PI 3‐Kinase signaling: A journey in three AKTs

Abstract

The PI 3‐kinase (PI3K) and AKT signaling pathway plays a critical role in regulating all aspects of normal cellular physiology, and is also frequently deregulated in human pathophysiologies, most evidently in cancer and diabetes. Growth factors and hormones stimulate PI3K leading to the biosynthesis of the lipid‐derived second messenger PIP3. In turn, PIP3 elicits the membrane recruitment of the protein kinase AKT, originally discovered in 1987 by Staal and colleagues as v‐Akt, a transforming oncogene. In the early 1990s, three independent groups cloned and described the cellular homolog c‐AKT, a serine/threonine protein kinase with a high degree of homology to other AGC family protein kinases. In the ensuing three decades, the mechanisms by which AKT transduces signals to cell growth, proliferation, motility and metabolism were uncovered. Three AKT isoforms exist in humans encoded by distinct genes (AKT1, AKT2, AKT3), and although originally thought to function redundantly, many studies have shown that AKT isoforms have non‐overlapping and unique roles in both normal physiology and disease. Similarly, genetic lesions in the PI3K and AKT oncogenes have been described, and many of the genes that contribute to PI3K/AKT pathway activation and also signal termination have been found to be altered in human cancers. Numerous drugs that inhibit PI3K as well AKT have been developed for therapeutic use in patients, and many of these are being evaluated in late‐stage clinical trials. During the lecture, I will highlight the major advances in PI3K and AKT field over the past 30 years, with a focus on mechanistic insight into this ubiquitous lipid signaling pathway. Genetic lesions in the PI3K/AKT pathway in human cancers will also be discussed, as well as efforts to target this pathway therapeutically. The second part of the lecture will focus on recent efforts in our laboratory to uncover novel mechanisms of AKT signaling and biology, with an emphasis on breast cancer and with a focus on metabolic reprogramming mediated by AKT. I will also present recent efforts aimed at targeting AKT with novel therapies, including degrader technologies and how these have illuminated novel aspects of AKT biology. I will conclude with some personal thoughts and future perspectives as to where the field is going, gaps in knowledge and what studying AKT for 30 years has taught me.