AKT/PKB Signaling: Navigating the Network

Abstract

The Ser/Thr kinase AKT, also known as protein kinase B (PKB), was discovered 25 years ago and has been the focus of tens of thousands of studies in diverse fields of biology and medicine. There have been many advances in our knowledge of the upstream regulatory inputs into AKT, key multifunctional downstream signaling nodes (GSK3, FoxO, mTORC1), which greatly expand the functional repertoire of Akt, and the complex circuitry of this dynamically branching and looping signaling network that is ubiquitous to nearly every cell in our body. Mouse and human genetic studies have also revealed physiological roles for the AKT network in nearly every organ system. Our comprehension of AKT regulation and functions is particularly important given the consequences of AKT dysfunction in diverse pathological settings, including developmental and overgrowth syndromes, cancer, cardiovascular disease, insulin resistance and type-2 diabetes, inflammatory and autoimmune disorders, and neurological disorders. There has also been much progress in developing AKT-selective small molecule inhibitors. Improved understanding of the molecular wiring of the AKT signaling network continues to make an impact that cuts across most disciplines of the biomedical sciences.

Myelination and mTOR

“…While deletion of TSC1 or TSC2 in OLs (i.e., mTORC1 hyperactivation, but suppression of PI3K‐Akt) resulted in CNS hypomyelination and OL death (Jiang et al, 2016), expression of constitutively active Akt, or deletion of the PI3K‐Akt inhibitor PTEN (i.e., hyperactivation of both mTORC1 and PI3K‐Akt), caused marked radial hypermyelination (Domenech‐Estevez et al, 2016; Flores et al, 2008; Goebbels et al, 2010). Since Akt can promote cell survival (Manning & Toker, 2017), Akt‐dependent but mTORC1‐independent survival pathways may be required during OL myelination. Inhibition of these pathways upon mTORC1 hyperactivation might contribute to the observed apoptosis of TSC1‐mutant OLs, in addition to ER stress (Jiang et al, 2016).…”

Transcription factor ATF3 mediates the radioresistance of breast cancer

“…Multiple biological processes, such as cell proliferation, cell metabolism and cell survival, are all regulated by Akt 10. The PI3K/Akt signal pathway mediates cell survival by promoting aerobic glycolysis 11.…”

Phosphorylation-Dependent Inhibition of Akt1

“…The pathway regulated by Akt is the most commonly activated signaling pathway in human cancers [3]. Given that more than 50% of human tumors contain hyper-activated Akt [2], effective inhibition of active Akt has the potential to treat several distinct cancers. There are three Akt genes in humans, encoding the isozymes Akt1, Akt2, and Akt3.…”

“…In the PH-out conformation, Akt1 is more susceptible to phosphorylation at Thr308 and Ser473 by PDK1 and mTORC2 respectively. Upon release from PIP3, Akt1 distributes rapidly in the cytosol and translocates to the nucleus to phosphorylate >100 cellular proteins [2,10].…”

“…In human cells, the activation of Akt1 occurs in response to growth factor stimulation ( Figure 1). Following activation by a receptor tyrosine kinase at the plasma membrane, phosphoinositide-3-phosphate kinase (PI3K) phosphorylates its immediate downstream target, a lipid second messenger called phosphatidylinositol-4, 5-bisphosphate (PIP2), converting PIP2 into phosphatidylinositol-3, 4, 5-triphosphate (PIP3) [2]. Membrane anchored PIP3 is a binding site for pleckstrin homology (PH) domain-containing proteins such as Akt1 and one of the upstream kinases that activates Akt1, phosphoinositide dependent kinase 1 (PDK1) [9].…”