title: Kindlin-3 is required for beta2 integrin-mediated leukocyte adhesion to endothelial cells.
abstract: Integrin activation is essential for the function of all blood cells, including platelets and leukocytes. The blood cell-specific FERM domain protein Kindlin-3 is required for the activation of the beta1 and beta3 integrins on platelets. Impaired activation of beta1, beta2 and beta3 integrins on platelets and leukocytes is the hallmark of a rare autosomal recessive leukocyte adhesion deficiency syndrome in humans called LAD-III, characterized by severe bleeding and impaired adhesion of leukocytes to inflamed endothelia. Here we show that Kindlin-3 also binds the beta2 integrin cytoplasmic domain and is essential for neutrophil binding and spreading on beta2 integrin-dependent ligands such as intercellular adhesion molecule-1 and the complement C3 activation product iC3b. Moreover, loss of Kindlin-3 expression abolished firm adhesion and arrest of neutrophils on activated endothelial cells in vitro and in vivo, whereas selectin-mediated rolling was unaffected. Thus, Kindlin-3 is essential to activate the beta1, beta2 and beta3 integrin classes, and loss of Kindlin-3 function is sufficient to cause a LAD-III-like phenotype in mice.
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Moser
authors.forename: Martina
authors.initials: M
authors.lastname: Bauer
authors.forename: Stephan
authors.initials: S
authors.lastname: Schmid
authors.forename: Raphael
authors.initials: R
authors.lastname: Ruppert
authors.forename: Sarah
authors.initials: S
authors.lastname: Schmidt
authors.forename: Michael
authors.initials: M
authors.lastname: Sixt
authors.forename: Hao-Ven
authors.initials: HV
authors.lastname: Wang
authors.forename: Markus
authors.initials: M
authors.lastname: Sperandio
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
mesh_terms: D000818:Animals; D018821:CD18 Antigens / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology*; D006801:Humans; D007962:Leukocytes / Q000166:cytology*; D008024:Ligands; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000502:physiology*
chemical_list: D018821:CD18 Antigens; C477322:FERMT3 protein, human; D008024:Ligands; D008565:Membrane Proteins; D009363:Neoplasm Proteins