells.	SIGNOR-199320
Q13077	Q12933	2	binding	up-regulates	0.636	Traf1 and traf2 can form homo- and heterotypic dimers.	SIGNOR-34768
Q9NQC7	O43318	1	deubiquitination	up-regulates activity	0.636	Mechanistically, CYLD interacts directly with the kinase TAK1 and removes its K63-linked polyubiquitin chain, which blocks downstream activation of the JNK-p38 cascades.	SIGNOR-266437
Q13043	Q9NRM7	1	phosphorylation	up-regulates	0.636	Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2.	SIGNOR-175821
P28702	P10828	1	binding	up-regulates	0.636	Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr	SIGNOR-81455
O60890	P61586	1	gtpase-activating protein	up-regulates activity	0.636	OPHN-1 colocalized with the actin cytoskeleton in neuronal and glial cells. We have previously shown that OPHN1 stimulates GTPases activity of RhoA, Cdc42, and Rac1 in vitro	SIGNOR-268397
Q13671	P01112	1	binding	up-regulates	0.636	We demonstrate that the ras effector protein rin1 binds to activated ras with an affinity (k(d), 22 nm) similar to that observed for raf1.	SIGNOR-113967
Q99767	Q9ULB1	1	binding	up-regulates activity	0.636	Mint1 and Mint2 Interact with the Cytoplasmic Domain of Neurexin I. The interaction of Mint1 with neurexins is mediated by its PDZ domains and allows the formation of mixed CASK-Mint complexes. Both CASK and Mint1 can bind directly to neurexins and to each other. Therefore, the assembly of various multimeric complexes could proceed as CASK could be indirectly recruited to neurexin-bound Mint1 and vice versa.	SIGNOR-264039
P12931	Q12913	2	phosphorylation	up-regulates activity	0.636	We demonstrate here that DEP-1 is phosphorylated in a Src- and Fyn-dependent manner on Y1311 and Y1320, which bind the Src SH2 domain. This allows DEP-1-catalyzed dephosphorylation of Src inhibitory Y529 and favors the VEGF-induced phosphorylation of Src substrates VE-cadherin and Cortactin.	SIGNOR-276373
P34947	P37840	1	phosphorylation	down-regulates activity	0.636	Grk5 phosphorylated ser-129 of alpha-synuclein at the plasma membrane and induced translocation of phosphorylated alpha-synuclein to the perikaryal area. Grk5-catalyzed phosphorylation also promoted the formation of soluble oligomers and aggregates of alpha-synuclein.	SIGNOR-149372
P10415	Q07812	2	binding	down-regulates activity	0.636	Bcl-2 has the unique oncogenic role of extending cell survival by inhibiting a variety of apoptotic deaths. Bcl-2 exerts its action through heterodimerization with bax.	SIGNOR-36898
P49840	P31749	2	phosphorylation	down-regulates activity	0.636	GSK3_ negatively regulates AKT activation by phosphorylating AKT at T312 in the substrate binding site, which inhibited IL-1-induced AKT activation and function.	SIGNOR-252434
Q07812	P10415	2	binding	down-regulates activity	0.636	Bax shows extensive amino acid homology with Bcl-2 and forms homodimers and heterodimers with Bcl-2 in vivo. When Bax predominates, programed cell death is accelerated, and the death repressor activity of Bcl-2 is countered.	SIGNOR-249612
Q13217	P19525	1	binding	down-regulates activity	0.635	The protein p58IPK {also known asDnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily C, member 3]} is known to inhibit the eIF2 kinases PKR (dsRNA-dependent protein kinase/eIF2 kinase 2) and PERK	SIGNOR-246207
P17612	P15056	1	phosphorylation	down-regulates activity	0.635	Direct phosphorylation of B-Raf by PKA exerts a negative effect on its kinase activity, essentially via phosphorylation of Ser429	SIGNOR-250339
Q9Y2K2	Q53ET0	1	phosphorylation	down-regulates activity	0.635	We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348\|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression	SIGNOR-249170
Q99835	P49407	1	binding	up-regulates	0.635	Grk2-mediated phosphorylation of vertebrate smo allows smo to bind to beta-arrestins 1 or 2	SIGNOR-132678
P58753	Q99836	1	binding	up-regulates activity	0.635	Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TlR-domain-containing protein in the human genome. Mal activates NF-_B, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2.	SIGNOR-252063
P02649	P98155	1	binding	up-regulates	0.635	Several ligands for the vldl receptor have been identified in addition to tfpi. These include apolipoprotein e (apoe)	SIGNOR-106221
