The Journal of Experimental Medicine
Torrey Pines Biolabs
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Published 2 February 2004. doi:10.1084/jem.20030652
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 3, 357-368
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WIP Regulates Signaling via the High Affinity Receptor for Immunoglobulin E in Mast Cells

Alexander Kettner1, Lalit Kumar1, Inés M. Antón3, Yoji Sasahara1, Miguel de la Fuente1, Vadim I. Pivniouk1, Hervé Falet2, John H. Hartwig2, and Raif S. Geha1

1 Division of Immunology, Children's Hospital
2 Division of Hematology, Brigham and Women's Hospital, Department of Pediatrics and Department of Medicine, Harvard Medical School, Boston, MA 02115
3 Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy

Address correspondence to Raif S. Geha, Division of Immunology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115. Phone: (617) 355-7603; Fax: (617) 739-3145; email: raif.geha{at}tch.harvard.edu

Wiskott-Aldrich syndrome protein–interacting protein (WIP) stabilizes actin filaments and is important for immunoreceptor-mediated signal transduction leading to actin cytoskeleton rearrangement in T and B cells. Here we report a role for WIP in signaling pathways downstream of the high affinity receptor for immunoglobulin (Ig)E (Fc{epsilon}RI) in mast cells. WIP-deficient bone marrow–derived mast cells (BMMCs) were impaired in their capacity to degranulate and secrete interleukin 6 after Fc{epsilon}RI ligation. Calcium mobilization, phosphorylation of Syk, phospholipase C-g2, and c-Jun NH2-terminal kinase were markedly decreased in WIP-deficient BMMCs. WIP was found to associate with Syk after Fc{epsilon}RI ligation and to inhibit Syk degradation as evidenced by markedly diminished Syk levels in WIP-deficient BMMCs. WIP-deficient BMMCs exhibited no apparent defect in their subcortical actin network and were normal in their ability to form protrusions when exposed to an IgE-coated surface. However, the kinetics of actin changes and the cell shape changes that follow Fc{epsilon}RI signaling were altered in WIP-deficient BMMCs. These results suggest that WIP regulates Fc{epsilon}RI-mediated mast cell activation by regulating Syk levels and actin cytoskeleton rearrangement.

Key Words: signal transduction • WIP • WASP • Wiskott-Aldrich syndrome • cytoskeleton

A. Kettner, L. Kumar, and I.M. Antón contributed equally to this work.

Abbreviations used in this paper: BMMC, bone marrow–derived mast cell; HSA, human serum albumin; MAP, mitogen-activated protein; PLC, phospholipase C; WAS, Wiskott-Aldrich syndrome; WASP, WAS protein; WCM, WEHI-3–conditioned medium; WIP, WASP-interacting protein.


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