Introduction: The tyrosine kinase Met receptor regulates a complex array of cellular behaviors known collectively as invasive growth. Although essential for normal development and wound repair, this pathway is frequently deregulated in tumors to promote their growth, motility, and invasion. Accordingly, Met is overexpressed in a variety of human tumors, and this aberrant expression correlates with a poor patient prognosis. Previous studies have shown that Met receptor levels are governed in part by Cbl-mediated ubiquitination and degradation, and the uncoupling of Met from this pathway promotes its transforming activity.
Methods: Here, we describe a novel mechanism of Met degradation in Non Small Cell Lung Cancer Cells and HeLa cells using western blot, immunocytochemistry, immunoprecipitation assay, invasion assay, cell viability assay and in vivo tumor growth model.
Results: Met receptor interacted with the C-terminus of heat shock protein 70-interacting protein (CHIP), leading to proteasomal degradation of the receptor in vitro. In addition, CHIP overexpression destabilized endogenous Met receptor in lung cancer cells, whereas CHIP knockdown increased Met receptor expression, indicating an essential role for CHIP in the regulation of Met degradation. CHIP overexpression inhibited Met-mediated lung cancer cell growth and invasion. Finally, we confirmed these results by tumor xenograft model.
Conclusion: Based on these findings, we conclude that CHIP is a suppressor of Met function, serving to regulate cellular receptor levels by promoting Met receptor degradation.