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Papers In Press, published online ahead of print December 11, 2007
J. Biol. Chem, 10.1074/jbc.M706550200
Submitted on August 7, 2007
Accepted on December 11, 2007

C-met must translocate to the nucleus to initiate calcium signals

Dawidson A. Gomes, Michele A. Rodrigues, M. Fatima Leite, Marcus V. Gomez, Peter Varnai, Tamas Balla, Anton M. Bennett, and Michael H. Nathanson

Dept. of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520-8019

Corresponding Author: michael.nathanson{at}yale.edu

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 PIP2 hydrolysis and InsP3 formation within the nucleus rather than within the cytoplasm. Translocation of c-met to the nucleus depends upon the adaptor protein Gab1 and Importin ß1, 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.


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