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

TY - JOUR

T1 - HS1-associated protein X-1 regulates carcinoma cell migration and invasion via clathrin-mediated endocytosis of integrin αvβ6

AU - Ramsay, Alan G.

AU - Keppler, Melanie D.

AU - Jazayeri, Mona

AU - Thomas, Gareth J.

AU - Parsons, Madeline

AU - Violette, Shelia

AU - Weinreb, Paul

AU - Hart, Ian R.

AU - Marshall, John F.

PY - 2007/6/1

Y1 - 2007/6/1

N2 - Enhanced expression levels of integrin alphavbeta6 have been linked to more aggressive invasive carcinoma cell behavior and poorer clinical prognosis. However, how alphavbeta6 determines invasion and the dynamics of integrin alphavbeta6 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 beta6 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 alphavbeta6-dependent migration and invasion require HAX-1 to bind directly to beta6 and thereby regulate clathrin-mediated endocytosis of alphavbeta6 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 alphavbeta6-dependent carcinoma cell motility and invasion and suggests that this process is an important mechanism in cancer progression.

AB - Enhanced expression levels of integrin alphavbeta6 have been linked to more aggressive invasive carcinoma cell behavior and poorer clinical prognosis. However, how alphavbeta6 determines invasion and the dynamics of integrin alphavbeta6 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 beta6 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 alphavbeta6-dependent migration and invasion require HAX-1 to bind directly to beta6 and thereby regulate clathrin-mediated endocytosis of alphavbeta6 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 alphavbeta6-dependent carcinoma cell motility and invasion and suggests that this process is an important mechanism in cancer progression.

KW - Adaptor Proteins, Signal Transducing Amino Acid Sequence Antigens, Neoplasm/metabolism Binding Sites Binding, Competitive Carcinoma, Squamous Cell/genetics/metabolism/pathology Cell Membrane Permeability Cell Movement/physiology Clathrin/metabolism Down-R

U2 - 10.1158/0008-5472.CAN-07-0318

DO - 10.1158/0008-5472.CAN-07-0318

M3 - Article

SN - 0008-5472

VL - 67

SP - 5275

EP - 5284

JO - Cancer Research

JF - Cancer Research

IS - 11

M1 - N/A

ER -