P06241	Q14114	1	phosphorylation	up-regulates quantity	0.635	Fyn phosphorylates ApoER2.\|Together these data demonstrate that Fyn activity is necessary for its effects increasing ApoER2 levels.	SIGNOR-278197
P17706	P00533	1	dephosphorylation	down-regulates	0.635	Here, we report that the 45-kda variant of the protein tyrosine phosphatase tcptp (tc45) can recognize delta egfr as a cellular substrate	SIGNOR-132316
Q16566	Q92793	1	phosphorylation	up-regulates activity	0.635	Ser301 of CBP was identified as a major target of CaMKIV phosphorylation in vitro and in vivo. CaM kinase inhibitors attenuated phosphorylation at Ser301 and blocked CBP-dependent transcription. Additionally, mutation of Ser301 impaired NMDA- and CaMKIV-stimulated transcription. These findings demonstrate that activity-induced CaMKIV signaling contributes to CREB/CBP-dependent transcription by phosphorylating CBP at Ser301.	SIGNOR-250710
P55291	P35222	1	binding	up-regulates activity	0.635	At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin	SIGNOR-265854
Q9Y219	Q04721	1	binding	up-regulates	0.635	Binding of delta1, jagged1, and jagged2 to notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of notch2	SIGNOR-81367
Q14344	O15085	1	binding	up-regulates activity	0.635	This RGS-like (RGL) domain provides a structural motif by which heterotrimeric G protein alpha subunits of the Galpha(12) family can bind and regulate the activity of RhoGEFs. Hence, these newly discovered RGL domain-containing RhoGEFs provide a direct link from Galpha(12) and Galpha(13) to Rho	SIGNOR-256517
Q99459	P52272	1	binding	up-regulates activity	0.635	hnRNP-M interacts directly with CDC5L and PLRG1 in vivo. we investigated whether the function of hnRNP-M in alternative splicing was affected by the central region mapped as essential for binding to the CDC5L/PLRG1 proteins. We conclude that loss of the CDC5L/PLRG1 interaction domain in hnRNP-M correlates with a loss of ability to modulate alternative splice site selection in this assay.	SIGNOR-239410
O95248	Q13614	1	binding	up-regulates activity	0.635	We also demonstrate that MTMR2 interacts with MTMR5 via its coiled-coil domain and that mutations in the coiled-coil domain of either MTMR2 or MTMR5 abrogate this interaction. Through this interaction, MTMR5 increases the enzymatic activity of MTMR2 and dictates its subcellular localization.	SIGNOR-269803
P51813	Q96T51	1	phosphorylation	up-regulates activity	0.634	Etk interacts with RUFY1 through its SH3 and SH2 domains. RUFY1 is tyrosine-phosphorylated and appears to be a substrate of Etk. Phosphorylation of the two tyrosine residues, Tyr-281 and Tyr-292, located in the linker region of the two coiled-coil domains by Etk seems to be critical for RUFY1 targeting to the endosomes.	SIGNOR-262679
O43524	Q15831	1	transcriptional regulation	down-regulates quantity	0.634	SGK-1 Negatively Regulates LKB1 Expression via FOXO3 Transcription Factor	SIGNOR-255758
P41134	P15923	1	binding	down-regulates activity	0.634	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241107
O94813	Q8WZ75	1	binding	up-regulates	0.634	We show that robo4 binds slit and inhibits cellular migration in a heterologous expression system, analogous to the role of known robo receptors in the nervous system.	SIGNOR-86380
O43663	Q15058	1	binding	up-regulates activity	0.634	KIF14 interacts with PRC1 and citron kinase. We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. I	SIGNOR-266423
Q9UKV0	Q06413	1	binding	down-regulates	0.633	Mirk activated mef2 not through direct phosphorylation of mef2 but by phosphorylation of its inhibitors, the class ii histone deacetylases (hdacs). Mef2 is sequestered by class ii hdacs such as hdac5 and mef2-interacting transcriptional repressor (mitr). Mirk antagonized the inhibition of mef2c by mitr, whereas kinase-inactive mirk was ineffective. Mirk phosphorylates class ii hdacs at a conserved site within the nuclear localization region, reducing their nuclear accumulation in a dose-dependent and kinase-dependent manner	SIGNOR-235642
O60641	P21579	1	binding	up-regulates quantity	0.633	the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively .Stonin-2 and AP-2 are also Required for Efficient Synaptotagmin-1 Retrieval. the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively.	SIGNOR-264114

