Data from HS1-Associated Protein X-1 Regulates Carcinoma Cell Migration and Invasion via Clathrin-Mediated Endocytosis of Integrin α_vβ₆

Enhanced expression levels of integrin α_vβ₆ have been linked to more aggressive invasive carcinoma cell behavior and poorer clinical prognosis. However, how α_vβ₆ determines invasion and the dynamics of integrin α_vβ₆ 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 β₆ cytoplasmic tail using a yeast two-hybrid screen. We show that α_vβ₆-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 α_vβ₆-dependent migration and invasion require HAX-1 to bind directly to β₆ and thereby regulate clathrin-mediated endocytosis of α_vβ₆ integrins. Progression of oral cancer is associated with enhanced expression of α_vβ₆ and HAX-1 proteins in patient tissue. This report establishes that integrin endocytosis is required for α_vβ₆-dependent carcinoma cell motility and invasion and suggests that this process is an important mechanism in cancer progression. [Cancer Res 2007;67(11):5275–84]