Hepatocyte growth factor (HGF) binds to and activates the receptor tyrosine kinase c-Met to stimulate cell proliferation, in part by way of the phospholipase C-γ (PLC-γ)-inositol 1,4,5-trisphosphate (IP 3 )-calcium signaling pathway. Like other receptor tyrosine kinases, c-Met is commonly thought to act at the plasma membrane. However, Gomes et al . used a combination of immunoblot analysis, confocal immunofluorescence microscopy, and biotinylation of cell surface proteins to show that, in SkHep1 liver cells, HGF stimulated the translocation of phosphorylated (active) c-Met from the plasma membrane to the nucleus. Constructs containing the ligand-binding domain of the type 1 IP 3 receptor that were targeted to the nucleus blocked c-Met-dependent calcium signaling, whereas constructs targeted to the cytoplasm had little effect on the calcium response to c-Met. In marked contrast, the calcium response to vasopressin [which acts through a plasma membrane heterotrimeric GTP-binding protein (G protein)-coupled receptor] was preferentially blocked by constructs targeted to the cytoplasm. Moreover, HGF elicited a specific decrease in the nuclear content of phosphatidylinositol 4,5-bisphosphate (PIP 2 , which is hydrolyzed by PLC, thereby producing IP 3 ). HGF stimulated the nuclear translocation of Gab1 (an adaptor protein that binds c-Met and has a nuclear localization sequence), and siRNA directed against Gab1 decreased nuclear translocation of c-Met and HGF-dependent calcium signaling, as did siRNA directed against importin β1. Thus, the authors conclude that, after stimulation by HGF, initiation of the calcium response to c-Met depends on its translocation to the nucleus. D. A. Gomes, M. A. Rodrigues, M. F. Leite, M. V. Gomez, P. Varnai, T. Balla, A. M. Bennett, M. H. Nathanson, c-Met must translocate to the nucleus to initiate calcium signals. J. Biol. Chem. 283 , 4344-4351 (2008). [Abstract] [Full Text]