PLC-γ and PI3K Link Cytokines to ERK Activation in Hematopoietic Cells with Normal and Oncogenic Kras
Résumé
Oncogenic K-Ras proteins, such as K-RasG12D, accumulate in the active, guanosine triphosphate
(GTP)–bound conformation and stimulate signaling through effector kinases. The presence of the
K-RasG12D oncoprotein at a similar abundance to that of endogenous wild-type K-Ras results in
only minimal phosphorylation and activation of the canonical Raf–mitogen-activated or
extracellular signal–regulated protein kinase kinase (MEK)–extracellular signal–regulated kinase
(ERK) and phosphoinositide-3 kinase (PI3K)–Akt–mammalian target of rapamycin (mTOR)
signaling cascades in primary hematopoietic cells, and these pathways remain dependent on
growth factors for efficient activation. Here, we show that phospholipase C γ (PLC-γ), PI3K, and
their generated second messengers link activated cytokine receptors to Ras and ERK signaling in
differentiated bone marrow cells and in a cell population highly enriched for leukemia stem cells.
Cells expressing endogenous oncogenic K-RasG12D remained dependent on the second messenger diacylglycerol for the efficient activation of Ras-ERK signaling. These data raise the unexpected
possibility of therapeutically targeting proteins that function upstream of oncogenic Ras in cancer
Domaines
Sciences du Vivant [q-bio]Origine | Fichiers produits par l'(les) auteur(s) |
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