Fer kinase is required for sustained p38 kinase activation and maximal chemotaxis of activated mast cells.
Mast cells play important roles in inflammation and immunity and express the high-affinity immunoglobulin E receptor (Fc epsilon RI) and the receptor protein-tyrosine kinase Kit. Aggregation of Fc epsilon RI 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 Fc epsilon RI 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 Fc epsilon RI 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 Fc epsilon RI 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.
Department of Biochemistry, Division of Cancer Biology and Genetics, Queen's University Cancer Research Institute, Queen's University, Kingston, Ontario, Canada K7L 3N6.
Andrew W B
AW
Craig
Peter A
PA
Greer
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D002448:Cell Adhesion; D002478:Cells, Cultured; D002633:Chemotaxis; D016207:Cytokines / Q000378:metabolism; D019281:Dimerization; D004789:Enzyme Activation; D006720:Homozygote; D015151:Immunoblotting; D015289:Leukotrienes / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008407:Mast Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D012190:Retroviridae / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases
D016207:Cytokines; D015289:Leukotrienes; D011518:Proto-Oncogene Proteins; C052602:proto-oncogene protein c-fes-fps; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases