title: α7 helix region of αI domain is crucial for integrin binding to endoplasmic reticulum chaperone gp96: a potential therapeutic target for cancer metastasis.
abstract: 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 αL and β2 is highly dependent on gp96. The αI domain (AID), a ligand binding domain shared by seven integrin α-subunits, is a critical region for integrin binding to gp96. Deletion of AID significantly reduced the interaction between integrin αL and gp96. Overexpression of AID intracellularly decreased surface expression of gp96 clients (integrins and Toll-like receptors) and cancer cell invasion. The α7 helix region is crucial for AID binding to gp96. A cell-permeable α7 helix peptide competitively inhibited the interaction between gp96 and integrins and blocked cell invasion. Thus, targeting the binding site of α7 helix of AID on gp96 is potentially a new strategy for treatment of cancer metastasis.
authors.affiliation: Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Hong
authors.forename: Bei
authors.initials: B
authors.lastname: Liu
authors.forename: Gabriela
authors.initials: G
authors.lastname: Chiosis
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Gewirth
authors.forename: Zihai
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D040881:CD11a Antigen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018821:CD18 Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005434:Flow Cytometry; D045325:HCT116 Cells; D006801:Humans; D015151:Immunoblotting; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization; D034622:RNA Interference
chemical_list: D040881:CD11a Antigen; D018821:CD18 Antigens; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D010455:Peptides; C053387:endoplasmin
keywords: Cancer Biology; HSP90b1; Heat Shock Protein; Innate Immunity; Integrin; Toll-like Receptor; Tumor Metastases; gp96; grp94