Regulation of the adhesion versus cytotoxic functions of the Mac-1/CR3/alphaMbeta2-integrin glycoprotein.
Mac-1/CR3 functions as both an adhesion molecule mediating the diapedesis of leukocytes across the endothelium and a receptor for the iC3b fragment of complement responsible for phagocytic/degranulation responses to microorganisms. Mac-1/CR3 has many functional characteristics shared with other integrins, including bidirectional signaling via conformational changes that originate in either the cytoplasmic domain or extracellular region. Another key to its functions is its ability to form membrane complexes with glycosylphosphatidylinositol (GPI)-anchored receptors such as Fc gammaRIIIB (CD16b) or uPAR (CD87), providing a transmembrane signaling mechanism for these outer membrane bound receptors that allows them to mediate cytoskeleton-dependent adhesion or phagocytosis and degranulation. Many functions appear to depend upon a membrane-proximal lectin site responsible for recognition of either microbial surface polysaccharides or GPI-linked signaling partners. Because of the importance of Mac-1/CR3 in promoting neutrophil inflammatory responses, therapeutic strategies to antagonize its functions have shown promise in treating both autoimmune diseases and ischemia/reperfusion injury. Conversely, soluble beta-glucan polysaccharides that bind to its lectin site prime the Mac-1/CR3 of circulating phagocytes and natural killer (NK) cells, permitting cytotoxic degranulation in response to iC3b-opsonized tumor cells that otherwise escape from this mechanism of cell-mediated cytotoxicity.
Ross
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Department of Pathology, University of Louisville, KY 40292, USA.
D000911:Antibodies, Monoclonal / Q000502:physiology; D002448:Cell Adhesion; D003602:Cytotoxicity, Immunologic; D000939:Epitopes / Q000276:immunology; D005936:Glucans / Q000378:metabolism; D006023:Glycoproteins / Q000737:chemistry / Q000276:immunology; D006801:Humans; D037102:Lectins / Q000737:chemistry; D016177:Macrophage-1 Antigen / Q000737:chemistry / Q000276:immunology*; D010587:Phagocytosis; D015398:Signal Transduction
D000911:Antibodies, Monoclonal; D000939:Epitopes; D005936:Glucans; D006023:Glycoproteins; D037102:Lectins; D016177:Macrophage-1 Antigen