title: Mac-1 promotes FcgammaRIIA-dependent cell spreading and migration on immune complexes.
abstract: The integrin Mac-1 plays a critical role in Fc receptor (FcR)-mediated antibody-dependent cellular cytotoxicity (ADCC). However, the mechanism by which Mac-1 facilitates the functions of FcgammaRIIA, a major FcR expressed on human leukocytes, is not fully understood. We report here that Mac-1 sustains cell adhesion, enhances cell spreading, and accelerates cell migration on preformed immune complexes (ICs) by directly interacting with FcgammaRIIA but not with the IC substrate. Coupling Mac-1 to FcgammaRIIA allows FcgammaRIIA to reside in the leading front of actin polymerization at the filopodial extension and thus could potentially enhance FcgammaRIIA-mediated cell spreading and migration. The direct interaction between Mac-1 and FcgammaRIIA is demonstrated by co-immunoprecipitation, by cell surface co-localization, and by solid-phase binding assays using recombinant alpha(M)I-domain and soluble FcgammaRIIA. Further mutational analysis identifies the E(253)-R(261) sequence within the alpha(M)I-domain as part of the FcgammaRIIA binding interface within Mac-1. Altogether, these results demonstrate that FcgammaRIIA recognizes Mac-1 via the alpha(M)I-domain but not the lectin domain, a distinct feature from other FcRs, and that Mac-1 binding confers FcgammaRIIA with the ability to prolong cell adhesion as well as to spread and migrate on the ICs, leading to effective cell killing by ADCC.
authors.affiliation: Center for Vascular and Inflammatory Diseases and Department of Physiology, University of Maryland School of Medicine, 800 W. Baltimore Street, Baltimore, Maryland 21201, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiong
authors.forename: Chunzhang
authors.initials: C
authors.lastname: Cao
authors.forename: Alexandra
authors.initials: A
authors.lastname: Makarova
authors.forename: Brad
authors.initials: B
authors.lastname: Hyman
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000936:Antigen-Antibody Complex / Q000502:physiology; D015703:Antigens, CD / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D016177:Macrophage-1 Antigen / Q000096:biosynthesis / Q000502:physiology*; D017434:Protein Structure, Tertiary; D017452:Receptors, IgG / Q000502:physiology*
chemical_list: D000936:Antigen-Antibody Complex; D015703:Antigens, CD; C080568:Fc gamma receptor IIA; D016177:Macrophage-1 Antigen; D017452:Receptors, IgG