Sci. Signal., 19 February 2008
Receptor Tyrosine Kinases Moving to the Nucleus
Elizabeth M. Adler
Science Signaling, AAAS, Washington, DC 20005, USA
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- (PLC-)-inositol 1,4,5-trisphosphate (IP3)-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 IP3 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 (PIP2, which is hydrolyzed by PLC, thereby producing IP3). 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]
Citation: E. M. Adler, Moving to the Nucleus. Sci. Signal. 1, ec61 (2008).
The editors suggest the following Related Resources on Science sites:
In Science Signaling
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882