title: The Rho-mDia1 pathway regulates cell polarity and focal adhesion turnover in migrating cells through mobilizing Apc and c-Src.
abstract: Directed cell migration requires cell polarization and adhesion turnover, in which the actin cytoskeleton and microtubules work critically. The Rho GTPases induce specific types of actin cytoskeleton and regulate microtubule dynamics. In migrating cells, Cdc42 regulates cell polarity and Rac works in membrane protrusion. However, the role of Rho in migration is little known. Rho acts on two major effectors, ROCK and mDia1, among which mDia1 produces straight actin filaments and aligns microtubules. Here we depleted mDia1 by RNA interference and found that mDia1 depletion impaired directed migration of rat C6 glioma cells by inhibiting both cell polarization and adhesion turnover. Apc and active Cdc42, which work together for cell polarization, localized in the front of migrating cells, while active c-Src, which regulates adhesion turnover, localized in focal adhesions. mDia1 depletion impaired localization of these molecules at their respective sites. Conversely, expression of active mDia1 facilitated microtubule-dependent accumulation of Apc and active Cdc42 in the polar ends of the cells and actin-dependent recruitment of c-Src in adhesions. Thus, the Rho-mDia1 pathway regulates polarization and adhesion turnover by aligning microtubules and actin filaments and delivering Apc/Cdc42 and c-Src to their respective sites of action.
authors.affiliation: Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto 606-8501, Japan.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Yamana
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Arakawa
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nishino
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kurokawa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tanji
authors.forename: Reina E
authors.initials: RE
authors.lastname: Itoh
authors.forename: James
authors.initials: J
authors.lastname: Monypenny
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Ishizaki
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Bito
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nozaki
authors.forename: Nobuo
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Michiyuki
authors.initials: M
authors.lastname: Matsuda
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002465:Cell Movement; D016764:Cell Polarity; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism*; D000080865:Formins; D005910:Glioma / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D021381:Protein Transport; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D050719:Crk-Associated Substrate Protein; C491464:Diap1 protein, mouse; D000080865:Formins; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D016392:Proto-Oncogene Proteins pp60(c-src); D020741:rho GTP-Binding Proteins