Data from HS1-Associated Protein X-1 Regulates Carcinoma Cell Migration and Invasion via Clathrin-Mediated Endocytosis of Integrin α<sub>v</sub>β<sub>6</sub>

Abstract

<div>Abstract<p>Enhanced expression levels of integrin α<sub>v</sub>β<sub>6</sub> have been linked to more aggressive invasive carcinoma cell behavior and poorer clinical prognosis. However, how α<sub>v</sub>β<sub>6</sub> determines invasion and the dynamics of integrin α<sub>v</sub>β<sub>6</sub> 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 β<sub>6</sub> cytoplasmic tail using a yeast two-hybrid screen. We show that α<sub>v</sub>β<sub>6</sub>-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<sub>v</sub>β<sub>6</sub>-dependent migration and invasion require HAX-1 to bind directly to β<sub>6</sub> and thereby regulate clathrin-mediated endocytosis of α<sub>v</sub>β<sub>6</sub> integrins. Progression of oral cancer is associated with enhanced expression of α<sub>v</sub>β<sub>6</sub> and HAX-1 proteins in patient tissue. This report establishes that integrin endocytosis is required for α<sub>v</sub>β<sub>6</sub>-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]</p></div>