Nuclear localization of active HGF receptor Met in aggressive MDA-MB231 breast carcinoma cells.

Hepatocyte growth factor (HGF)/Met system is deregulated in tumors and is implicated in different aspects of invasive growth. Here, we report that in the highly aggressive MDA-MB231 breast carcinoma cells, Met cytosolic fragments [C-terminal fragment (CTF)] were present in the nuclei. They were constitutively active because tyrosine phosphorylated at regulatory and catalytic domains and endowed with transactivating activity independently of HGF exposure. In fact, various constructs containing juxtamembrane (Jxtm) Met fragments, fused with Gal4 DNA-binding domain, transactivated Gal4Luc activity. MDA-MB231 cells were devoid of WW domain-containing oxidoreductase (Wwox) tumor suppressor. Exogenous Wwox protein expression negatively regulated Jxtm3-transactivating activity and decreased spontaneous migration of MDA-MB231 cells. Also, we demonstrate that the lack of endogenous Wwox in MDA-MB231 cells represented a molecular mechanism for intranuclear Met-CTF accumulation and for the decrease of full-length Met stability. Yes-associated proteins maintained constitutively activated nuclear Met fragments that played a role as transcription factors regulating genes probably including those for motile phenotype. The difference with low invasive MCF-7 cells was evident because the latter did not show intranuclear Met and the transfected constructs-containing Jxtm fragments were inactive also in the presence of HGF. The constitutive activation of nuclear Met-signaling pathway in MDA-MB231 cells, possibly determined at genetic or epigenetic levels of WWOX gene, might participate in breast carcinoma progression influencing invasive/metastatic phenotype. Wwox/Met system can be suggested as a potential target to impair breast carcinoma progression.