PI3K: A Crucial Piece in the RAS Signaling Puzzle

Abstract

RAS proteins are key signaling switches essential for control of proliferation, differentiation, and survival of eukaryotic cells. RAS proteins are mutated in 30% of human cancers. In addition, mutations in upstream or downstream signaling components also contribute to oncogenic activation of the pathway. RAS proteins exert their functions through activation of several signaling pathways and dissecting the contributions of these effectors in normal cells and in cancer is an ongoing challenge. In this review, we summarize our current knowledge about how RAS regulates type I phosphatidylinositol 3-kinase (PI3K), one of the main RAS effectors. RAS signaling through PI3K is necessary for normal lymphatic vasculature development and for RAS-induced transformation in vitro and in vivo, especially in lung cancer, where it is essential for tumor initiation and necessary for tumor maintenance.

Figure 1.

RAS activation/deactivation cycle by guanine nucleotide exchange factors (GEFs) and guanosine triphosphate (GTP)ase-activating proteins (GAPs). RAS proteins cycle between an inactive (guanosine diphosphate [GDP]-bound) and an active (GTP-bound) state. After receptor tyrosine kinase (RTK) engagement, RAS are activated by GEFs, which stimulate the exchange of GDP for GTP, and inactivated by GAPs that bind to RAS and stimulate its intrinsic GTPase activity.

Figure 2.

RAS effector pathways. Once activated, RAS proteins signal through multiple effector pathways, thus activating many different signal transduction pathways, such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K). The RAS signaling network gets more complex because PI3K is also directly activated by receptor tyrosine kinases (RTKs) or G protein–coupled receptors (GPCRs). Besides, there are several points in which the MAPK and PI3K pathways cross talk, leading to either activation or inhibition at different levels. Raf can be inhibited by PI3K in different situations. PI3K pathway can also be activated or inhibited by Raf under certain conditions. Another level of connection of these two pathways involves target of rapamycin complex 1 (mTORC1) and insulin receptor substrate 1 (IRS1). When these proteins get inhibited, a feedback signal through RTKs is initiated that activates MAPK in a RAS-dependent manner, thus provoking extracellular signal-regulated kinase (ERK) and AKT phosphorylation and activation of both pathways. PTEN, Phosphatase and tensin homolog; PDK1, PI3K-dependent kinase 1; MEK1/2, mitogen-activated protein kinases 1 and 2.