Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Syntenin is a PDZ protein that binds the cytoplasmic C-terminal FYA motif of the syndecans. Syntenin is widely expressed. In cell fractionation experiments, syntenin partitions between the cytosol and microsomes. Immunofluorescence microscopy localizes endogenous and epitope-tagged syntenin to cell adhesion sites, microfilaments, and the nucleus. Syntenin is composed of at least three domains. Both PDZ domains of syntenin are necessary to target reporter tags to the plasma membrane. The addition of a segment of 10 amino acids from the N-terminal domain of syntenin to these PDZ domains increases the localization of the tags to stress fibers and induces the formation of long, branching plasma membrane extensions. The addition of the complete N-terminal region, in contrast, reduces the localization of the tags to plasma membrane/adhesion sites and stress fibers, and reduces the morphotypical effects. Recombinant domains of syntenin with the highest plasma membrane localization display the lowest nuclear localization. Syndecan-1, E-cadherin, beta-catenin, and alpha-catenin colocalize with syntenin at cell-cell contacts in epithelial cells, and coimmunoprecipitate with syntenin from extracts of these cells. These results suggest a role for syntenin in the composition of adherens junctions and the regulation of plasma membrane dynamics, and imply a potential role for syntenin in nuclear processes.
Mol Biol Cell 2001 Feb
PMID:Characterization of syntenin, a syndecan-binding PDZ protein, as a component of cell adhesion sites and microfilaments. 1117 19

Cell adhesion is important in the regulation of cell proliferation, migration, survival, and apoptosis. The major components of cell adhesion are the cadherin family of proteins, alpha-, beta- and gamma-catenins, and cytoskeletons. In addition, beta-catenin, when associated with adenomatous polyposis coli (APC) protein, an oncosuppressor, is implicated in the regulation of beta-catenin/APC-related signaling pathways. To examine the correlation between impairment of cell adhesion events and apoptosis, we used human non-small-cell lung cancer H460 and H520 cell lines as models to determine whether paclitaxel-induced apoptosis is associated with disruption of the components of cell adhesion and their functions. Paclitaxel treatment resulted in cells rounding up and losing contact with their neighboring cells, suggesting that the drug does indeed affect cell adhesion and related events. Western blot analysis revealed that paclitaxel caused a time- and concentration-dependent cleavage of beta-catenin, gamma-catenin, and APC protein, but not alpha-catenin or E-cadherin. These cleavages of beta-catenin and gamma-catenin were apoptosis-dependent, not mitosis-dependent. Paclitaxel treatment led to the proteolysis and activation of caspase-3 and -7, but not caspase-1. Furthermore, paclitaxel-induced apoptosis and cleavage of beta-catenin and gamma-catenin were inhibited by the pan-caspase inhibitor Z-VAD-FMK and partially inhibited by the caspase-3 inhibitor Z-DEVD-FMK but were not affected by the caspase-1 inhibitor AC-YVAD-CMK. Although the pan-caspase inhibitor blocked the cleavage of beta-catenin as well as DNA fragmentation, it did not affect paclitaxel-induced M-phase arrest and only partially prevented cell-growth inhibition. Biochemical studies revealed that cleaved beta-catenin was detected only in the Triton X-100 insoluble fraction, suggesting that it might localize in nuclear and/or membrane structures. Interestingly, the paclitaxel-induced beta-catenin fragment lost its ability to bind to E-cadherin, alpha-catenin, or APC protein and to serve as a substrate for tyrosine kinase. All our data demonstrate that the caspase-mediated cleavage of beta-catenin, gamma-catenin, and APC protein might contribute to paclitaxel-induced apoptosis.
Mol Pharmacol 2001 Mar
PMID:Disruption of cell adhesion and caspase-mediated proteolysis of beta- and gamma-catenins and APC protein in paclitaxel-induced apoptosis. 1117 55

Beta-catenin plays a structural role in cell adhesion by binding to cadherins at the intracellular surface of the plasma membrane and a signaling role in the cytoplasm as the penultimate downstream mediator of the wnt signaling pathway. The ultimate mediator of this pathway is a nuclear complex of beta-catenin acting as a coactivtor with lymphoid enhancer factor/T cell factor (Lef/Tcf) transcription factors to stimulate transcription of a variety of target genes. Signaling through beta-catenin is regulated by modulating its degradation and nuclear translocation. In the absence of an activating signal, phosphorylation of beta-catenin by glycogen synthase kinase 3 (GSK3) acting in conjunction with adenomatous polyposis coli and axin/conductin causes beta-catenin to interact with the beta-transducin repeat-containing protein which results in its ubiquitination and degradation. Signaling from the wnt pathway activates dishevelled which, in an as yet undefined manner, inhibits the activity of GSK3 resulting in an increase in the cytoplasmic free pool of beta-catenin, and translocation into the nucleus. The integrin-linked kinase (ILK) pathway also activates beta-catenin-Lef/Tcf signaling. ILK phosphorylates GSK3 to inhibit its activity and translocates beta-catenin into the nucleus. In addition, ILK downregulates the expression of E-cadherin and upregulates Lef-1 expression. In the final step of the beta-catenin-Lef/Tcf signaling pathway, nuclear beta-catenin binds pontin52-TATA binding protein and displaces Groucho-related gene or CREB-binding protein corepressors from Lef/Tcf resulting in stimulation of transcription. During development, beta-catenin-Lef/Tcf signaling is involved in the formation of dorsal mesoderm and dorsal axis. Furthermore, defects in the beta-catenin-Lef/Tcf pathway are involved in the development of several types of cancers.
Cell Mol Life Sci 1999 Oct 30
PMID:Signaling through beta-catenin and Lef/Tcf. 1121 2