Q05397

P07949

2

phosphorylation

up-regulates

0.639

Focal adhesion kinase (fak) binds ret kinase via its ferm domain, priming a direct and reciprocal ret-fak transactivation mechanism. following gdnf stimulation, increased phosphorylation of fak at tyr-576/577 as well as phosphorylation of ret at tyr-905 was observed.

SIGNOR-173009

P40189

O60674

1

phosphorylation

up-regulates activity

0.639

All IL-6-type cytokines recruit gp130to their receptot complexes They either signal via gp130 alone [8] or in combination with LIFR [9] or the recently cloned OSMR [10], which are all able to activate Jaks proteins. Two tyrosine residues at the corresponding positions of Jak2 (tyrosine-1007 and tyrosine-1008) were found to be phosphorylated, and a single mutation of tyrosine-1007 eliminated essentially all tyrosine kinase activity [59].

SIGNOR-238634

P07949

Q05397

2

phosphorylation

up-regulates

0.639

The identification of focal adhesion kinase (fak) as a direct substrate for ret kinase revealed (i) a ret-fak transactivation mechanism consisting of direct phosphorylation of fak tyr-576/577 by ret and a reciprocal phosphorylation of ret by fak, which crucially is able to rescue the kinase-impaired ret k758m mutant and (ii) that fak binds ret via its ferm domain. Interestingly, this interaction is abolished upon ret phosphorylation, indicating that ret binding to the ferm domain of fak is a priming step for ret-fak transactivation.

SIGNOR-173013

P28482

P00533

1

phosphorylation

down-regulates activity

0.639

A growth factor-stimulated protein kinase activity that phosphorylates the epidermal growth factor (EGF) receptor at Thr669 has been described Anion-exchange chromatography demonstrated that this protein kinase activity was accounted for by two enzymes. The first peak of activity eluted from the column corresponded to the microtubule-associated protein 2 (MAP2) kinase

SIGNOR-20545

Q9NX09

P49815

1

binding

up-regulates activity

0.639

Redd1 is a negative regulator of mTOR, mediating dissociation of 14-3-3 from tuberous sclerosis complex (TSC)2, which allows formation of a TSC-TSC2 complex.

SIGNOR-277469

P42574

P55211

2

cleavage

up-regulates activity

0.639

Active caspase-3 itself is able to process its upstream , caspase-8 and caspase-9, establishing a self-amplifying loop of caspase activation

SIGNOR-90397

P78504

Q04721

1

binding

up-regulates

0.639

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

SIGNOR-81364

P12931

Q99961

1

phosphorylation

down-regulates

0.639

Further, we identified an interaction between fak's second pro-rich motif and endophilin a2's sh3 domain. This interaction served as an autophosphorylation-dependent scaffold to allow src phosphorylation of endophilin a2 at tyr315. Tyr315 phosphorylation inhibited endophilin/dynamin interactions, and blockade of tyr315 phosphorylation promoted endocytosis of mt1-mmp. Together, these results suggest a regulatory mechanism of cell invasion whereby fak promotes cell-surface presentation of mt1-mmp by inhibiting endophilin a2-dependent endocytosis.

SIGNOR-139150

Q8NCW0

O75581

1

binding

down-regulates

0.639

Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to block wnt/beta-catenin signalling. Kremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of the wnt receptor lrp6 from the plasma membrane.

SIGNOR-88894

P54727

P28715

1

binding

up-regulates activity

0.639

GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo

SIGNOR-275702

P42574

P06396

1

cleavage

down-regulates

0.639

Caspase-3 mediates cleavage of gelsolin, generating a fragment that severs actin filaments in an unregulated fashion. The cleavage of gelsolin causes cells to round up, detach and undergo nuclear fragmentation.

SIGNOR-51652

Q9Y6R4

P46734

1

phosphorylation

up-regulates activity

0.639

These results, therefore, suggest that mtk1 directly phosphorylates and activates mkk3, mkk6 and sek1.

SIGNOR-50891

P55211

P42574

2

cleavage

up-regulates activity

0.639

Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3.

SIGNOR-133267

Q04725

Q9UJU2

1

binding

down-regulates

0.638

Mapping studies reveal that groucho/tle binds two regions in lef-1.

SIGNOR-185736

P06493

Q13042

1

phosphorylation

up-regulates

0.638

Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation

SIGNOR-119762

Q13387

P45983

1

binding

up-regulates

0.638

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

SIGNOR-70860

P53350

Q9H0H5

1

phosphorylation

up-regulates

0.638

Tandem mass spectrometry analysis of a purified hscyk-4 fragment (hscyk-4n) phosphorylated by plk1 in vitro identified four major sites (s157, s170, s214, and s260 plk1 phosphorylation of hscyk-4 localizes ect2 at the midzone and stimulates rhoa-dependent contractile ring assembly at the equatorial cortex.

