The Role of PI3K in Met Driven Cancer: A Recap

Abstract

The Receptor Tyrosine Kinase (RTK) Met, overexpressed or mutated in cancer, plays a major role in cancer progression and represents an attractive target for cancer therapy. However RTK inhibitors can lead to drug resistance, explaining the necessity to develop therapies that target downstream signaling. Phosphatidylinositide 3-kinase (PI3K) is one of the most deregulated pathways in cancer and implicated in various types of cancer. PI3K signaling is also a major signaling pathway downstream of RTK, including Met. PI3K major effectors include Akt and "mechanistic Target of Rapamycin" (mTOR), which each play key roles in numerous and various cell functions. Advancements made due to the development of molecular and pharmaceutical tools now allow us to delve into the roles of each independently. In this review, we summarize the current understanding we possess of the activation and role of PI3K/Akt/mTOR, downstream of Met, in cancer.

Keywords: Akt; Met; PI3K; cancer; mTOR; signaling.

Figure 1

PI3K activation by Met. (A) Table of PI3K isoforms and classes. Height PI3K isoforms divided into three classes depending on their lipid substrate, their catalytic subunit and their regulatory subunit. (B) Met, directly or indirectly, through adaptors, scaffolding molecules or other downstream signaling molecules, regulates class I PI3K activation. Dashed line: not demonstrated downstream of Met. Ptdlns(4,5)P2, phosphatidylinositol-4,5-bisphosphate; Ptdlns, phosphatidylinositol; Ptdlns4P, phosphatidylinositoi-4-phosphate; HGF, hepatocyte growth factor; PI3K, p110-p85; Grb2, growth factor receptor bound protein 2; She, Sarcoma (SRC) homology-2-containing; Gab1, Grb2-associated binding protein 1; SHP2, Src homology domain-containing 5′ inositol phosphatase 2; p120, p120-ras-GTPase activating protein; SOS, son of sevenless; FAK, focal adhesion kinase.

Figure 2

PI3K signaling activated by Met. Summary of Met/PI3K class I downstream signaling, that regulates migration, proliferation, apoptosis, protein translation and cell growth. Dashed line: not demonstrated downstream of Met. HGF, hepatocyte growth factor; PI3K, phosphatidylinositol 3-kinase; GTP, guanosine triphosphate; GSK3 beta, glycogen synthase kinase 3 beta; BAD, Bcl-2 antagonist of cell death; MDM2, mouse double minute 2 homolog; mTOR, mechanistic target of rapamycin; eiF, eukaryotic translation initiation factor; 4E-BP1, 4E–binding protein 1; FLIP, FLICE-like inhibitory protein; casp, caspase 3/8.