The colony stimulating factor-1 receptor associates with and activates phosphatidylinositol-3 kinase


COLONY stimulating f actor-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 (Ptdlns) kinase, termed Ptdlns-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 Ptdlns, and its products do not participate in the generation of the second messenger inositol 1,4,5-trisphosphate (Ins(l,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 Dl), which contains CSF-1 receptors, and in BALB/c fibro-blasts 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 phosphory-lated 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.

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Varticovski, L., Druker, B., Morrison, D. et al. The colony stimulating factor-1 receptor associates with and activates phosphatidylinositol-3 kinase. Nature 342, 699–702 (1989).

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