SIGNOR-185758

P19474

Q02556

1

ubiquitination

down-regulates quantity

0.638

From these results, we concluded that TRIM21 down-regulated IRF8 and enhanced the secretion of IL-12/23p40 in BD monocytes.|IRF8 is ubiquitinated by TRIM21, which promotes secretion of IL-12/23p40 after TLR/IFN-\u03b3 stimulation xref .

SIGNOR-278791

P32121

Q9Y496

1

binding

up-regulates

0.638

Betaarrestin 2 was subsequentialy shown to bridge smo to the kinestesin motor kif3 to promote ciliary accumulation of smo in mammalian cells

SIGNOR-199107

P06493

P52732

1

phosphorylation

up-regulates activity

0.638

Nek6 phosphorylated Eg5 at several sites in vitro and one of these sites, Ser1033, is phosphorylated in vivo during mitosis. Whereas CDK1 phosphorylates nearly all Eg5 at Thr926 during mitosis, Nek6 phosphorylates approximately 3% of Eg5, primarily at the spindle poles.

SIGNOR-273887

P09619

P16333

1

binding

up-regulates

0.638

Growth factor binding to receptor protein tyrosine kinases (r-ptks)1 induces their dimerization and trans-phosphorylation, creating docking sites for proteins containing sh2 and ptb protein interaction domains. Nck binds to the pdgf and egfr receptors (figure 3c).

SIGNOR-64737

Q14766

P01137

1

binding

up-regulates activity

0.638

Together these data form strong support for the hypothesis that the LTBP plays an essential role in the activation of latent TGF-b in heterotypic cultures.

SIGNOR-235754

O43815

P67775

1

binding

up-regulates activity

0.638

The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms

SIGNOR-261698

P16871

P23458

1

binding

up-regulates

0.638

For instance, jak1 is associated with the ? Subunits of ?c Cytokines such as il-7r? And IL-4R. jak3 is associated with the ?c20,21. Cytokine binding mediates the trans-phosphorylation of receptor associated jak kinases, which in turn phosphorylate tyrosine residues on the receptors themselves. The receptor phosphotyrosines serve as docking sites for sh2 domain proteins including the stat family of transcription factors which are activated by jak-mediated phosphorylation.

SIGNOR-178494

P42226

O15524

1

transcriptional regulation

up-regulates quantity by expression

0.638

We found that IL-4, like IFN-gamma, induces rapid de novo expression of SOCS-1 in primary macrophages. Induction of SOCS-1 gene expression by IL-4 is STAT6-dependent.

SIGNOR-249570

P40763

P01189

1

transcriptional regulation

up-regulates quantity by expression

0.638

We show that phospho-STAT3 activates POMC promoter in response to leptin signaling through a mechanism that requires an SP1-binding site in the POMC promoter.

SIGNOR-263497

P19474

Q9UJV9

1

ubiquitination

down-regulates quantity

0.638

Furthermore, overexpression of TRIM21 in mDCs led to lower expression of DDX41 in these mDCs and up to 70% less IFN-beta production by mDCs in response to intracellular DNA (XREF_FIG).|Here we report that the E3 ligase TRIM21 negatively regulated the type I interferon response in myeloid dendritic cells (mDCs) and monocytes that had been induced by cytosolic double stranded DNA (dsDNA), mainly by promoting the ubiquitination and degradation of DDX41.

SIGNOR-278790

Q9NWZ3

Q9HAT8

1

phosphorylation

up-regulates

0.638

Pellino2 is one of the firstsubstrates identified for irak1 andirak4.

SIGNOR-103717

P45983

P04150

1

phosphorylation

down-regulates

0.638

Taken together, these findings suggest that jnk-mediated phosphorylation of the gr-ser226 enhances gr nuclear export and may contribute to termination of gr-mediated transcription.

SIGNOR-93558

P22681

P29317

1

binding

down-regulates quantity by destabilization

0.638

In our present study, we demonstrate that ligand-mediated stimulation causes EphA2 to be internalized and degraded. The mechanism of this response involves ligand-mediated autophosphorylation of EphA2, which promotes an association between EphA2 and the c-Cbl adaptor protein. We also show that c-Cbl promotes stimulation-dependent EphA2 degradation.

SIGNOR-272590

Q9UPN9

Q15796

1

binding

up-regulates activity

0.638

The ubiquitious nuclear protein transcriptional intermediary factor 1gamma (tif1gamma) selectively binds receptor-phosphorylated smad2/3 in competition with smad4. Rapid and robust binding of tif1gamma to smad2/3 occurs in hematopoietic, mesenchymal, and epithelial cell types in response to tgfbeta. Tif1gamma mediates the differentiation response while smad4 mediates the antiproliferative response with smad2/3 participating in both responses.

