title: The tetraspanin superfamily member CD151 regulates outside-in integrin alphaIIbbeta3 signaling and platelet function.
abstract: The tetraspanin family member CD151 forms complexes with integrins and regulates cell adhesion and migration. While CD151 is highly expressed in megakaryocytes and to a lesser extent in platelets, its physiologic role in platelets is unclear. In this study, we investigate the physical and functional importance of CD151 in murine platelets. Immunoprecipitation/Western blot studies reveal a constitutive physical association of CD151 with integrin alpha(IIb)beta(3) complex under strong detergent conditions. Using CD151-deficient mice, we show that the platelets have impaired "outside-in" integrin alpha(IIb)beta(3) signaling with defective platelet aggregation responses to protease-activated receptor 4 (PAR-4) agonist peptide, collagen, and adenosine diphosphate (ADP); impaired platelet spreading on fibrinogen; and delayed kinetics of clot retraction in vitro. This functional integrin alpha(IIb)beta(3) defect could not be attributed to altered expression of integrin alpha(IIb)beta(3). CD151(-/-) platelets displayed normal platelet alpha granule secretion, dense granule secretion, and static platelet adhesion. In addition, CD151(-/-) platelets displayed normal "inside-out" integrin alpha(IIb)beta(3) signaling properties as demonstrated by normal agonist-induced binding of soluble fluorescein isothiocyanate (FITC)-fibrinogen, JON/A antibody binding, and increases in cytosolic-free calcium and inositol 1,4,5 triphosphate (IP(3)) levels. This study provides the first direct evidence that CD151 is essential for normal platelet function and that disruption of CD151 induced a moderate outside-in integrin alpha(IIb)beta(3) signaling defect.
authors.affiliation: Kronheimer Building, Austin Research Institute, Austin Hospital, Studley Rd, Heidelberg, Victoria 3084 Australia.
authors.forename: Lai-Man
authors.initials: LM
authors.lastname: Lau
authors.forename: Janet L
authors.initials: JL
authors.lastname: Wee
authors.forename: Mark D
authors.initials: MD
authors.lastname: Wright
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Moseley
authors.forename: P Mark
authors.initials: PM
authors.lastname: Hogarth
authors.forename: Leonie K
authors.initials: LK
authors.lastname: Ashman
authors.forename: Denise E
authors.initials: DE
authors.lastname: Jackson
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001792:Blood Platelets / Q000166:cytology* / Q000378:metabolism*; D002448:Cell Adhesion; D003599:Cytoskeleton / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010974:Platelet Aggregation / Q000235:genetics; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D011485:Protein Binding; D022142:Secretory Vesicles / Q000378:metabolism; D015398:Signal Transduction; D060185:Tetraspanin 24
chemical_list: D015703:Antigens, CD; C554715:CD151 protein, human; C554716:Cd151 protein, mouse; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D060185:Tetraspanin 24