Skap2 is required for β 2 integrin-mediated neutrophil recruitment and functions

J Exp Med. 2017 Mar 6;214(3):851-874. doi: 10.1084/jem.20160647. Epub 2017 Feb 9.

Abstract

Integrin activation is required for neutrophil functions. Impaired integrin activation on neutrophils is the hallmark of leukocyte adhesion deficiency (LAD) syndrome in humans, characterized by impaired leukocyte recruitment and recurrent infections. The Src kinase-associated phosphoprotein 2 (Skap2) is involved in integrin functions in different leukocyte subtypes. However, the role of Skap2 in β2 integrin activation and neutrophil recruitment is unknown. In this study, we demonstrate the crucial role of Skap2 in regulating actin polymerization and binding of talin-1 and kindlin-3 to the β2 integrin cytoplasmic domain, thereby being indispensable for β2 integrin activation and neutrophil recruitment. The direct interaction of Skap2 with the Wiskott-Aldrich syndrome protein via its SH3 domain is critical for integrin activation and neutrophil recruitment in vivo. Furthermore, Skap2 regulates integrin-mediated outside-in signaling events and neutrophil functions. Thus, Skap2 is essential to activate the β2 integrins, and loss of Skap2 function is sufficient to cause a LAD-like phenotype in mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD18 Antigens / physiology*
  • Cell Adhesion
  • Chemotaxis, Leukocyte
  • Cytoskeletal Proteins / metabolism
  • E-Selectin / physiology
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Macrophage-1 Antigen / physiology
  • Mice
  • Mice, Inbred C57BL
  • Neutrophil Infiltration*
  • Neutrophils / physiology*
  • Protein Multimerization
  • Talin / metabolism
  • Wiskott-Aldrich Syndrome Protein / physiology
  • src Homology Domains

Substances

  • CD18 Antigens
  • Cytoskeletal Proteins
  • E-Selectin
  • Intracellular Signaling Peptides and Proteins
  • Macrophage-1 Antigen
  • Talin
  • Was protein, mouse
  • Wiskott-Aldrich Syndrome Protein
  • kindlin-3 protein, mouse
  • src kinase associated phosphoprotein 2
  • talin protein, mouse