Abstract
The PI3K–AKT–mTOR signal transduction pathway regulates a variety of biological processes including cell growth, cell cycle progression and proliferation, cellular metabolism, and cytoskeleton reorganization. Fine-tuning of the phosphatidylinositol 3-kinase (PI3K) pathway signaling output is essential for the maintenance of tissue homeostasis and uncontrolled activation of this cascade leads to a number of human pathologies including cancer. Inactivation of the tumor suppressor phosphatase and tensin homologue deleted on Chromosome 10 (PTEN) and/or activating mutations in the proto-typical lipid kinase PI3K have emerged as some of the most frequent events associated with human cancer and as a result the PI3K pathway has become a highly sought-after target for cancer therapies. In this review we summarize the essential role of the PTEN–PI3K axis in controlling cellular behaviors by modulating activation of key proto-oncogenic molecular nodes and functional targets. Further, we highlight important functional redundancies and peculiarities of these two critical enzymes that over the last few decades have become a central part of the cancer research field and have instructed hundreds of pre-clinical and clinical trials to better cancer treatments.
Highlights
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, MA 02215, USA
All p110-isoforms contribute to class IA phosphatidylinositol 3-kinase (PI3K) signaling but the p110α-encoding gene, PIK3CA, is the only isoform frequently mutated in cancer [2,3]
Receptor tyrosine kinases (RTKs) and G-protein coupled receptors (GPCRs) activate PI3K which catalyzes the phosphorylation of the lipid substrate phosphatidylinositol (4,5)-bisphosphate (PIP2) to generate phosphatidylinositol (3,4,5)-trisphosphate (PIP3) [4]
Summary
The phosphatidylinositol 3-kinase (PI3K) is the upstream lipid kinase of the PI3K–AKT–mTOR signal transduction pathway. PDK1 directly phosphorylates and activates AKT on Thr 308 which, in turn, can engage and activate over 100 reported effector targets including the glycogen synthase kinase 3 (GSK3), the Forkhead Box O (FoxO) proteins, and the mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1), controlling multiple pro-survival cellular processes [5,6]. Because of its essential role in controlling multiple pro-survival processes, activation of the PI3K signal is tightly modulated by negative regulators that act by ensuring the timely inhibition of the pathway and by preventing excessive growth. PTEN and PI3K define a key functional axis that in a coordinated fashion modulates the activation status of multiple proto-oncogenic signals that can be scavenged during tumorigenesis and are frequently exploited by cancerous cells for survival
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