{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T16:34:55Z","timestamp":1787502895204,"version":"build-2736575974"},"reference-count":32,"publisher":"Portland Press Ltd.","issue":"1","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2004,11,15]]},"abstract":"<jats:p>Migration of cells is critical to development of the central nervous system. Reelin, which was identified from the reeler mutant mice having a defect in the multilamellar structure of the brain, is thought to be a key signalling molecule that functions as a cue for determination of cell position. mDab1 (mouse Disabled homologue 1) functions downstream of Reelin. However, the mechanism by which mDab1 regulates cell migration during brain development is unknown. In the present paper, we show that mDab1 associates with N-WASP (neuronal Wiskott\u2013Aldrich syndrome protein) in vitro and in brains of embryonic mice. mDab1 activates N-WASP directly, and induces actin polymerization through the Arp2\/3 (actin-related protein 2\/3) complex. mDab1 induces formation of filopodia when it is overexpressed in COS-7\u00a0cells. This filopodium formation is dependent on N-WASP, because expression of an N-WASP mutant that cannot induce Arp2\/3-complex-mediated actin polymerization suppressed filopodium formation. The PTB (phosphotyrosine-binding) domain of mDab1 binds to N-WASP via the NRFY (Asn-Arg-Phe-Tyr) sequence close to the CRIB (Cdc42\/Rac-interactive binding) motif of N-WASP and activates N-WASP in vitro. When mDab1 is phosphorylated by Fyn kinase in COS-7\u00a0cells, mDab1 is ubiquitinated in a Cbl-dependent manner, and mDab1 does not induce filopodium in the presence of activated Fyn. These findings suggest that mDab1 regulates the actin cytoskeleton through N-WASP, which is negatively regulated by phosphorylation-mediated ubiquitination of mDab1.<\/jats:p>","DOI":"10.1042\/bj20041103","type":"journal-article","created":{"date-parts":[[2004,11,9]],"date-time":"2004-11-09T06:43:29Z","timestamp":1099982609000},"page":"1-8","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":73,"title":["Regulation of actin cytoskeleton by mDab1 through N-WASP and ubiquitination of mDab1"],"prefix":"10.1042","volume":"384","author":[{"given":"Shiro","family":"SUETSUGU","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo, 108-8639, Japan"},{"name":"CREST, Japan Science and Technology Corporation (JST), 4-6-1 Shirokane-dai, Minato-ku, Tokyo, 108-8639, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tohru","family":"TEZUKA","sequence":"additional","affiliation":[{"name":"Department of Oncology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo, 108-8639, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshifumi","family":"MORIMURA","sequence":"additional","affiliation":[{"name":"Department of Molecular Neurobiology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo, 108-8639, Japan"},{"name":"Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, 2-1, Hirosawa, Wako, Saitama 351-0198, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuharu","family":"HATTORI","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan"},{"name":"PREST, Japan Science and Technology Corporation (JST), Tanabe-dori, Mizuho-ku, Nagoya, 467-8603, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuhiko","family":"MIKOSHIBA","sequence":"additional","affiliation":[{"name":"Department of Molecular Neurobiology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo, 108-8639, Japan"},{"name":"Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, 2-1, Hirosawa, Wako, Saitama 351-0198, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadashi","family":"YAMAMOTO","sequence":"additional","affiliation":[{"name":"Department of Oncology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo, 108-8639, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadaomi","family":"TAKENAWA","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo, 108-8639, Japan"},{"name":"CREST, Japan Science and Technology Corporation (JST), 4-6-1 Shirokane-dai, Minato-ku, Tokyo, 108-8639, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2004,11,9]]},"reference":[{"key":"2021112212581819100_B1","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1007\/BF02996215","article-title":"Two mutations trembler and reeler, with neurological actions in the house mouse","volume":"50","author":"Falconer","year":"1951","journal-title":"J. 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Cell Sci."},{"key":"2021112212581819100_B19","doi-asserted-by":"crossref","first-page":"6516","DOI":"10.1093\/emboj\/17.22.6516","article-title":"The essential role of profilin in the assembly of actin for microspike formation","volume":"17","author":"Suetsugu","year":"1998","journal-title":"EMBO J."},{"key":"2021112212581819100_B20","doi-asserted-by":"crossref","first-page":"5322","DOI":"10.1093\/nar\/18.17.5322","article-title":"pEF-BOS, a powerful mammalian expression vector","volume":"18","author":"Mizushima","year":"1990","journal-title":"Nucleic Acids Res."},{"key":"2021112212581819100_B21","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/34208","article-title":"Induction of filopodium formation by WASP-related actin-depolymerizing protein N-WASP","volume":"391","author":"Miki","year":"1998","journal-title":"Nature (London)"},{"key":"2021112212581819100_B22","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/S1534-5807(02)00324-6","article-title":"Sustained activation of N-WASP through phosphorylation is essential for neurite extension","volume":"3","author":"Suetsugu","year":"2002","journal-title":"Dev. 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