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¹ Graduate School of Life Science, University of Hyogo, Harima Science Garden City, Hyogo-ken 978-1297, Japan
² Department of Biomolecular Sciences, Institute of Biomedical Sciences, Fukushima Medical University, Hikariga-oka, Fukushima 960-1295, Japan

There is a class of GTPase activating proteins for the Rho family GTPases (RhoGAPs) that contain the steroidogenic acute regulatory protein (STAR)-related lipid transfer (START) domain. In mammals three genes encode such proteins and they are designated START-GAP1–3 or deleted in liver cancer 1–3 (DLC1–3). In this study, we examined the intracellular localization and roles of START-GAP1/DLC1 in cell motility. Immunofluorescence microscopic analysis of NRK cells and HeLa cells revealed that START-GAP1 was localized in focal adhesions. Amino acid residues 265–459 of START-GAP1 were found to be necessary for focal adhesion targeting and we name the region "the focal adhesion-targeting (FAT) domain." It was previously known that ectopic expression of START-GAP1 induced cell rounding. We demonstrated that the FAT domain of START-GAP1 was partially required for this morphological change. Furthermore, expression of this domain in HeLa cells resulted in dissociation of endogenous START-GAP1 from focal adhesions as a dominant negative modulator, reducing cell migration and spreading. Taken together, START-GAP1 is targeted to focal adhesions via the FAT domain and regulates actin rearrangement through down-regulation of active RhoA and Cdc42. Its absence from focal adhesions could, therefore, cause abnormal cell motility and spreading.

^aPresent address: Department of Biochemistry, University of Wisconsin–Madison, 433 Babcock Dr, Madison, WI 53706, USA

^* Correspondence: yagisawa{at}sci.u-hyogo.ac.jp

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