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J. Biol. Chem. 283 (7): 4344-4351

© 2008 by The American Society for Biochemistry and Molecular Biology, Inc.

c-Met Must Translocate to the Nucleus to Initiate Calcium Signals*{diamondsuit}

Dawidson A. Gomes{ddagger}§, Michele A. Rodrigues{ddagger}§, M. Fatima Leite§, Marcus V. Gomez, Peter Varnai||, Tamas Balla||, Anton M. Bennett**, , and Michael H. Nathanson{ddagger}1

{ddagger}Department of Internal Medicine and **Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8019, the §Department of Physiology and Biophysics and Department of Pharmacology, Federal University of Minas Gerais, Belo Horizonte, MG, CEP 31270-901 Brazil, and the ||Section on Molecular Signal Transduction, NICHD/National Institutes of Health, Bethesda, Maryland 20892

Abstract: Hepatocyte growth factor (HGF) is important for cell proliferation, differentiation, and related activities. HGF acts through its receptor c-Met, which activates downstream signaling pathways. HGF binds to c-Met at the plasma membrane, where it is generally believed that c-Met signaling is initiated. Here we report that c-Met rapidly translocates to the nucleus upon stimulation with HGF. Ca2+ signals that are induced by HGF result from phosphatidylinositol 4,5-bisphosphate hydrolysis and inositol 1,4,5-trisphosphate formation within the nucleus rather than within the cytoplasm. Translocation of c-Met to the nucleus depends upon the adaptor protein Gab1 and importin β1, and formation of Ca2+ signals in turn depends upon this translocation. HGF may exert its particular effects on cells because it bypasses signaling pathways in the cytoplasm to directly activate signaling pathways in the nucleus.

Received for publication August 7, 2007. Revision received October 15, 2007.

* This work was supported by National Institutes of Health Grants DK57751, DK34989, and DK45710, and by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico. Fundaçao de Amparo à Pesquisa do Estado de Minas Gerais, and Howard Hughes Medical Institute. 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.

{diamondsuit} This article was selected as a Paper of the Week.

1 To whom correspondence should be addressed: Digestive Diseases, Rm. TAC S241D, Yale University School of Medicine, New Haven, CT 06520-8019. Tel.: 203-785-7312; Fax: 203-785-4306; E-mail: michael.nathanson{at}yale.edu.

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