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Neural Wiskott-Aldrich Syndrome Protein Is Involved in Hepatocyte Growth Factor-induced Migration, Invasion, and Tubulogenesis of Epithelial Cells¹

Division of Biochemistry [H. Y., T. T.] and Cancer Genomics [H. M.], Institute of Medical Science, University of Tokyo, Tokyo 108-8639, and CREST [H. Y., T. T.] and PRESTO [H. M.], Japan Science and Technology Corp., Saitama 332-0012, Japan

Neural Wiskott-Aldrich syndrome protein (N-WASP), a member of the WASPfamily, regulates reorganization of the actin cytoskeleton through activation of the Arp2/3 complex. To date, most studies of N-WASP have focused on intracellular and morphological phenomena, such as vesicle transport and filopodium formation. We investigated the importance of N-WASP in epithelial morphogenesis, using Madin-Darby canine kidney epithelial cells, which form branching tubules when cultured with hepatocyte growth factor (HGF) in collagen gel. We established MDCK cell lines that overexpress wild-type N-WASP (WT-NW) or a dominant-negative form of N-WASP (DN-NW). WT-NW and parental Madin-Darby canine kidney cells formed branching tubules in collagen gel in response to HGF. However, formation of branching tubules was suppressed in DN-NW cells. During tubulogenesis, endogenous N-WASP accumulated at cell extensions protruding from the walls of the cysts and at the tips of the extending tubules. Gross cell morphology, cell-cell adhesion, cell polarity, and scattering in response to HGF were unaffected in WT-NW and DN-NW cells. In contrast, directed cell migration and HGF-induced invasion were significantly repressed in DN-NW cells. These results indicate that N-WASP regulates HGF-induced cell migration and invasion, which are required for epithelial tubulogenesis.

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