SIGNOR-236064

Q9NPH3

Q9H0E2

1

binding

down-regulates activity

0.638

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-251979

P06493

Q13415

1

phosphorylation

up-regulates

0.637

Horc1p contains three (s/t)px(k/r) consensus sites for cdk phosphorylation (ser258, ser273, and thr375). These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability.

SIGNOR-116329

P27361

P04049

1

phosphorylation

down-regulates activity

0.637

Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2

SIGNOR-143688

P18031

P08581

1

dephosphorylation

down-regulates activity

0.637

It has been reported that the protein tyrosine phosphatase PTP1B could inactivate MET by direct dephosphorylation of Tyr 1234 and 1235 in its activation loop, and that this dephosphorylation takes place in peri-nuclear region of the cell [ xref ].

SIGNOR-277001

Q05655

Q15717

1

phosphorylation

up-regulates

0.637

Tandem phosphorylation of serines 221 and 318 by protein kinase cdelta coordinates mrna binding and nucleocytoplasmic shuttling of hurstabilization of mrna by the ubiquitous rna binding protein human antigen r (hur), a member of the embryonic lethal abnormal vision (elav) protein family, requires canonical binding to au-rich element (are)-bearing target mrna and export of nuclear hur-mrna complexes to the cytoplasm. In human mesangial cells (hmc) both processes are induced by angiotensin ii (angii) via protein kinase cdelta (pkcdelta)-triggered serine phosphorylation of hur.

SIGNOR-163524

O60890

P60953

1

gtpase-activating protein

up-regulates activity

0.637

OPHN-1 colocalized with the actin cytoskeleton in neuronal and glial cells. We have previously shown that OPHN1 stimulates GTPases activity of RhoA, Cdc42, and Rac1 in vitro

SIGNOR-268398

O14733

P45984

1

phosphorylation

up-regulates

0.637

Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1). These results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway.

SIGNOR-83744

Q8N2W9

Q12888

1

sumoylation

up-regulates

0.637

Pias1 and pias4 are recruited to dna-damage sites and mediate 53bp1 recruitment and sumoylation

SIGNOR-162167

P27361

P17302

1

phosphorylation

down-regulates activity

0.637

These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication.

SIGNOR-249466

P42229

O14543

1

transcriptional regulation

up-regulates quantity by expression

0.637

We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling

SIGNOR-261548

P00533

O14964

1

phosphorylation

up-regulates activity

0.637

We have analysed hrs phosphorylation in response to epidermal growth factor (egf) stimulation and show that the evolutionary conserved tyrosines y329 and y334 provide the principal phosphorylation sitesover-expression of wild-type hrs or a double mutant, y329/334f, defective in egf-dependent phosphorylation, substantially retard egf receptor (egfr) degradation

SIGNOR-100246

P12931

Q05193

1

phosphorylation

up-regulates activity

0.637

Endocytosis of ligand-activated receptors requires dynamin-mediated GTP hydrolysis, which is regulated by dynamin self-assembly. Here, we demonstrate that phosphorylation of dynamin I by c-Src induces its self-assembly and increases its GTPase activity. Electron microscopic analyses reveal that tyrosine-phosphorylated dynamin I spontaneously self-assembles into large stacks of rings. Tyrosine 597 was identified as being phosphorylated both in vitro and in cultured cells following epidermal growth factor receptor stimulation.

SIGNOR-247129

Q16539

Q8IW41

1

phosphorylation

up-regulates activity

0.637

In hela cells, prak was activated in response to cellular stress and proinflammatory cytokines. Prak activity was regulated by p38alpha and p38beta both in vitro and in vivo and thr182 was shown to be the regulatory phosphorylation site.

SIGNOR-58135

Q08881

P19174

1

phosphorylation

up-regulates

0.637

In t cells, the predominant tec kinase is itk, which functions downstream of the t-cell receptor to regulate phospholipase c-gamma.

SIGNOR-165803

P45984

O43521

1

phosphorylation

up-regulates activity

0.637

JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity.

SIGNOR-250134

O75385

O95166

1

binding

up-regulates

0.637

N-terminal proline/serine rich (ps) domain of ulk1 (amino acid 287-416) is required for ulk1-gate-16 and ulk1-gabarap protein interactions

SIGNOR-85614

P49674

O14640

1

phosphorylation

up-regulates activity

0.637

Phenotypic analysis of mutant mDvl-1 indicates that phosphorylation of these sites stimulates the Dvl-activated beta-catenin-dependent Wnt signaling pathway in both cell culture and in Xenopus development.

