Role of RAS in the Regulation of PI 3-Kinase

Abstract

Ras proteins are key regulators of signalling cascades, controlling many processes such as proliferation, differentiation and apoptosis. Mutations in these proteins or in their effectors, activators and regulators are associated with pathological conditions, particularly the development of various forms of human cancer. RAS proteins signal through direct interaction with a number of effector enzymes, one of the best characterized being type I phosphatidylinositol (PI) 3-kinases. Although the ability of RAS to control PI 3-kinase has long been well established in cultured cells, evidence for a role of the interaction of endogenous RAS with PI 3-kinase in normal and malignant cell growth in vivo has only been obtained recently. Mice with mutations in the PI 3-kinase catalytic p110a isoform that block its ability to interact with RAS are highly resistant to endogenous KRAS oncogene induced lung tumourigenesis and HRAS oncogene induced skin carcinogenesis. Cells from these mice show proliferative defects and selective disruption of signalling from certain growth factors to PI 3-kinase, while the mice also display delayed development of the lymphatic vasculature. The interaction of RAS with p110a is thus required in vivo for some normal growth factor signalling and also for RAS-driven tumour formation. RAS family members were among the first oncogenes identified over 40 years ago. In the late 1960s, the rat-derived Harvey and Kirsten murine sarcoma retroviruses were discovered and subsequently shown to promote cancer formation through related oncogenes, termed RAS (from rat sarcoma virus). The central role of RAS proteins in human cancer is highlighted by the large number of tumours in which they are activated by mutation: approximately 20% of human cancers carry a mutation in RAS proteins. Because of the complex signalling network in which RAS operates, with multiple activators and effectors, each with a different pattern of tissue-specific expression and a distinct set of intracellular functions, one of the critical issues concerns the specific role of each effector in RAS-driven oncogenesis. In this chapter, we summarize current knowledge about how RAS regulates one of its best-known effectors, phosphoinositide 3-kinase (PI3K).

PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context

“…Finally it is possible that there exists a direct molecular mechanism linking p110β to Pten. In any case, an activated allele of Kras would be expected to directly engage p110α (18)(19)(20)41) providing a new "accelerating" signal in the PK tumors.…”

Ras Activation Induces Expression of Raet1 Family NK Receptor Ligands

“…In accordance, we found that growth factor-activated and mutant RAS can induce NKG2D ligand expression. Ras induces several effector pathways including RAF-MAPK/MEK, PI3K, and RALGDS pathways (18). A role for RAF-and PI3K-initiated pathways was suggested by the finding that NKG2D ligand upregulation in response to H-RasV12 expression was abrogated by PI3K and MAPK/MEK inhibitors.…”

“…Ras activates multiple downstream pathways, including RAF, PI3K, and RAL GTPase pathways (18). The RAF family members, A-RAF, B-RAF, and C-RAF, are intermediate molecules in the MAPK/MEK pathway.…”

“…Ras is a membraneassociated GTP-binding protein that is activated by many growth factor receptors and plays a role in many cellular functions, including proliferation, apoptosis, and migration (16,17). When bound to GTP, Ras interacts with effector proteins, thereby activating a number of signaling pathways, including the Raf-MAPK/ MEK, RalGDS, and PI3K pathway (18,19). Oncogenic mutations in Ras genes often impair their hydrolytic GTP function and lock Ras in a perpetual "on" state (16).…”

The Helicase HAGE Expressed by Malignant Melanoma-Initiating Cells Is Required for Tumor Cell Proliferation in Vivo

“…RAS oncoproteins mediate their functions by activating, among others, the PI3K/AKT and RAF/MEK/ERK pathways through a series of phosphorylation cascades, resulting in AKT and ERK phosphorylation, subsequently leading to their activation (24,36,41). The phosphorylated forms of AKT and ERK were consistently and markedly decreased upon HAGE knockdown, suggesting a role for HAGE in activating those signaling pathways by regulating NRAS protein expression.…”