Abstract
SWAP-70, an unusual phosphatidylinositol-3-kinase-dependent protein that interacts with the RhoGTPase Rac, is highly expressed in mast cells. Cultured bone marrow mast cells (BMMC) from SWAP-70(-/-) mice are reduced in FcepsilonRI-triggered degranulation. This report describes the hitherto-unknown role of SWAP-70 in c-kit receptor signaling, a key proliferation and differentiation pathway in mast cells. Consistent with the role of Rac in cell motility and regulation of the actin cytoskeleton, mutant cells show abnormal actin rearrangements and are deficient in migration in vitro and in vivo. SWAP-70(-/-) BMMC are impaired in calcium flux, in proper translocation and activity of Akt kinase (required for mast cell activation and survival), and in translocation of Rac1 and Rac2 upon c-kit stimulation. Adhesion to fibronectin is reduced, but homotypic cell association induced through c-kit is strongly increased in SWAP-70(-/-) BMMC. Homotypic association requires extracellular Ca(2+) and depends on the integrin alpha(L)beta(2) (LFA-1). ERK is hyperactivated upon c-kit signaling in adherent and dispersed mutant cells. Together, we suggest that SWAP-70 is an important regulator of specific effector pathways in c-kit signaling, including mast cell activation, migration, and cell adhesion.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Actins / metabolism
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Animals
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Calcium / metabolism
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Cell Adhesion
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Cell Differentiation
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Cell Membrane / metabolism
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Cell Movement
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Cell Proliferation
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Cell Survival
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Cells, Cultured
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Cytoplasm / metabolism
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Cytoskeleton / metabolism
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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Dose-Response Relationship, Drug
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Fibronectins / metabolism
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Flavonoids / pharmacology
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Glutathione Transferase / metabolism
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Guanine Nucleotide Exchange Factors / metabolism
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Guanine Nucleotide Exchange Factors / physiology*
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Lymphocyte Function-Associated Antigen-1 / metabolism
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Mast Cells / cytology*
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Mice
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Mice, Knockout
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Minor Histocompatibility Antigens
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Mutation
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Nuclear Proteins / metabolism
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Nuclear Proteins / physiology*
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Protein Serine-Threonine Kinases / metabolism
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Protein Transport
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-kit / metabolism*
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RAC2 GTP-Binding Protein
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Signal Transduction
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Stem Cell Factor / metabolism
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Subcellular Fractions / metabolism
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Time Factors
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rac GTP-Binding Proteins / metabolism
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rac1 GTP-Binding Protein / metabolism
Substances
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Actins
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DNA-Binding Proteins
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Enzyme Inhibitors
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Fibronectins
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Flavonoids
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Guanine Nucleotide Exchange Factors
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Lymphocyte Function-Associated Antigen-1
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Minor Histocompatibility Antigens
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Nuclear Proteins
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Proto-Oncogene Proteins
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Stem Cell Factor
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Swap70 protein, mouse
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Glutathione Transferase
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Proto-Oncogene Proteins c-kit
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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rac GTP-Binding Proteins
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rac1 GTP-Binding Protein
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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Calcium