Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2007 Jun 29;129(7):1261-74.
doi: 10.1016/j.cell.2007.06.009.

AKT/PKB signaling: navigating downstream

Brendan D Manning  1 , Lewis C Cantley
Affiliations
Review

AKT/PKB signaling: navigating downstream

Brendan D Manning et al. Cell. .

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Upstream Activation of Akt by Growth Factors
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.
Figure 2
Figure 2. Cellular Functions of Ten Akt Substrates
Akt-mediated phosphorylation of these proteins leads to their activation (arrows) or inhibition (blocking arrows). Regulation of these substrates by Akt contributes to activation of the various cellular processes shown (i.e., survival, growth, proliferation, glucose uptake, metabolism, and angiogenesis). As illustrated by these ten targets, a high degree of functional versatility and overlap exists amongst Akt substrates. See text for detailed descriptions of substrates and functions.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Accili D, Arden KC. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell. 2004;117:421–426. - PubMed
    1. Ackah E, Yu J, Zoellner S, Iwakiri Y, Skurk C, Shibata R, Ouchi N, Easton RM, Galasso G, Birnbaum MJ, et al. Akt1/protein kinase Balpha is critical for ischemic and VEGF-mediated angiogenesis. J Clin Invest. 2005;115:2119–2127. - PMC - PubMed
    1. Alessi DR, Andjekovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 1996a;15:6541–6551. - PMC - PubMed
    1. Alessi DR, Caudwell FB, Andejelkovic M, Hemmings BA, Cohen P. Molecular basis for the substrate specificity of protein kinase B; comparison with MAPKAP kinase-1 and p70 S6 kinase. FEBS Lett. 1996b;399:333–338. - PubMed
    1. Andjelkovic M, Alessi D, Meier R, Fernandez A, Lamb NJC, Frech M, Cron P, Cohen P, Lucocq JM, Hemmings BA. Role of translocation in the activation and function of protein kinase B. J Biol Chem. 1997;272:31515–31524. - PubMed

Publication types

MeSH terms

Substances