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J. Biol. Chem., Vol. 282, Issue 31, 22823-22833, August 3, 2007

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Differentially Spliced Isoforms of FAT1 Are Asymmetrically Distributed within Migrating Cells^*

Gerald S. Braun, Matthias Kretzler^¶, Torsten Heider, Jürgen Floege, Lawrence B. Holzman^¶, Wilhelm Kriz, and Marcus J. Moeller¹

From the Institute for Anatomy and Cell Biology 1, University of Heidelberg, 69120 Heidelberg, Germany, the Division of Nephrology and Immunology, Rheinisch-Westfälische Technische Hochschule University of Aachen, 52074 Aachen, Germany, and the ^¶Division of Nephrology, Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109-0676

Cadherin FAT1 is localized along the leading edge of mammalian cells and is necessary for polarization and directed migration. It is essential for maintenance of the complex cytoarchitecture of the glomerular filtration barrier within the kidney. In this study, three novel splice isoforms of FAT1 with important functional differences in comparison with wild-type FAT1, FAT1(WT), were identified. The novel variants contained additional short peptide sequences at a specific site of the cytoplasmic domain (+12 or +32 or +8 amino acids, the latter resulting in a premature stop codon). FAT1(+12) was expressed in all peripheral tissues together with FAT1(WT), whereas FAT1(+32) and -(+8TR) were brain-specific. At the subcellular level, exclusively FAT1(WT) was localized along the cellular leading edge, whereas spliced FAT1 isoforms were confined to intercellular junctions. A shift of FAT1(WT) expression toward a predominance of FAT1(+12) was observed in migratory versus quiescent cells. A similar shift was observed in vivo when glomeruli from healthy individuals were compared with those from patients affected by glomerulonephritis. At the molecular level, the differential subcellular localization of FAT1 isoforms was mediated by a novel region harboring a phosphotyrosine-binding-like motif (DN_XYH), which was disrupted by the peptide inserts in the alternative splice variants. Overexpression of FAT1(WT) or specific knockdown of spliced FAT1 isoforms resulted in formation of cellular protrusions or increased wound healing, respectively. In summary, FAT1(WT) is the only FAT1 isoform located along the cellular leading edge. Only FAT1(WT) is up-regulated in migration, induces cellular process formation when overexpressed, and is necessary for efficient wound healing.

Received for publication, February 28, 2007 , and in revised form, May 3, 2007.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) DQ320124, DQ320125, DQ320126, and DQ320127.

^* This work was supported by a postdoctoral fellowship from the Faculty of Medicine Heidelberg, a grant from the Deutsche Nierenstiftung and the Stiftung Friedrich-Fischer Nachlass (to G. S. B.), and by a grant of the Deutsche Forschungsgemeinschaft (MO1082/1-1, 1-2), Stiftung Herbert Daus and Stiftung Krebs- and Scharlach-Forschung Mannheim (to M. J. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental movie 1.

¹ To whom correspondence should be addressed: Division of Nephrology and Immunology, RWTH University of Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany. Tel.: 49-241-89530; Fax: 49-241-8082446; E-mail: mmoeller{at}ukaachen.de.

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