AKT/PKB Signaling: Navigating Downstream
Abstract
The serine/threonine kinase Akt, also known as protein kinase B (PKB), is a central node in cell signaling downstream of growth factors, cytokines, and other cellular stimuli. Aberrant loss or gain of Akt activation underlies the pathophysiological properties of a variety of complex diseases, including type-2 diabetes and cancer. Here, we review the molecular properties of Akt and the approaches used to characterize its true cellular targets. In addition, we discuss those Akt substrates that are most likely to contribute to the diverse cellular roles of Akt, which include cell survival, growth, proliferation, angiogenesis, metabolism, and migration.
The serine/threonine kinase Akt/PKB has emerged as a critical signaling node within all cells of higher eukaryotes and as one of the most important and versatile protein kinases at the core of human physiology and disease. Since its discovery as an oncogene within the mouse leukemia virus AKT8 (Bellacosa et al., 1991; Staal, 1987) and as a homolog of protein kinase C (Jones et al., 1991), there have been many exciting breakthroughs elucidating the mechanism of upstream regulation of Akt (summarized in Figure 1). Several excellent recent reviews have covered the molecular details of Akt regulation and its role in human disease (such as Bellacosa et al., 2005; Engelman et al., 2006). Here, we focus on signaling downstream of Akt, with an emphasis on direct phosphorylation targets of the kinase and its bona fide cellular functions.
Also depicted is the complex relationship between Akt signaling and mTOR. Activated receptor tyrosine kinases (RTKs) activate class I phosphatidylinositol 3-kinase (PI3K) through direct binding or through tyrosine phosphorylation of scaffolding adaptors, such as IRS1, which then bind and activate PI3K. PI3K phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3), in a reaction that can be reversed by the PIP3 phosphatase PTEN. AKT and PDK1 bind to PIP3 at the plasma membrane, and PDK1 phosphorylates the activation loop of AKT at T308. RTK signaling also activates mTOR complex 2 (mTORC2) through a currently unknown mechanism, and mTORC2 phosphorylates Akt on the hydrophobic motif S473, which can be dephosphorylated by the S473 phosphatase PHLPP. Akt activates mTOR complex 1 (mTORC1) through multisite phosphorylation of TSC2 within the TSC1-TSC2 complex, and this blocks the ability of TSC2 to act as a GTPase-activating protein (GAP) for Rheb, thereby allowing Rheb-GTP to accumulate. Rheb-GTP activates mTORC1, which phosphorylates downstream targets such as 4E-BP1 and the hydrophobic motif on the S6 kinases (S6Ks; T389 on S6K1). PDK1 phosphorylates the activation loop on the S6Ks (T229 on S6K1) in a reaction independent of PDK1 binding to PIP3. Akt can also activate mTORC1 by phosphorylating PRAS40, thereby relieving the PRAS40-mediated inhibition of mTORC1. Once active, both mTORC1 and S6K can phosphorylate serine residues on IRS1, which targets IRS1 for degradation, and this serves as a negative feedback mechanism to attenuate PI3K-Akt signaling. See text for references to recent reviews detailing Akt regulation and mTOR signaling.
Footnotes
Supplemental Data include one table and can be found with this article online at http://www.cell.com/cgi/content/full/129/7/1261/DC1/.