c-Met must translocate to the nucleus to initiate calcium signals.
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. Ca(2+) 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 beta1, and formation of Ca(2+) 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.
Gomes
Dawidson A
DA
Department of Internal Medicine and Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8019, USA.
Rodrigues
Michele A
MA
Leite
M Fatima
MF
Gomez
Marcus V
MV
Varnai
Peter
P
Balla
Tamas
T
Bennett
Anton M
AM
Nathanson
Michael H
MH
D020013:Calcium Signaling; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D021381:Protein Transport; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D034741:RNA, Small Interfering
D034741:RNA, Small Interfering; D019859:Proto-Oncogene Proteins c-met