SIGNOR-217849

P06493

Q9ULW0

1

phosphorylation

down-regulates activity

0.637

In this study, we characterize the phosphorylation of threonine 72 (Thr(72)) in human TPX2, a residue highly conserved across species. We find that Cdk1/2 phosphorylate TPX2 in vitro and in vivo. |Endogenous TPX2 phosphorylated at Thr(72) does not associate with the mitotic spindle. Furthermore, ectopic GFP-TPX2 T72A preferentially concentrates on the spindle

SIGNOR-265096

O14625

P25106

1

binding

up-regulates activity

0.637

This paper characterizes an alternate receptor, CXCR7, which binds with high affinity to SDF-1 and to a second chemokine, interferon-inducible T cell alpha chemoattractant (I-TAC; also known as CXCL11)

SIGNOR-268415

Q9H171

Q9Y572

1

binding

up-regulates activity

0.637

ZBP1 initiates RIPK3-driven cell death by sensing IAV RNA and activating RIPK3. Here, we show that replicating IAV generates Z-RNAs, which activate ZBP1 in the nucleus of infected cells. ZBP1 then initiates RIPK3-mediated MLKL activation in the nucleus, resulting in nuclear envelope disruption, leakage of DNA into the cytosol, and eventual necroptosis.

SIGNOR-266430

Q9H1J7

Q9NPG1

1

binding

up-regulates

0.636

Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors.

SIGNOR-141440

Q12913

P12931

2

phosphorylation

up-regulates activity

0.636

CK2-dependent phosphorylation of DEP-1 T1318 promotes Y1320 phosphorylation and Src activation upon VEGF stimulation.

SIGNOR-277877

Q8IW93

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.636

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

SIGNOR-260543

P06493

Q9UJX2

1

phosphorylation

up-regulates

0.636

Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation

SIGNOR-119821

P17081

Q9UPT5

1

binding

up-regulates

0.636

Here we show that tc10 interacts with one of the components of the exocyst complex, exo70.

SIGNOR-100486

Q12933

Q13077

2

binding

up-regulates

0.636

Our analysis indicates that traf1 and traf2 are associated with the cytoplasmic domain of tnf-r2 in a heterodimeric complex in which traf2 contacts the receptor directly. Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2.

SIGNOR-35881

P01023

P08253

2

binding

down-regulates activity

0.636

Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.

SIGNOR-261803

P27361

Q07889

1

phosphorylation

down-regulates

0.636

For example, inactivation of sos through phosphorylation by the downstream mapk

SIGNOR-26338

Q96S42

Q8NER5

1

binding

up-regulates activity

0.636

Human activin receptor-like kinase 7 (ALK7), a type I receptor for Nodal. activation of the Nodal-ALK7 signaling pathway leads to induction of apoptosis and inhibition of cell proliferation.

SIGNOR-251936

Q13315

Q9HB75

1

phosphorylation

up-regulates activity

0.636

ATM phosphorylates PIDD on Thr788 within the DD. This phosphorylation is necessary and sufficient for RAIDD binding and caspase-2 activation. Conversely, nonphosphorylatable PIDD fails to bind RAIDD or activate caspase-2, and engages prosurvival RIP1 instead. Thus, ATM phosphorylation of the PIDD DD enables a binary switch through which cells elect to survive or die upon DNA injury.

SIGNOR-262640

Q7Z699

P21359

1

binding

up-regulates quantity

0.636

Sprouty-related, EVH1 domain-containing (SPRED) proteins negatively regulate RAS/mitogen-activated protein kinase (MAPK) signaling following growth factor stimulation. This inhibition of RAS is thought to occur primarily through SPRED1 binding and recruitment of neurofibromin, a RasGAP, to the plasma membrane. Here, we report the structure of neurofibromin (GTPase-activating protein [GAP]-related domain) complexed with SPRED1 (EVH1 domain) and KRAS. The structure provides insight into how the membrane targeting of neurofibromin by SPRED1 allows simultaneous interaction with activated KRAS.

SIGNOR-273660

P08253

P01023

2

cleavage

down-regulates quantity by destabilization

0.636

The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.

SIGNOR-261739

P31749

P49840

2

phosphorylation

down-regulates

0.636

In response to insulin, gsk3a inhibited by phosphorylation at ser-21 by pkb/akt1;phosphorylation at this site causes a conformational change, preventing access of substrates to the active site.

SIGNOR-252589

P06241

P15498

1

phosphorylation

up-regulates

0.636

Study of t cells from a fyn-deficient tcr transgenic mouse also showed that fyn was required for tyrosine phosphorylation and activation of vav induced by both antagonist and agonist peptides.

SIGNOR-82287

P12931

P19174

1

phosphorylation

up-regulates activity

0.636

The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.

