This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ramsay, A. G. Articles by Marshall, J. F. Search for Related Content PubMed PubMed Citation Articles by Ramsay, A. G. Articles by Marshall, J. F.

HS1-Associated Protein X-1 Regulates Carcinoma Cell Migration and Invasion via Clathrin-Mediated Endocytosis of Integrin _vß₆

¹ Centre for Tumour Biology, Institute of Cancer and Cancer Research UK Clinical Centre; ² John Vane Science Centre, Barts and The London, Queen Mary's School of Medicine and Dentistry; ³ Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom; and ⁴ Biogen Idec, Cambridge, Massachusetts

Requests for reprints: Ian R. Hart, Centre for Tumour Biology, Institute of Cancer and Cancer Research UK Clinical Centre, John Vane Science Centre, Ground Floor, London EC1M 6BQ, United Kingdom. Phone: 44-207-014-0402; Fax: 44-207-014-0401; E-mail: ian.hart{at}cancer.org.uk or John F. Marshall, Phone: 44-207-014-0407; Fax: 44-207-014-0401; E-mail: john.marshall{at}cancer.org.uk.

Enhanced expression levels of integrin _vß₆ have been linked to more aggressive invasive carcinoma cell behavior and poorer clinical prognosis. However, how _vß₆ determines invasion and the dynamics of integrin _vß₆ 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 ß₆ cytoplasmic tail using a yeast two-hybrid screen. We show that _vß₆-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 _vß₆-dependent migration and invasion require HAX-1 to bind directly to ß₆ and thereby regulate clathrin-mediated endocytosis of _vß₆ integrins. Progression of oral cancer is associated with enhanced expression of _vß₆ and HAX-1 proteins in patient tissue. This report establishes that integrin endocytosis is required for _vß₆-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]