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Hepatocyte Growth Factor Induces MAPK-Dependent Formin IV Translocation in Renal Epithelial Cells

DAWN A. O'ROURKE, ZHEN-XIANG LIU^*, LORENZ SELLIN, KATHERINE SPOKES^§, ROLF ZELLER^|| and LLOYD G. CANTLEY^*

^* Section of Nephrology, Yale University, School of Medicine, New Haven, Connecticut
ACLARA Biosciences, Mountain View, California
Section of Nephrology, University of Freiburg, Freiburg, Germany
^§ Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
^|| University of Utrecht, Utrecht, The Netherlands.

Correspondence to Dr. Zhen-Xiang Liu, Section of Nephrology, Yale University, School of Medicine, 333 Cedar Street, LMP 2093, P.O. Box 208029, New Haven, CT 06520-8029. Phone: 203-785-7111; Fax: 203-785-7068; E-mail: zhen-xiang.Liu{at}yale.edu

Abstract. Renal epithelial tubule formation in cultured cells occurs after the addition of tubulogenic growth factors such as the hepatocyte growth factor (HGF). HGF activates the tyrosine kinase receptor c-met, initiating a series of complex events that regulate cell morphology, cell—cell interactions, and cell—matrix interactions and eventually result in the formation of branching tubular structures. The discovery that disruption of the formin gene locus in mice causes agenesis of the kidneys secondary to failure of ureteric bud outgrowth and branching tubule formation suggested that this family of proteins may be critical to the development of renal epithelial tubules. In this study, we investigated whether formin is involved in the HGF/c-met signaling pathway of in vitro tubulogenesis in renal epithelial cells. mIMCD-3 cells were analyzed by reverse transcription-PCR and found to express formin IV mRNA. With the use of an antibody that recognizes the carboxy terminus of all known formin isoforms, it was observed a formin isoform of approximately 165 kD markedly increased in the detergent soluble cell lysate after 10 min of stimulation with HGF. An antibody that is specific for formin IV was then generated and confirmed that the formin isoform regulated by HGF was formin IV. Cell fractionation and confocal localization of formin IV revealed that formin IV is primarily found in a submembranous band that co-localizes with the actin cytoskeleton and in a perinuclear location in quiescent epithelial cells but undergoes a rapid relocalization after HGF stimulation with translocation into the cell cytosol and into the nucleus. Formin IV was found to be a phosphorylation substrate for activated extracellular signal-regulated kinase in vitro, and pretreatment of cells with the mitogen-activated protein kinase inhibitor U0126 prevented the translocation of formin IV and inhibited HGF-dependent phosphorylation of formin IV in intact cells. In conclusion, activation of the c-met receptor results in cellular relocalization of formin IV in a mitogen-activated protein kinase—dependent manner.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673