Fer Kinase Is Required for Sustained p38 Kinase Activation and Maximal Chemotaxis of Activated Mast Cells

Abstract

Mast cells play important roles in inflammation and immunity and express the high-affinity immunoglobulin E receptor (FcεRI) and the receptor protein-tyrosine kinase Kit. Aggregation of FcεRI via antigen binding elicits signals leading to the release of preformed inflammatory mediators as well as de novo-synthesized lipid mediators and cytokines and to elevated cell adhesion and migration. Here, we report that in mouse bone marrow-derived mast cells, Fer kinase is activated downstream of activated FcεRI and activated Kit receptor, and this activation is abolished in cells homozygous for a kinase-inactivating mutation in Fer (fer ^DR/DR ). Interestingly, the highly related Fps/Fes kinase is also activated upon FcεRI aggregation. This report represents the first description of a common signaling pathway activating Fer and Fps/Fes. While Fer-deficient cells showed similar activation of the Erk mitogen-activated protein (MAP) kinases, p38 MAP kinase activation was less sustained than that in wild-type cells. Although no major defects were observed in degranulation, leukotriene biosynthesis, and cytokine secretion, Fer-deficient cells displayed increased adhesion and decreased motility upon activation of FcεRI and the Kit receptor. The restoration of Fer kinase activity in fer ^DR/DR mast cells resulted in prolonged p38 kinase activation and increased antigen-mediated cell migration of sensitized mast cells. Thus, Fer is required for maximal p38 kinase activation to promote the chemotaxis of activated mast cells. Further studies with mast cells derived from fps/fes-deficient mice will be required to provide insight into the role of Fps/Fes in mast cell activation.

We thank Derek Schulze, Karen Williams, Michelle Scott, and Shuhong Cao for excellent technical assistance. We also gratefully acknowledge Gerald Krystal, Garry Nolan, Robert Hawley, Rob Rottapel, and Juan Rivera for providing reagents and Jacqueline Damen and Gerald Krystal for providing protocols and advice on mast cell cultures. We also thank Yotis Senis for helpful comments on the manuscript.

A.W.B.C is supported by a senior research fellowship from the Canadian Institutes for Health Research (CIHR). This work was supported by grants to P.A.G. from CIHR and the National Cancer Institute of Canada with funds from the Canadian Cancer Society.