Activation of the MAP kinase pathway by c-Kit is PI-3 kinase dependent in hematopoietic progenitor/stem cell lines

• 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.

Nyckelord

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

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)