The colony stimulating factor-1 receptor associates with and activates phosphatidylinositol-3 kinase.
Colony stimulating factor-1 (CSF-1) is a lineage-specific growth factor required for proliferation and survival of mononuclear phagocytes and their precursors. The CSF-1 receptor belongs to a family of ligand-activated protein-tyrosine kinases. Activation of the platelet-derived growth factor receptor, but not the CSF-1 receptor, leads to an increase in phospholipase C activity and a subsequent elevation in intracellular calcium. Recent studies have shown that a novel phosphoinositol (PtdIns) kinase, termed PtdIns-3 kinase, is stimulated by the platelet-derived growth factor receptor and certain oncogenes in the protein-tyrosine kinase family. PtdIns-3 kinase phosphorylates the D-3 hydroxyl position of the inositol ring of PtdIns, and its products do not participate in the generation of the second messenger inositol 1,4,5-trisphosphate (Ins(1,4,5)P3). Here we report that addition of CSF-1 is followed by activation of PtdIns-3 kinase in a macrophage cell line (P388 D1), which contains CSF-1 receptors, and in BALB/c fibroblasts made to express the human CSF-1 receptor. Furthermore, we show that activation of the CSF-1 receptor results in the accumulation in intact cells of polyphosphoinositides phosphorylated at the D-3 position of the inositol ring. Thus activation of the CSF-1 receptor stimulates PtdIns-3 kinase activity, indicating a novel pathway for CSF-1 receptor-mediated signal transduction.
Varticovski
L
L
Department of Physiology, Tufts University School of Medicine, Boston, Massachusetts 02111.
Druker
B
B
Morrison
D
D
Cantley
L
L
Roberts
T
T
D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D003115:Colony-Stimulating Factors / Q000494:pharmacology; D004789:Enzyme Activation; D005347:Fibroblasts / Q000201:enzymology; D015870:Gene Expression; D007163:Immunosorbent Techniques; D007700:Kinetics; D016173:Macrophage Colony-Stimulating Factor; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols / Q000378:metabolism; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D016186:Receptor, Macrophage Colony-Stimulating Factor; D015398:Signal Transduction; D014162:Transfection; D014170:Transformation, Genetic
D003115:Colony-Stimulating Factors; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; D011518:Proto-Oncogene Proteins; D016173:Macrophage Colony-Stimulating Factor; D010770:Phosphotransferases; D019869:Phosphatidylinositol 3-Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor