α7 Helix Region of αI Domain Is Crucial for Integrin Binding to Endoplasmic Reticulum Chaperone gp96 A POTENTIAL THERAPEUTIC TARGET FOR CANCER METASTASIS

Integrins play important roles in regulating a diverse array of cellular functions crucial to the initiation, progression, and metastasis of tumors. Previous studies have shown that a majority of integrins are folded by the endoplasmic reticulum chaperone gp96. Here, we demonstrate that the dimerization of integrin alpha L and beta 2 is highly dependent on gp96. The alpha I domain (AID), a ligand binding domain shared by seven integrin alpha-subunits, is a critical region for integrin binding to gp96. Deletion of AID significantly reduced the interaction between integrin alpha L and gp96. Overexpression of AID intracellularly decreased surface expression of gp96 clients (integrins and Toll-like receptors) and cancer cell invasion. The alpha 7 helix region is crucial for AID binding to gp96. A cell-permeable alpha 7 helix peptide competitively inhibited the interaction between gp96 and integrins and blocked cell invasion. Thus, targeting the binding site of alpha 7 helix of AID on gp96 is potentially a new strategy for treatment of cancer metastasis.