The Importance of Being PI3K in the RAS Signaling Network

Abstract

Ras proteins are essential mediators of a multitude of cellular processes, and its deregulation is frequently associated with cancer appearance, progression, and metastasis. Ras-driven cancers are usually aggressive and difficult to treat. Although the recent Food and Drug Administration (FDA) approval of the first Ras G12C inhibitor is an important milestone, only a small percentage of patients will benefit from it. A better understanding of the context in which Ras operates in different tumor types and the outcomes mediated by each effector pathway may help to identify additional strategies and targets to treat Ras-driven tumors. Evidence emerging in recent years suggests that both oncogenic Ras signaling in tumor cells and non-oncogenic Ras signaling in stromal cells play an essential role in cancer. PI3K is one of the main Ras effectors, regulating important cellular processes such as cell viability or resistance to therapy or angiogenesis upon oncogenic Ras activation. In this review, we will summarize recent advances in the understanding of Ras-dependent activation of PI3K both in physiological conditions and cancer, with a focus on how this signaling pathway contributes to the formation of a tumor stroma that promotes tumor cell proliferation, migration, and spread.

Keywords: PI3-Kinase; Ras oncogenes.

Figure 1

Ras effector pathways. GTP binding to Ras induces changes in protein conformation that increases Ras affinity for downstream effectors, thus activating many different signal transduction pathways. Among them, Raf/MEK/ERK, PI3K/AKT, and Ral are the best understood. Further, Ras crosslinks with other signaling pathways such as proteins from the Rho family and YAP. Through the regulation of the different downstream pathways, Ras proteins play a key role in the control of proliferation, survival, metastasis, apoptosis, migration, angiogenesis, and endocytosis.

Figure 2

Mechanisms of activation of PI3K and downstream effectors. GCPRs and RTKs are upstream signals that control PI3K activation through direct interaction with the regulatory subunit of PI3K. Further, RTK can activate PI3K indirectly through Ras activation that in turn activates PI3K in a p110-dependent manner. Once activated, PI3K generates PIP₃ that promotes AKT phosphorylation, which subsequently phosphorylates a large number of downstream targets to control cell survival, proliferation and apoptosis. Other PI3K effectors are TEC family tyrosine kinase, such as BTK, and GTPases of the Rho/Rac/cdc42 family. Activation of PI3K-AKT pathway is an important mechanism in the development of resistance to chemotherapy (through protection of drug-induced apoptosis [79]) and radiotherapy (through repair of radiation-induced DSBs [80,81]).

Figure 3

PI3K activation. Under unstimulated conditions, interactions between the regulatory and the catalytic subunit keep PI3Ks in the inactive state. The nSH2 and iSH2 (coiled portion) domains of p85 are the minimal fragment of the regulatory subunit required for full inhibition of p110α lipid kinase activity. In PI3K activation by RTKs, binding of p85 to phosphorylated RTKs disrupts the inhibitory contact between the regulatory and the catalytic subunit, which generates conformational changes in p110α for substrate catalysis. In PI3K activation by Ras, the interaction of Ras with p110 displaces nSH2 and iSH2 in p85 from the p110α subunit, facilitating the full activation of PI3Kα.