SIGNOR-247316

O00548

Q04721

1

binding

up-regulates

0.636

In this study, we demonstrate that dll1 can activate notch signaling mostly through notch2 receptor and can contribute to drug resistance to bortezomib, both in murine and human mm cells.

SIGNOR-199320

Q13077

Q12933

2

binding

up-regulates

0.636

Traf1 and traf2 can form homo- and heterotypic dimers.

SIGNOR-34768

Q9NQC7

O43318

1

deubiquitination

up-regulates activity

0.636

Mechanistically, CYLD interacts directly with the kinase TAK1 and removes its K63-linked polyubiquitin chain, which blocks downstream activation of the JNK-p38 cascades.

SIGNOR-266437

Q13043

Q9NRM7

1

phosphorylation

up-regulates

0.636

Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2.

SIGNOR-175821

P28702

P10828

1

binding

up-regulates

0.636

Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr

SIGNOR-81455

O60890

P61586

1

gtpase-activating protein

up-regulates activity

0.636

OPHN-1 colocalized with the actin cytoskeleton in neuronal and glial cells. We have previously shown that OPHN1 stimulates GTPases activity of RhoA, Cdc42, and Rac1 in vitro

SIGNOR-268397

Q13671

P01112

1

binding

up-regulates

0.636

We demonstrate that the ras effector protein rin1 binds to activated ras with an affinity (k(d), 22 nm) similar to that observed for raf1.

SIGNOR-113967

Q99767

Q9ULB1

1

binding

up-regulates activity

0.636

Mint1 and Mint2 Interact with the Cytoplasmic Domain of Neurexin I. The interaction of Mint1 with neurexins is mediated by its PDZ domains and allows the formation of mixed CASK-Mint complexes. Both CASK and Mint1 can bind directly to neurexins and to each other. Therefore, the assembly of various multimeric complexes could proceed as CASK could be indirectly recruited to neurexin-bound Mint1 and vice versa.

SIGNOR-264039

P12931

Q12913

2

phosphorylation

up-regulates activity

0.636

We demonstrate here that DEP-1 is phosphorylated in a Src- and Fyn-dependent manner on Y1311 and Y1320, which bind the Src SH2 domain. This allows DEP-1-catalyzed dephosphorylation of Src inhibitory Y529 and favors the VEGF-induced phosphorylation of Src substrates VE-cadherin and Cortactin.

SIGNOR-276373

P34947

P37840

1

phosphorylation

down-regulates activity

0.636

Grk5 phosphorylated ser-129 of alpha-synuclein at the plasma membrane and induced translocation of phosphorylated alpha-synuclein to the perikaryal area. Grk5-catalyzed phosphorylation also promoted the formation of soluble oligomers and aggregates of alpha-synuclein.

SIGNOR-149372

P10415

Q07812

2

binding

down-regulates activity

0.636

Bcl-2 has the unique oncogenic role of extending cell survival by inhibiting a variety of apoptotic deaths. Bcl-2 exerts its action through heterodimerization with bax.

SIGNOR-36898

P49840

P31749

2

phosphorylation

down-regulates activity

0.636

GSK3_ negatively regulates AKT activation by phosphorylating AKT at T312 in the substrate binding site, which inhibited IL-1-induced AKT activation and function.

SIGNOR-252434

Q07812

P10415

2

binding

down-regulates activity

0.636

Bax shows extensive amino acid homology with Bcl-2 and forms homodimers and heterodimers with Bcl-2 in vivo. When Bax predominates, programed cell death is accelerated, and the death repressor activity of Bcl-2 is countered.

SIGNOR-249612

Q13217

P19525

1

binding

down-regulates activity

0.635

The protein p58IPK {also known asDnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily C, member 3]} is known to inhibit the eIF2 kinases PKR (dsRNA-dependent protein kinase/eIF2 kinase 2) and PERK

SIGNOR-246207

P17612

P15056

1

phosphorylation

down-regulates activity

0.635

Direct phosphorylation of B-Raf by PKA exerts a negative effect on its kinase activity, essentially via phosphorylation of Ser429

SIGNOR-250339

Q9Y2K2

Q53ET0

1

phosphorylation

down-regulates activity

0.635

We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression

SIGNOR-249170

Q99835

P49407

1

binding

up-regulates

0.635

Grk2-mediated phosphorylation of vertebrate smo allows smo to bind to beta-arrestins 1 or 2

SIGNOR-132678

P58753

Q99836

1

binding

up-regulates activity

0.635

Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TlR-domain-containing protein in the human genome. Mal activates NF-_B, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2.

