title: PLC-γ and PI3K link cytokines to ERK activation in hematopoietic cells with normal and oncogenic Kras.
abstract: 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-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 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.
authors.affiliation: 1Department of Pediatrics and Benniof Children's Hospital, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Diaz-Flores
authors.forename: Hana
authors.initials: H
authors.lastname: Goldschmidt
authors.forename: Philippe
authors.initials: P
authors.lastname: Depeille
authors.forename: Victor
authors.initials: V
authors.lastname: Ng
authors.forename: Jon
authors.initials: J
authors.lastname: Akutagawa
authors.forename: Kimberly
authors.initials: K
authors.lastname: Krisman
authors.forename: Michael
authors.initials: M
authors.lastname: Crone
authors.forename: Michael R
authors.initials: MR
authors.lastname: Burgess
authors.forename: Olusegun
authors.initials: O
authors.lastname: Williams
authors.forename: Benjamin
authors.initials: B
authors.lastname: Houseman
authors.forename: Kevan
authors.initials: K
authors.lastname: Shokat
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.forename: Gideon
authors.initials: G
authors.lastname: Bollag
authors.forename: Jeroen P
authors.initials: JP
authors.lastname: Roose
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Braun
authors.forename: Kevin
authors.initials: K
authors.lastname: Shannon
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D020125:Mutation, Missense; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D015290:Second Messenger Systems / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D048049:Extracellular Signal-Regulated MAP Kinases; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma; D016283:Proto-Oncogene Proteins p21(ras); D058570:TOR Serine-Threonine Kinases; C546843:mTOR protein, mouse; C495971:Hras protein, mouse