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: Markus Moser, Martina Bauer, Stephan Schmid, Raphael Ruppert, Sarah Schmidt, Michael Sixt, Hao-Ven Wang, Markus Sperandio, Reinhard Fässler
• Journal: Nature medicine (Nat Med) Vol. 15 Issue 3 Pg. 300-5 (Mar 2009) ISSN: 1546-170X [Electronic] United States
• PMID: 19234461 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD18 Antigens
• FERMT3 protein, human
• Ligands
• Membrane Proteins
• Neoplasm Proteins

Topics

• Animals
• CD18 Antigens (physiology)
• Cell Adhesion (physiology)
• Endothelium, Vascular (cytology)
• Humans
• Leukocytes (cytology)
• Ligands
• Membrane Proteins (physiology)
• Mice
• Mice, Knockout
• Neoplasm Proteins (physiology)