Activation of the MAP kinase pathway by c-Kit is PI-3 kinase dependent in hematopoietic progenitor/stem cell lines
2004 (English)In: Blood, ISSN 0006-4971, Vol. 104, no 1, 51-57 p.Article in journal (Refereed) Published
The Steel factor (SF) and its receptor c-Kit play a critical role for various cell types at different levels in the hematopoietic hierarchy. Whether similar or distinct signaling pathways are used upon c-Kit activation in different cell types within the hematopoietic hierarchy is not known. To study c-Kit signaling pathways in the hematopoietic system we have compared c-Kit downstream signaling events in SF-dependent hematopoietic stem cell (HSC)–like cell lines to those of mast cells. Both Erk and protein kinase B (PKB)/Akt are activated by ligand-induced activation of the c-Kit receptor in the HSC-like cell lines. Surprisingly, phosphoinositide-3 (PI-3) kinase inhibitors block not only PKB/Akt activation but also activation of Raf and Erk. SF-induced activation of Ras is not affected by inhibition of PI-3 kinase. In mast cells and other more committed hematopoietic precursors, the activation of Erk by SF is not PI-3 kinase dependent. Our results suggest that a molecular signaling switch occurs during differentiation in the hematopoietic system whereby immature hematopoietic progenitor/stem cells use a PI-3 kinase–sensitive pathway in the activation of both Erk and PKB/Akt, which is then switched upon differentiation to the more commonly described PI-3 kinase–independent mitogen-activated protein (MAP) kinase pathway.
Place, publisher, year, edition, pages
2004. Vol. 104, no 1, 51-57 p.
1-Phosphatidylinositol 3-Kinase/antagonists & inhibitors/*metabolism, Animals, Cell Line, Chromones/pharmacology, Enzyme Activation, Enzyme Inhibitors/pharmacology, Femur/cytology, Hematopoietic Stem Cells/cytology/*enzymology, MAP Kinase Signaling System/*physiology, Mice, Mice; Inbred C57BL, Mitogen-Activated Protein Kinases/metabolism, Morpholines/pharmacology, Phosphorylation, Protein-Serine-Threonine Kinases/metabolism, Proto-Oncogene Proteins/metabolism, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-kit/*metabolism, Proto-Oncogene Proteins c-raf/metabolism, Stem Cell Factor/metabolism, ras Proteins/metabolism
IdentifiersURN: urn:nbn:se:umu:diva-15405DOI: 10.1182/blood-2003-07-2554PubMedID: 14996702OAI: oai:DiVA.org:umu-15405DiVA: diva2:155077