Article
- The EMBO Journal (2004) 23, 3769 - 3779
- doi:10.1038/sj.emboj.7600380
Published online: 2 September 2004
Subject Categories:
Protocadherin FAT1 binds Ena/VASP proteins and is necessary for actin dynamics and cell polarization
Marcus J Moeller1,3, Abdulsalam Soofi3, Gerald S Braun1, Xiaodong Li3, Carsten Watzl2, Wilhelm Kriz1 and Lawrence B Holzman3
- Institute for Anatomy and Cell Biology, University of Heidelberg, Heidelberg, Germany
- Institute for Immunology, University of Heidelberg, Heidelberg, Germany
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
Correspondence to:
Lawrence B Holzman, University of Michigan Medical School, 1560 MSRB II, Ann Arbor, MI 48109-0676, USA. Tel.: +1 734 764 3157; Fax: +1 734 763 0982; E-mail: lholzman@umich.edu
Received 17 March 2004; Accepted 3 August 2004
Abstract
Cell migration requires integration of cellular processes resulting in cell polarization and actin dynamics. Previous work using tools of Drosophila genetics suggested that protocadherin fat serves in a pathway necessary for determining cell polarity in the plane of a tissue. Here we identify mammalian FAT1 as a proximal element of a signaling pathway that determines both cellular polarity in the plane of the monolayer and directed actin-dependent cell motility. FAT1 is localized to the leading edge of lamellipodia, filopodia, and microspike tips where FAT1 directly interacts with Ena/VASP proteins that regulate the actin polymerization complex. When targeted to mitochondrial outer leaflets, FAT1 cytoplasmic domain recruits components of the actin polymerization machinery sufficient to induce ectopic actin polymerization. In an epithelial cell wound model, FAT1 knockdown decreased recruitment of endogenous VASP to the leading edge and resulted in impairment of lamellipodial dynamics, failure of polarization, and an attenuation of cell migration. FAT1 may play an integrative role regulating cell migration by participating in Ena/VASP-dependent regulation of cytoskeletal dynamics at the leading edge and by transducing an Ena/VASP-independent polarity cue.
Keywords:
- actin dynamics,
- cellular migration,
- FAT1,
- planar cell polarity,
- VASP
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