Activation of Rac-1, Rac-2, and Cdc42 by hemopoietic growth factors or cross-linking of the B-lymphocyte receptor for antigen.
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.
Grill
Brock
B
The Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
Schrader
John W
JW
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011905:Genes, ras; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D007377:Interleukin-3 / Q000494:pharmacology; D015848:Interleukin-5 / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D019089:Stem Cell Factor / Q000494:pharmacology; D020764:cdc42 GTP-Binding Protein / Q000187:drug effects* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000097766:RAC2 GTP-Binding Protein
D002867:Chromones; D004791:Enzyme Inhibitors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016298:Hematopoietic Cell Growth Factors; D007377:Interleukin-3; D015848:Interleukin-5; D016173:Macrophage Colony-Stimulating Factor; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016283:Proto-Oncogene Proteins p21(ras); D011947:Receptors, Antigen, B-Cell; D019089:Stem Cell Factor; D020764:cdc42 GTP-Binding Protein; D048051:p38 Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one