| First Author | Diaz-Flores E | Year | 2013 |
| Journal | Sci Signal | Volume | 6 |
| Issue | 304 | Pages | ra105 |
| PubMed ID | 24300897 | Mgi Jnum | J:259460 |
| Mgi Id | MGI:6141390 | Doi | 10.1126/scisignal.2004125 |
| Citation | Diaz-Flores E, et al. (2013) PLC-gamma and PI3K link cytokines to ERK activation in hematopoietic cells with normal and oncogenic Kras. Sci Signal 6(304):ra105 |
| abstractText | Oncogenic K-Ras proteins, such as K-Ras(G12D), accumulate in the active, guanosine triphosphate (GTP)-bound conformation and stimulate signaling through effector kinases. The presence of the K-Ras(G12D) 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. We showed that phospholipase C-gamma (PLC-gamma), 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 enriched for leukemia stem cells. Cells expressing endogenous oncogenic K-Ras(G12D) 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. |