SIGNOR-252063

P02649

P98155

1

binding

up-regulates

0.635

Several ligands for the vldl receptor have been identified in addition to tfpi. These include apolipoprotein e (apoe)

SIGNOR-106221

P06241

Q14114

1

phosphorylation

up-regulates quantity

0.635

Fyn phosphorylates ApoER2.|Together these data demonstrate that Fyn activity is necessary for its effects increasing ApoER2 levels.

SIGNOR-278197

P17706

P00533

1

dephosphorylation

down-regulates

0.635

Here, we report that the 45-kda variant of the protein tyrosine phosphatase tcptp (tc45) can recognize delta egfr as a cellular substrate

SIGNOR-132316

Q16566

Q92793

1

phosphorylation

up-regulates activity

0.635

Ser301 of CBP was identified as a major target of CaMKIV phosphorylation in vitro and in vivo. CaM kinase inhibitors attenuated phosphorylation at Ser301 and blocked CBP-dependent transcription. Additionally, mutation of Ser301 impaired NMDA- and CaMKIV-stimulated transcription. These findings demonstrate that activity-induced CaMKIV signaling contributes to CREB/CBP-dependent transcription by phosphorylating CBP at Ser301.

SIGNOR-250710

P55291

P35222

1

binding

up-regulates activity

0.635

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

SIGNOR-265854

Q9Y219

Q04721

1

binding

up-regulates

0.635

Binding of delta1, jagged1, and jagged2 to notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of notch2

SIGNOR-81367

Q14344

O15085

1

binding

up-regulates activity

0.635

This RGS-like (RGL) domain provides a structural motif by which heterotrimeric G protein alpha subunits of the Galpha(12) family can bind and regulate the activity of RhoGEFs. Hence, these newly discovered RGL domain-containing RhoGEFs provide a direct link from Galpha(12) and Galpha(13) to Rho

SIGNOR-256517

Q99459

P52272

1

binding

up-regulates activity

0.635

hnRNP-M interacts directly with CDC5L and PLRG1 in vivo. we investigated whether the function of hnRNP-M in alternative splicing was affected by the central region mapped as essential for binding to the CDC5L/PLRG1 proteins. We conclude that loss of the CDC5L/PLRG1 interaction domain in hnRNP-M correlates with a loss of ability to modulate alternative splice site selection in this assay.

SIGNOR-239410

O95248

Q13614

1

binding

up-regulates activity

0.635

We also demonstrate that MTMR2 interacts with MTMR5 via its coiled-coil domain and that mutations in the coiled-coil domain of either MTMR2 or MTMR5 abrogate this interaction. Through this interaction, MTMR5 increases the enzymatic activity of MTMR2 and dictates its subcellular localization.

SIGNOR-269803

P51813

Q96T51

1

phosphorylation

up-regulates activity

0.634

Etk interacts with RUFY1 through its SH3 and SH2 domains. RUFY1 is tyrosine-phosphorylated and appears to be a substrate of Etk. Phosphorylation of the two tyrosine residues, Tyr-281 and Tyr-292, located in the linker region of the two coiled-coil domains by Etk seems to be critical for RUFY1 targeting to the endosomes.

SIGNOR-262679

O43524

Q15831

1

transcriptional regulation

down-regulates quantity

0.634

SGK-1 Negatively Regulates LKB1 Expression via FOXO3 Transcription Factor

SIGNOR-255758

P41134

P15923

1

binding

down-regulates activity

0.634

All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.

SIGNOR-241107

O94813

Q8WZ75

1

binding

up-regulates

0.634

We show that robo4 binds slit and inhibits cellular migration in a heterologous expression system, analogous to the role of known robo receptors in the nervous system.

SIGNOR-86380

O43663

Q15058

1

binding

up-regulates activity

0.634

KIF14 interacts with PRC1 and citron kinase. We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. I

SIGNOR-266423

Q9UKV0

Q06413

1

binding

down-regulates

0.633

Mirk activated mef2 not through direct phosphorylation of mef2 but by phosphorylation of its inhibitors, the class ii histone deacetylases (hdacs). Mef2 is sequestered by class ii hdacs such as hdac5 and mef2-interacting transcriptional repressor (mitr). Mirk antagonized the inhibition of mef2c by mitr, whereas kinase-inactive mirk was ineffective. Mirk phosphorylates class ii hdacs at a conserved site within the nuclear localization region, reducing their nuclear accumulation in a dose-dependent and kinase-dependent manner

SIGNOR-235642

O60641

P21579

1

binding

up-regulates quantity

0.633

the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively .Stonin-2 and AP-2 are also Required for Efficient Synaptotagmin-1 Retrieval. the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively.

SIGNOR-264114