Skap2 is required for β2integrin-mediated neutrophil recruitment and functions.
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 β2integrin 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 β2integrin cytoplasmic domain, thereby being indispensable for β2integrin 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 β2integrins, and loss of Skap2 function is sufficient to cause a LAD-like phenotype in mice.
Department of Anesthesiology, Intensive Care, and Pain Medicine, University of Münster, 48149 Münster, Germany.
Mark
0000-0003-0244-7722
M
Boras
Department of Anesthesiology, Intensive Care, and Pain Medicine, University of Münster, 48149 Münster, Germany.
Stephanie
S
Volmering
Department of Anesthesiology, Intensive Care, and Pain Medicine, University of Münster, 48149 Münster, Germany.
Arne
0000-0002-4238-751X
A
Bokemeyer
Department of Anesthesiology, Intensive Care, and Pain Medicine, University of Münster, 48149 Münster, Germany.
Jan
J
Rossaint
Department of Anesthesiology, Intensive Care, and Pain Medicine, University of Münster, 48149 Münster, Germany.
Helena
H
Block
Department of Anesthesiology, Intensive Care, and Pain Medicine, University of Münster, 48149 Münster, Germany.
Bernadette
B
Bardel
Gerhard-Domagk-Institute of Pathology, University Hospital Münster, University of Münster, 48149 Münster, Germany.
Veerle
V
Van Marck
Gerhard-Domagk-Institute of Pathology, University Hospital Münster, University of Münster, 48149 Münster, Germany.
Barbara
B
Heitplatz
Institute of Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, 39106 Magdeburg, Germany.
Stefanie
S
Kliche
Institute of Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, 39106 Magdeburg, Germany.
Annegret
A
Reinhold
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143.|The Program in Immunology, University of California, San Francisco, San Francisco, CA 94143.
Clifford
C
Lowell
Department of Anesthesiology, Intensive Care, and Pain Medicine, University of Münster, 48149 Münster, Germany zarbock@uni-muenster.de.
Alexander
0000-0002-2124-1714
A
Zarbock
D000818:Animals; D018821:CD18 Antigens / Q000502:physiology*; D002448:Cell Adhesion; D002634:Chemotaxis, Leukocyte; D003598:Cytoskeletal Proteins / Q000378:metabolism; D019040:E-Selectin / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D016177:Macrophage-1 Antigen / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000502:physiology*; D055503:Protein Multimerization; D016608:Talin / Q000378:metabolism; D051316:Wiskott-Aldrich Syndrome Protein / Q000502:physiology; D018909:src Homology Domains
D018821:CD18 Antigens; D003598:Cytoskeletal Proteins; D019040:E-Selectin; D047908:Intracellular Signaling Peptides and Proteins; D016177:Macrophage-1 Antigen; D016608:Talin; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; C527818:kindlin-3 protein, mouse; C116431:src kinase associated phosphoprotein 2; C496077:Tln1 protein, mouse