The formation of a complex between beta-catenin and members of the TCF/LEF family of high-mobility group proteins is a key regulatory event in the wnt-signaling pathway, essential for embryonal development as well as the growth of normal and malignant colon epithelium. We have characterized the binding of TCF4 to human beta-catenin by steady-state intrinsic fluorescence quenching experiments, surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC). Binding studies in solution and in heterogeneous phase showed that TCF4 binds reversibly to beta-catenin with an affinity (KB) of 3(+/-1) 10(8) M(-1). Site-directed mutagenesis, together with calorimetric measurements, revealed that residue D16 in TCF4 plays a crucial role in high-affinity binding. Mutation of this residue to alanine resulted in a decrease of KB by two orders of magnitude as well as a significant reduction in binding enthalpy. Binding of TCF4 to beta-catenin gave rise to a large negative enthalpy change at 25 degrees C (-29.7 kcal/mol). Binding enthalpies were strongly temperature dependent, which resulted in the determination of a large heat capacity change upon binding of -1.5 kcal/(mol K). The molecular events that take place upon complex formation are discussed using the measured thermodynamic data together with the crystal structure of the beta-catenin arm repeat region/TCF complex.
J Mol Biol 2001 Mar 09
PMID:Thermodynamics of the high-affinity interaction of TCF4 with beta-catenin. 1123 26

We have determined that I-mfa, an inhibitor of several basic helix-loop-helix (bHLH) proteins, and XIC, a Xenopus ortholog of human I-mf domain-containing protein that shares a highly conserved cysteine-rich C-terminal domain with I-mfa, inhibit the activity and DNA binding of the HMG box transcription factor XTcf3. Ectopic expression of I-mfa or XIC in early Xenopus embryos inhibited dorsal axis specification, the expression of the Tcf3/beta-catenin-regulated genes siamois and Xnr3, and the ability of beta-catenin to activate reporter constructs driven by Lef/Tcf binding sites. I-mfa domain proteins can regulate both the Wnt signaling pathway and a subset of bHLH proteins, possibly coordinating the activities of these two critical developmental pathways.
Mol Cell Biol 2001 Mar
PMID:Inhibition of Tcf3 binding by I-mfa domain proteins. 1123 23

We have previously proposed that IQGAP1, an effector of Rac1 and Cdc42, negatively regulates cadherin-mediated cell-cell adhesion by interacting with beta-catenin and by causing the dissociation of alpha-catenin from cadherin-beta-catenin-alpha-catenin complexes and that activated Rac1 and Cdc42 positively regulate cadherin-mediated cell-cell adhesion by inhibiting the interaction of IQGAP1 with beta-catenin. However, it remains to be clarified in which physiological processes the Rac1-Cdc42-IQGAP1 system is involved. We here examined whether the Rac1-IQGAP1 system is involved in the cell-cell dissociation of Madin-Darby canine kidney II cells during 12-O-tetradecanoylphorbol-13-acetate (TPA)- or hepatocyte growth factor (HGF)-induced cell scattering. By using enhanced green fluorescent protein (EGFP)-tagged alpha-catenin, we found that EGFP-alpha-catenin decreased prior to cell-cell dissociation during cell scattering. We also found that the Rac1-GTP level decreased after stimulation with TPA and that the Rac1-IQGAP1 complexes decreased, while the IQGAP1-beta-catenin complexes increased during action of TPA. Constitutively active Rac1 and IQGAP1 carboxyl terminus, a putative dominant-negative mutant of IQGAP1, inhibited the disappearance of alpha-catenin from sites of cell-cell contact induced by TPA. Taken together, these results indicate that alpha-catenin is delocalized from cell-cell contact sites prior to cell-cell dissociation induced by TPA or HGF and suggest that the Rac1-IQGAP1 system is involved in cell-cell dissociation through alpha-catenin relocalization.
Mol Cell Biol 2001 Mar
PMID:Involvement of IQGAP1, an effector of Rac1 and Cdc42 GTPases, in cell-cell dissociation during cell scattering. 1123 50

