Regulation of epithelial cell migration and tumor formation by beta-catenin signaling.
Cell migration requires precise control, which is altered or lost when tumor cells become invasive and metastatic. beta-catenin plays a dual role in this process: as a member of adherens junctions it is essential to link cadherins to the cytoskeleton thereby allowing tight intercellular adhesion, and as a member of the Wnt-signaling pathway, beta-catenin is translocated into the nucleus and serves together with the LEF1/TCF-transcription factors to drive gene expression necessary for the epithelial-to-mesenchymal transition (EMT). Activated beta-catenin signaling has been implicated in the genesis of a variety of tumors. Here we demonstrate a pivotal function for beta-catenin signaling in epithelial cell migration and tumorigenesis. Hepatocyte growth factor (HGF) and epidermal growth factor (EGF) induce beta-catenin signaling under conditions where they stimulate cell motility. Ectopic expression of either stabilized beta-catenin or a regulatable form of activated beta-catenin induces cell migration in different cell types and cooperates with EGF and HGF in this process. Activation of beta-catenin signaling induces expression of the new target gene osteopontin during migration. Cells expressing stabilized beta-catenin also exhibit significantly increased capability to form tumors in a nude mouse xenograft model. The data suggest that a critical threshold of beta-catenin signaling, activated by cooperative mechanisms, may be important during the EMT and tumorigenesis.
Müller
Thomas
T
Aventis Pharmaceuticals, Cambridge Genomics Center, Massachusetts 02139, USA. Mueller@Kosan.com
Bain
Gerard
G
Wang
Xin
X
Papkoff
Jackie
J
D000818:Animals; D016590:Aphidicolin / Q000494:pharmacology; D002277:Carcinoma / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D003513:Cycloheximide / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000502:physiology*; D018390:Gene Targeting; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000209:etiology*; D053495:Osteopontin; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D012795:Sialoglycoproteins / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000473:pathology; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D011500:Protein Synthesis Inhibitors; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; C506897:Spp1 protein, rat; D015534:Trans-Activators; D051176:beta Catenin; D053495:Osteopontin; D016590:Aphidicolin; D004815:Epidermal Growth Factor; D003513:Cycloheximide