HS1-associated protein X-1 regulates carcinoma cell migration and invasion via clathrin-mediated endocytosis of integrin αvβ6

Enhanced expression levels of integrin (alpha(v)beta(6) have been linked to more aggressive invasive carcinoma cell behavior and poorer clinical prognosis. However, how alpha(v)beta(6) determines invasion and the dynamics of integrin (alpha(v)beta(6) regulation in tumor cells are poorly understood. We have identified the 35-kDa HSI-associated protein X-1 (HAX-1) protein as a novel binding partner of the beta(6) cytoplasmic tail using a yeast two-hybrid screen. We show that alpha(v)beta(6)-dependent migration is blocked following small interfering RNA (siRNA)-mediated depletion of HAX- I in oral squamous cell carcinoma cell lines. Using both ARNA and membrane-permeable peptides, we show that alpha(v)beta(6) dependent migration and invasion require HAX-1 to bind directly to 06 and thereby regulate clathrin-mediated endocytosis of alpha(v)beta(6) integrins. Progression of oral cancer is associated with enhanced expression of alpha(v)beta(6) and HAX-1 proteins in patient tissue. This report establishes that integrin endocytosis is required for (alpha(v)beta(6)-dependent carcinoma cell motility and invasion and suggests that this process is an important mechanism in cancer progression.