The ubiquitin-proteasome pathway regulates gene expression through protein degradation. Here we show that the F-box protein betaTrCP, the receptor component of the SCF E3 ubiquitin ligase responsible for IkappaBalpha and beta-catenin degradation, is colocalized in the nucleus with ATF4, a member of the ATF-CREB bZIP family of transcription factors, and controls its stability. Association between the two proteins depends on ATF4 phosphorylation and on ATF4 serine residue 219 present in the context of DSGXXXS, which is similar but not identical to the motif found in other substrates of betaTrCP. ATF4 ubiquitination in HeLa cells is enhanced in the presence of betaTrCP. The F-box-deleted betaTrCP protein behaves as a negative transdominant mutant that inhibits ATF4 ubiquitination and degradation and, subsequently, enhances its activity in cyclic AMP-mediated transcription. ATF4 represents a novel substrate for the SCF(betaTrCP) complex, which is the first mammalian E3 ubiquitin ligase identified so far for the control of the degradation of a bZIP transcription factor.
Mol Cell Biol 2001 Mar
PMID:ATF4 degradation relies on a phosphorylation-dependent interaction with the SCF(betaTrCP) ubiquitin ligase. 1123 52

The effect of HGF/SF on the association between the E-cadherin/catenin complex and the tyrosine kinase receptor c-Met, was examined in prostate cancer cells LNCap FGC. Stimulation by HGF/SF showed E-cadherin and beta-catenin to be co-precipitated and located at areas of cell-cell contact with the HGF/SF receptor c-Met, as detected by immunoprecipitation and immunofluorescence respectively. Furthermore, continued exposure to this motogen increased the level of co-precipitations between the E-cadherin/catenin complex with c-Met, and also increased tyrosine phosphorylation of c-Met. In contrast, continued stimulation by HGF/SF decreased the level of co-localised peripheral staining and increased the level of cytoplasmic staining. In conclusion, the association between the E-cadherin/catenin complex with the HGF/SF receptor c-Met, may influence or regulate intercellular adhesion in prostate cancer following stimulation by HGF/SF.
Int J Mol Med 2001 Apr
PMID:HGF/SF modifies the interaction between its receptor c-Met, and the E-cadherin/catenin complex in prostate cancer cells. 1125 78

Drosophila Armadillo and its mammalian homologue beta-catenin are scaffolding proteins involved in the assembly of multiprotein complexes with diverse biological roles. They mediate adherens junction assembly, thus determining tissue architecture, and also transduce Wnt/Wingless intercellular signals, which regulate embryonic cell fates and, if inappropriately activated, contribute to tumorigenesis. To learn more about Armadillo/beta-catenin's scaffolding function, we examined in detail its interaction with one of its protein targets, cadherin. We utilized two assay systems: the yeast two-hybrid system to study cadherin binding in the absence of Armadillo/beta-catenin's other protein partners, and mammalian cells where interactions were assessed in their presence. We found that segments of the cadherin cytoplasmic tail as small as 23 amino acids bind Armadillo or beta-catenin in yeast, whereas a slightly longer region is required for binding in mammalian cells. We used mutagenesis to identify critical amino acids required for cadherin interaction with Armadillo/beta-catenin. Expression of such short cadherin sequences in mammalian cells did not affect adherens junctions but effectively inhibited beta-catenin-mediated signaling. This suggests that the interaction between beta-catenin and T cell factor family transcription factors is a sensitive target for disruption, making the use of analogues of these cadherin derivatives a potentially useful means to suppress tumor progression.
Mol Biol Cell 2001 Apr
PMID:Cadherin sequences that inhibit beta-catenin signaling: a study in yeast and mammalian cells. 1129 15

Given the importance of intercellular adhesion for many regulatory processes, we have investigated the control of protein kinase Calpha (PKCalpha) targeting to the cell-cell contacts. We have previously shown that, upon treatment of the pituitary cell line GH3B6 with thyrotropin-releasing hormone (TRH) or phorbol 12-myristate 13-acetate (PMA), human PKCalpha (hPKCalpha) is selectively targeted to the cell-cell contacts (42). Here we show that the D294G mutation of hPKCalpha, previously identified in a subpopulation of human tumors, induces the loss of this selective targeting. The D294G mutant is instead targeted to the entire plasma membrane, including the cell-cell contacts, and the duration of the first rapid and transient translocation induced by TRH (42) is longer than that of the wild-type enzyme (93.3 versus 22.5 s), coinciding with the duration of the [Ca(2+)](i) increase. We found that in the presence or absence of PMA, RACK1 is never localized at the cell-cell contacts nor was it coimmunoprecipitated with hPKCalpha wild type or the D294G mutant. In contrast, PMA treatment or long-term TRH stimulation resulted in the presence of F-actin and beta-catenin at the cell-cell contacts and their exclusion from the rest of the plasma membrane. Upon disruption of the F-actin network with phalloidin or cytochalasin D, wild-type hPKCalpha translocates but did not accumulate at the plasma membrane and beta-catenin did not accumulate at the cell-cell contacts. In contrast, the disruption of the F-actin network affected neither translocation nor accumulation of the D294G mutant. These results show that the presence of PKCalpha at the cell-cell contacts is a regulated process which depends upon the integrity of both PKCalpha and the actin microfilament network.
Mol Cell Biol 2001 May
PMID:A single point mutation in the V3 region affects protein kinase Calpha targeting and accumulation at cell-cell contacts. 1131 61


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