Distinct activities of the alpha-catenin family, alpha-catulin and alpha-catenin, on beta-catenin-mediated signaling.
Alpha-catenin, an integral part of cadherin-catenin adhesion complexes, is a major binding partner of beta-catenin, a key component of the Wnt pathway, which activates T-cell factor (TCF)/lymphoid enhancer factor (LEF) transcription and is often upregulated in cancers. Recently, we identified an alpha-catenin-related protein, alpha-catulin, whose function is poorly understood, as part of a Rho GTPase signaling complex. Here, based on evidence suggesting that alpha-catulin may associate with a beta-catenin fraction, we investigated the role of alpha-catenin family members in beta-catenin-mediated signals. Expression of the full length or a 103-residue region of alpha-catenin strongly inhibits the induction of the TCF/LEF-responsive TOPFLASH reporter in HEK293T cells expressing activated beta-catenin or in cancer cells with constitutively upregulated Wnt signaling, whereas alpha-catulin expression had no effect. Interestingly, alpha-catulin expression attenuates the activation of the cyclin D1 promoter, a target of Wnt pathway signals. Alpha-catulin appears to inhibit Ras-mediated signals to the cyclin D1 promoter, rather than beta-catenin signals, and the synergy between Ras and beta-catenin required to fully activate this promoter. Data suggesting the involvement of Rho in this response are presented and discussed. These results suggest a novel function for alpha-catulin and imply that alpha-catenin and alpha-catulin have distinct activities that downregulate, respectively, beta-catenin and Ras signals converging on the cyclin D1 promoter.
Department of Physiology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA. keith.merdek@tufts.edu.
Keith D
KD
Merdek
Nhan T
NT
Nguyen
Deniz
D
Toksoz
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000595:Amino Acid Sequence; D002460:Cell Line; D019938:Cyclin D1 / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D066298:In Vitro Techniques; D018021:Lithium Chloride / Q000494:pharmacology; D008954:Models, Biological; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D016596:Vinculin / Q000235:genetics / Q000378:metabolism; D051178:alpha Catenin; D051176:beta Catenin; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
C495273:CTNNA1 protein, human; C495274:CTNNAL1 protein, human; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D051178:alpha Catenin; D051176:beta Catenin; D016596:Vinculin; D019938:Cyclin D1; D018631:ras Proteins; D020742:rhoA GTP-Binding Protein; D018021:Lithium Chloride