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Molecular and Cellular Biology, December 2004, p. 10277-10288, Vol. 24, No. 23
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.23.10277-10288.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

SWAP-70 Regulates c-kit-Induced Mast Cell Activation, Cell-Cell Adhesion, and Migration{dagger}

Raja Rajeswari Sivalenka and Rolf Jessberger*

Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York

Received 23 April 2004/ Returned for modification 27 May 2004/ Accepted 24 August 2004

SWAP-70, an unusual phosphatidylinositol-3-kinase-dependent protein that interacts with the RhoGTPase Rac, is highly expressed in mast cells. Cultured bone marrow mast cells (BMMC) from SWAP-70–/– mice are reduced in Fc{varepsilon}RI-triggered degranulation. This report describes the hitherto-unknown role of SWAP-70 in c-kit receptor signaling, a key proliferation and differentiation pathway in mast cells. Consistent with the role of Rac in cell motility and regulation of the actin cytoskeleton, mutant cells show abnormal actin rearrangements and are deficient in migration in vitro and in vivo. SWAP-70–/– BMMC are impaired in calcium flux, in proper translocation and activity of Akt kinase (required for mast cell activation and survival), and in translocation of Rac1 and Rac2 upon c-kit stimulation. Adhesion to fibronectin is reduced, but homotypic cell association induced through c-kit is strongly increased in SWAP-70–/– BMMC. Homotypic association requires extracellular Ca2+ and depends on the integrin {alpha}Lß2 (LFA-1). ERK is hyperactivated upon c-kit signaling in adherent and dispersed mutant cells. Together, we suggest that SWAP-70 is an important regulator of specific effector pathways in c-kit signaling, including mast cell activation, migration, and cell adhesion.

* Corresponding author. Mailing address: Mount Sinai School of Medicine, Department of Gene and Cell Medicine, 1425 Madison Ave., Box 1496, New York, NY 10029-6574. Phone: (212) 659-8259. Fax: (212) 849-2437. E-mail: rolf.jessberger{at}mssm.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, December 2004, p. 10277-10288, Vol. 24, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.23.10277-10288.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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