HS1-associated protein X-1 regulates carcinoma cell migration and invasion via clathrin-mediated endocytosis of integrin ?v?6

Abstract

Enhanced expression levels of integrin ?v?6 have been linked to more aggressive invasive carcinoma cell behavior and poorer clinical prognosis. However, how alphavbeta6 determines invasion and the dynamics of integrin ?v?6 regulation in tumor cells are poorly understood. We have identified the 35-kDa HS1- associated protein X-1 (HAX-1) protein as a novel binding partner of the ?6 cytoplasmic tail using a yeast two-hybrid screen. We show that alphavbeta6 -dependent migration is blocked following small interfering RNA (siRNA)–mediated depletion of HAX-1 in oral squamous cell carcinoma cell lines. Using both siRNA and membrane-permeable peptides, we show that ?v?6-dependent migration and invasion require HAX-1 to bind directly to ?6 and thereby regulate clathrin-mediated endocytosis of ?v?6 integrins. Progression of oral cancer is associated with enhanced expression of alphavbeta6 and HAX-1 proteins in patient tissue. This report establishes that integrin endocytosis is required for ?v?6-dependent carcinoma cell motility and invasion and suggests that this process is an important mechanism in cancer progression.

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