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c-Met Signaling from the Nucleus

Hepatocyte growth factor (HGF) stimulates cell proliferation and differentiation through binding to the receptor tyrosine kinase (RTK) c-Met, which, in turn, activates intracellular signaling pathways including Ca²⁺ cascades. It is generally believed that RTKs like c-Met initiate their signaling at the plasma membrane. However in this Paper of the Week, Dawidson Gomes and colleagues report that, following HGF stimulation, c-Met translocates to the nucleus before initiating its signaling cascade. c-Met triggers Ca²⁺ release through the phospholipase C-/inositol 1,4,5-trisphosphate (InsP₃) pathway, and the researchers detected phosphatidylinositol 4,5-bisphosphate (PIP₂) hydrolysis and InsP₃ generation almost exclusively in the nucleus. In addition, they found that inhibiting either Gab1 or importin β1, which assist protein transport across the nuclear pore complex, significantly reduced c-Met nuclear localization and eliminated HGF-induced calcium signals. These results highlight how calcium can exert distinct cellular effects including calcium signaling in the nucleus, depending on signal origin. The work also revealed that c-Met-induced Ca²⁺ signals, and likely those of other RTKs, are fundamentally different from G-protein-induced Ca²⁺ cascades.

The c-Met receptor (green) rapidly translocates to the nucleus (blue) following stimulation with HGF.

FOOTNOTES

See referenced article, J. Biol. Chem. 2008, 283, 4344-4351

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