Pathway Description:

Since its initial discovery as a proto-oncogene, the serine/threonine kinase Akt (also known as protein kinase B or PKB) has become a major focus of attention because of its critical role in regulating diverse cellular functions including metabolism, growth, proliferation, survival, transcription and protein synthesis. The Akt signaling cascade is activated by receptor tyrosine kinases, integrins, B and T cell receptors, cytokine receptors, G-protein-coupled receptors and other stimuli that induce production of phospha- tidylinositol (3,4,5) trisphosphates (PIP3) by phosphoinositide 3-kinase (PI3K). These lipids serve as plasma membrane docking sites for proteins that harbor pleckstrin-homol- ogy (PH) domains, including Akt and its upstream activator PDK1. At the membrane PDK1 phosphorylates Akt at Thr308 leading to partial activation of Akt. Phosphorylation of Akt at Ser473 by mTORC2 stimulates full enzymatic activity. Members of the PI3K-related kinase (PIKK) family, including DNA-PK, can also phosphorylate Akt at Ser473. Akt is dephosphorylated by protein phosphatase 2A (PP2A) and the PH-domain leucine-rich-repeat-containing protein phosphatases (PHLPP1/2). In addition, the tumor suppres- sor phosphatase and tensin homolog (PTEN) inhibits Akt activity by dephosphorylating PIP3.

Dysregulation of the PI3K/Akt pathway is implicated in a number of human diseases including cancer, diabetes, cardiovascular disease and neurological diseases. In cancer, two mutations that increase the intrinsic kinase activity of PI3K have been identified. In addition, PTEN is frequently mutated or lost in human tumors. Activating mutations in Akt have also been described. The frequency with which dysregulated Akt signaling contributes to human disease has culminated in the aggressive development of small molecule inhibitors of PI3K and Akt.

There are three highly related isoforms of Akt (Akt1, Akt2 and Akt3), which phosphorylate substrates containing the consensus phosphorylation motif RxRxxS/T. Akt isoforms share many substrates but isoform-specific Akt substrates have also been identified. For example, all Akt isoforms are able to phosphorylate PRAS40 (proline-rich Akt sub- strate of 40 kDa) but only Akt1 can phosphorylate the actin-associated protein palladin.

Akt regulates cell growth through its effects on the TSC1/TSC2 complex and mTORC signaling. Akt contributes to cell proliferation via phosphorylation of the CDK inhibitors p21 and p27. Akt is a major mediator of cell survival through direct inhibition of pro-apoptotic proteins like Bad or inhibition of pro-apoptotic signals generated by transcription factors like FoxO. Akt is critically involved in the regulation of metabolism through activation of AS160 and PFKFB2. In addition, Akt has been shown to regulate proteins involved in neuronal function including the GABA receptor, ataxin-1 and huntingtin proteins. Akt contributes to cell migration and invasion via phosphorylation of palladin and vimentin. Akt also regulates NF-κB signaling by phosphorylating IKKα and Tpl2. Due to the critical role of Akt/PKB in regulating diverse cellular functions it is an important therapeutic target for the treatment of human disease.