Journal
BLOOD
Volume 115, Issue 14, Pages 2818-2826Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-07-235804
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Funding
- Italian Association for Cancer Research
- Istituto Pasteur-Fondazione Cenci Bolognetti
- Ministero dell'Istruzione
- dell'Universita e della Ricerca
- European Union [QLG1-CT1999-01090]
- EUROPID [QLG1-CT-2001-01395]
- National Institutes of Health [P01-HL-059561-11A1]
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We analyzed the involvement of Wiskott-Aldrich syndrome protein (WASp), a critical regulator of actin cytoskeleton remodeling, in the control of natural killer (NK)-cell migration. NK cells derived from patients with Wiskott-Aldrich syndrome/X-linked thrombocytopenia (WAS/XLT), carrying different mutations in the WASP coding gene, displayed reduced migration through intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), or endothelial cells in response to CXCL12/stromal cell-derived factor-1 and CX3CL1/fractalkine. Inhibition of WAS/XLT NK-cell migration was associated with reduced ability of these cells to up-regulate the expression of CD18 activation neoepitope and to adhere to ICAM-1 or VCAM-1 following chemokine stimulation. Moreover, chemokine receptor or beta 1 or beta 2 integrin engagement on NK cells rapidly resulted in Cdc42 activation and WASp tyrosine phosphorylation as well as in WASp association with Fyn and Pyk-2 tyrosine kinases. NK-cell pretreatment with wiskostatin, to prevent Cdc42/WASp association, impaired chemokine-induced NK-cell migration through ICAM-1 and beta 2 integrin activation-dependent neoepitope expression. These results show that the Cdc42/WASp pathway plays a crucial role in the regulation of NK-cell migration by acting as a critical component of the chemokine-induced inside-out signaling that regulates lymphocyte function-associated antigen-1 function and suggest that after integrin or chemokine receptor engagement WASp function is regulated by the coordinate action of both Cdc42 and tyrosine kinases. (Blood. 2010; 115(14): 2818-2826)
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