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Sci. Signal., 3 December 2013
Vol. 6, Issue 304, p. ra105
[DOI: 10.1126/scisignal.2004125]

RESEARCH ARTICLES

PLC-{gamma} and PI3K Link Cytokines to ERK Activation in Hematopoietic Cells with Normal and Oncogenic Kras

Ernesto Diaz-Flores1, Hana Goldschmidt1, Philippe Depeille2, Victor Ng1, Jon Akutagawa1, Kimberly Krisman1, Michael Crone1, Michael R. Burgess3, Olusegun Williams4, Benjamin Houseman4, Kevan Shokat4, Deepak Sampath5, Gideon Bollag6, Jeroen P. Roose2, Benjamin S. Braun1, and Kevin Shannon1*

1 Department of Pediatrics and Benniof Children’s Hospital, University of California, San Francisco, San Francisco, CA 94158, USA.
2 Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
3 Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
4 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
5 Genentech Inc., South San Francisco, CA 94080, USA.
6 Plexxikon Inc., Berkeley, CA 94710, USA.

Abstract: 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. 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-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.

* Corresponding author. E-mail: shannonk{at}peds.ucsf.edu

Citation: E. Diaz-Flores, H. Goldschmidt, P. Depeille, V. Ng, J. Akutagawa, K. Krisman, M. Crone, M. R. Burgess, O. Williams, B. Houseman, K. Shokat, D. Sampath, G. Bollag, J. P. Roose, B. S. Braun, K. Shannon, PLC-{gamma} and PI3K Link Cytokines to ERK Activation in Hematopoietic Cells with Normal and Oncogenic Kras. Sci. Signal. 6, ra105 (2013).

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