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Vol. 11, Issue 10, 3661-3673, October 2000

Mutant RBL Mast Cells Defective in FcRI Signaling and Lipid Raft Biosynthesis Are Reconstituted by Activated Rho-family GTPases

Kenneth A. Field,^* John R. Apgar,^§ Elizabeth Hong-Geller, Reuben P. Siraganian,^¶ Barbara Baird,^* and David Holowka^*#

 ^*Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York;  ^§Scripps Research Institute, LaJolla, California 92093;  Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, and  ^¶NIDCR, National Institutes of Health, Bethesda, Maryland 21814

Characterization of defects in a variant subline of RBL mast cells has revealed a biochemical event proximal to IgE receptor (FcRI)-stimulated tyrosine phosphorylation that is required for multiple functional responses. This cell line, designated B6A4C1, is deficient in both FcRI-mediated degranulation and biosynthesis of several lipid raft components. Agents that bypass receptor-mediated Ca²⁺ influx stimulate strong degranulation responses in these variant cells. Cross-linking of IgE-FcRI on these cells stimulates robust tyrosine phosphorylation but fails to mobilize a sustained Ca²⁺ response. FcRI-mediated inositol phosphate production is not detectable in these cells, and failure of adenosine receptors to mobilize Ca²⁺ suggests a general deficiency in stimulated phospholipase C activity. Antigen stimulation of phospholipases A₂ and D is also defective. Infection of B6A4C1 cells with vaccinia virus constructs expressing constitutively active Rho family members Cdc42 and Rac restores antigen-stimulated degranulation, and active Cdc42 (but not active Rac) restores ganglioside and GPI expression. The results support the hypothesis that activation of Cdc42 and/or Rac is critical for FcRI-mediated signaling that leads to Ca²⁺ mobilization and degranulation. Furthermore, they suggest that Cdc42 plays an important role in the biosynthesis and expression of certain components of lipid rafts.

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Current address: G.W. Hooper Foundation, University of California, San Francisco, CA 94143-0552.

The first three authors contributed equally to this study.

^# Corresponding author: E-mail address: dah24{at}cornell.edu.

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Molecular Biology of the Cell
Vol. 11, 3661-3673, October 2000
Copyright © 2000 by The American Society for Cell Biology

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