AKT/PKB signaling: navigating downstream. Cell

Department of Genetics and Complex Diseases, Harvard School of Public Health, SPH2-117, Boston, MA 02115, USA.
Cell (Impact Factor: 32.24). 07/2007; 129(7):1261-74. DOI: 10.1016/j.cell.2007.06.009
Source: PubMed

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.

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    • "There are a number of factors that contribute to these complex processes in multicellular organisms, and alterations in such critical pathways can be embryonically lethal or may cause phenotypically recognizable diseases. One of the critical pathways controlling cell growth and proliferation during development is the PI3K–AKT–mTOR pathway (Figure 1; Manning and Cantley, 2007; Laplante and Sabatini, 2012; Vanhaesebroeck et al., 2012). This complex intracellular pathway entails phosphatidylinositol-3 kinase (PI3K), which is activated in response to cell surface tyrosine kinase receptor-ligand binding, and subsequently converts phosphatidylinositol (4, 5)-bisphosphate (PIP2) through phosphorylation to phosphatidylinositol (3, 4, 5)-triphosphate (PIP3; Figure 1; Whitman et al., 1988; Ruderman et al., 1990; Hawkins et al., 1992). "
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    ABSTRACT: A number of critical signaling pathways are required for homeostatic regulation of cell survival, differentiation, and proliferation during organogenesis. One of them is the PI3K–AKT–mTOR pathway consisting of a cascade of inhibitor/activator molecules. Recently, a number of heritable diseases with skin involvement, manifesting particularly with tissue overgrowth, have been shown to result from mutations in the genes in the PI3K–AKT–mTOR and interacting intracellular pathways. Many of these conditions represent an overlapping spectrum of phenotypic manifestations forming a basis for novel, unifying classifications. Identification of the mutant genes and specific mutations in these patients has implications for diagnostics and genetic counseling and provides a rational basis for the development of novel treatment modalities for this currently intractable group of disorders.
    Journal of Investigative Dermatology 09/2015; DOI:10.1038/jid.2015.331. · 7.22 Impact Factor
    • "Multiple growth factor receptors expressed at the PM share the ability to initiate a signal transduction cascade involving Class I PI3K that impinges on the activation of AKT1 (Manning and Cantley, 2007). Active AKT1 phosphorylates many substrates including TSC2, eventually resulting in the derepression of MTORC1 (Manning and Cantley, 2007), and BECN1, favoring its sequestration by 14-3-3ε (Wang et al., 2012). Moreover, growth factor signaling is required for the normal expression of various glucose transporters, including (but not limited to) solute carrier family 2 (facilitated glucose transporter), member 1 (SLC2A1, best known as GLUT1), and SLC2A4 (best known as GLUT4) (Leto and Saltiel, 2012). "
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    ABSTRACT: Autophagy constitutes a prominent mechanism through which eukaryotic cells preserve homeostasis in baseline conditions and in response to perturbations of the intracellular or extracellular microenvironment. Autophagic responses can be relatively non-selective or target a specific subcellular compartment. At least in part, this depends on the balance between the availability of autophagic substrates ("offer") and the cellular need of autophagic products or functions for adaptation ("demand"). Irrespective of cargo specificity, adaptive autophagy relies on a panel of sensors that detect potentially dangerous cues and convert them into signals that are ultimately relayed to the autophagic machinery. Here, we summarize the molecular systems through which specific subcellular compartments-including the nucleus, mitochondria, plasma membrane, reticular apparatus, and cytosol-convert homeostatic perturbations into an increased offer of autophagic substrates or an accrued cellular demand for autophagic products or functions. Copyright © 2015 Elsevier Inc. All rights reserved.
    Molecular cell 08/2015; 59(4):522-539. DOI:10.1016/j.molcel.2015.07.021 · 14.02 Impact Factor
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    • "Akt is involved in the PI3K/Akt/mTOR pathway. Following growth factor stimulation, activated PI3Ks catalyze the conversion of PIP 2 to PIP 3 , which directs the translocation of Akt to the plasma membrane (Woodgett, 2005; Manning and Cantley, 2007). At the membrane, T308 of Akt1 undergoes phosphorylation by PDK1. "
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    ABSTRACT: Kinases use ATP to phosphorylate substrates; recent findings underscore the additional regulatory roles of ATP. Here, we propose a mechanism for allosteric regulation of Akt1 kinase phosphorylation by ATP. Our 4.7-μs molecular dynamics simulations of Akt1 and its mutants in the ATP/ADP bound/unbound states revealed that ATP occupancy of the ATP-binding site stabilizes the closed conformation, allosterically protecting pT308 by restraining phosphatase access and key interconnected residues on the ATP→pT308 allosteric pathway. Following ATP→ADP hydrolysis, pT308 is exposed and readily dephosphorylated. Site-directed mutagenesis validated these predictions and indicated that the mutations do not impair PDK1 and PP2A phosphatase recruitment. We further probed the function of residues around pT308 at the atomic level, and predicted and experimentally confirmed that Akt1(H194R/R273H) double mutant rescues pathology-related Akt1(R273H). Analysis of classical Akt homologs suggests that this mechanism can provide a general model of allosteric kinase regulation by ATP; as such, it offers a potential avenue for allosteric drug discovery. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Structure 08/2015; 23(9). DOI:10.1016/j.str.2015.06.027 · 5.62 Impact Factor
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