Genetic evidence for convergence of c-Kit- and alpha4 integrin-mediated signals on class IA PI-3kinase and the Rac pathway in regulating integrin-directed migration in mast cells

Blood. 2003 Jun 15;101(12):4725-32. doi: 10.1182/blood-2002-08-2521. Epub 2003 Jan 30.

Abstract

Mast cells play a critical role in host defense against a number of pathogens. Increased mast cell infiltration has been described in allergic asthma, in rheumatoid arthritis, and during helminthes infection. Despite the importance of mast cells in allergic disease and defense against infection, little is known about the mechanisms by which mast cells migrate to various tissues under steady state conditions or during infection or inflammation. Here, we show that activation of c-Kit by its ligand, stem cell factor (SCF), cooperates with alpha4 integrin in inducing directed migration of mast cells on fibronectin. A reduction in migration and activation of a small G protein, Rac, was observed in mast cells derived from class IA phosphoinositide-3 kinase (PI-3kinase)-deficient mice in response to SCF stimulation and in mast cells expressing the dominant-negative Rac (RacN17), as well as in mast cells deficient in the hematopoietic-specific small G protein, Rac2. In addition, a PI-3kinase inhibitor inhibited alpha4- as well as SCF-induced migration in a dose-dependent fashion. In contrast, a mitogen-activated protein kinase (MAPK) inhibitor had little effect. Consistent with the pharmacologic results, abrogating the binding of the p85alpha subunit of class IA PI-3kinase to c-Kit also resulted in inhibition of SCF-induced migration on fibronectin. These genetic and biochemical data demonstrate that both c-Kit and alpha4 integrin signaling are linked to class IA PI-3kinase and Rac pathways and regulate integrin-directed (haptotactic) migration in mast cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Binding Sites
  • Chemotaxis
  • Enzyme Inhibitors / pharmacology
  • Fibronectins
  • Gene Expression
  • Integrin alpha4 / physiology*
  • Integrin alpha4beta1 / immunology
  • Integrin alpha4beta1 / metabolism
  • Integrin alpha5beta1 / metabolism
  • Mast Cells / chemistry
  • Mast Cells / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphatidylinositol 3-Kinases / deficiency
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-kit / immunology
  • Proto-Oncogene Proteins c-kit / physiology*
  • RAC2 GTP-Binding Protein
  • Signal Transduction*
  • Stem Cell Factor / pharmacology
  • rac GTP-Binding Proteins / deficiency
  • rac GTP-Binding Proteins / genetics
  • rac GTP-Binding Proteins / metabolism*
  • rac GTP-Binding Proteins / physiology

Substances

  • Antibodies
  • Enzyme Inhibitors
  • Fibronectins
  • Integrin alpha4beta1
  • Integrin alpha5beta1
  • Phosphoinositide-3 Kinase Inhibitors
  • Stem Cell Factor
  • Integrin alpha4
  • Proto-Oncogene Proteins c-kit
  • rac GTP-Binding Proteins