Abstract
Interleukin-3 (IL-3)-induced activation of endogenous Rac-1, Rac-2, and Cdc42. Rac-1 was also activated by colony-stimulating factor-1 (CSF-1), Steel locus factor (SLF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5 or by cross-linking the B-lymphocyte receptor for antigen (BCR). The activation of Rac-1 induced by cross-linking the BCR or by IL-3 stimulation was blocked only partially by Ly294002, with about 25% to 30% of Rac-1 activation still occurring in the absence of detectable increases in phosphatidyl-inositol-3 kinase (PI-3K) activity. Overexpression of constitutively active mutants of H-Ras, N-Ras, or M-Ras resulted in activation of coexpressed Rac-1 through an Ly29402-resistant, PI-3K-independent mechanism. Overexpression of constitutively active mutants of p21 Ras, or Rac-1, but not of PI-3K, was sufficient for activation of p38 mitogen-activated protein kinase (MAPK) in cells of hemopoietic origin. Inhibition of increases in PI-3K activity by Ly294002 had no effect on the IL-3-induced activation of p38 MAPK. In contrast, Ly294002 partially inhibited the activation of p38 MAPK induced by cross-linking of the BCR, although some p38 MAPK activation occurred in the absence of increases in the activity of Rac-1 or PI-3K. The activation of Rac-1, Rac-2, and Cdc42 by IL-3 and other hemopoietic growth factors is likely to be an important component of their actions in promoting growth, survival, and function.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Marrow Cells / drug effects
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Bone Marrow Cells / metabolism
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Cell Line / drug effects
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Cell Line / metabolism
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Chromones / pharmacology
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Genes, ras
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Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
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Hematopoietic Cell Growth Factors / pharmacology*
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / metabolism
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Interleukin-3 / pharmacology
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Interleukin-5 / pharmacology
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MAP Kinase Signaling System
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Macrophage Colony-Stimulating Factor / pharmacology
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Mice
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Morpholines / pharmacology
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / pharmacology
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins p21(ras) / physiology
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RAC2 GTP-Binding Protein
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Receptors, Antigen, B-Cell / immunology*
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Stem Cell Factor / pharmacology
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cdc42 GTP-Binding Protein / drug effects*
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cdc42 GTP-Binding Protein / metabolism
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p38 Mitogen-Activated Protein Kinases
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rac GTP-Binding Proteins / drug effects*
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rac GTP-Binding Proteins / metabolism
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rac1 GTP-Binding Protein / drug effects*
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rac1 GTP-Binding Protein / genetics
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rac1 GTP-Binding Protein / metabolism
Substances
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Chromones
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Enzyme Inhibitors
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Hematopoietic Cell Growth Factors
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Interleukin-3
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Interleukin-5
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Receptors, Antigen, B-Cell
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Stem Cell Factor
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Macrophage Colony-Stimulating Factor
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Granulocyte-Macrophage Colony-Stimulating Factor
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Proto-Oncogene Proteins p21(ras)
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cdc42 GTP-Binding Protein
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rac GTP-Binding Proteins
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rac1 GTP-Binding Protein