The serine/threonine kinase Akt is an effector of PI3K-generated phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P3] and is a principle mediator of growth factor-induced signal transduction. Akt is activated through phosphorylation by specific kinases, and its activity is reduced directly by phosphorylation-site-specific phosphatases. In addition, Akt activity is effectively reduced by the action of phosphatases which dephosphorylate PI(3,4,5)P3, thereby reducing the levels of the essential lipid activators of PDK1 and Akt. The functions of Akt are pleiotropic and include regulation of cellular proliferation, differentiation, protein synthesis, and survival. Akt stimulates protein synthesis through actions on mTOR/p70S6K, and promotes survival by phosphorylating and inactivating pro-apoptotic molecules such as Ask1, Bad, Bax, and FoxO3a. Furthermore, loss of Akt decreases the intracellular ATP:AMP ratio, thus establishing a role for Akt in energy regulation. Three isoforms of Akt have been identified, and although redundant functions between isoforms exist, recent investigations have enumerated unique functions for each. Therefore, targeting specific Akt isozymes in a tissue- and context-specific fashion may lead to a greater understanding of Akt-mediated processes.
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Current perspectives on akt akt-ivation and akt-ions. / Matheny, Ronald W.; Adamo, Martin L.In: Experimental Biology and Medicine, Vol. 234, No. 11, 11.2009, p. 1264-1270.
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TY - JOUR
T1 - Current perspectives on akt akt-ivation and akt-ions
AU - Matheny, Ronald W.
AU - Adamo, Martin L.
N1 - Funding Information: Much has been learned about Akt regulation and function since it was first discovered, yet much still remains to be elucidated. For instance, what elements control intracellular localization of Akt? Akt activation depends on proximity to PI( 3 , 4 )P2 and PI( 3 , 4 , 5 )P3 in cell membranes and it is important to define those factors within the cell that are responsible for membrane recruitment. Interaction of the PH domain with phosphoinositide lipids is essential for activation, but identification of the processes and molecules involved in executing this specifically targeted relocation is of importance. It then follows that the location of Akt in unstimulated cells is of interest in order to define movement patterns of Akt after stimuli. Defining intracellular localization also extends to isoform-specific locations within the cell, as well as isoform-specific activation in response to stimuli. What are the determining factors that contribute to activation of Akt isoforms in response to growth factors? Why is one isoform preferentially activated over another? One answer may be that Akt isoforms are expressed at different levels in a given cell-type. If availability of one isoform is greater than another, then it may be a matter of proximity to membrane-located signaling complexes. For example, if Akt1 is the most highly expressed Akt isoform in a cell, then it would logically follow that there would be more Akt1 available for recruitment to membranes than Akt2 or Akt3. It is also possible that inactive Akt may be localized to specific intracellular compartments or areas within the cell, possibly near the membrane, that contain increased densities of a particular isoform. In addition to activation of Akt, it is important to further characterize existing known phosphatases as well as to discover new methods to de-activate the enzyme. The identification of isoform-specific de-phosphorylation of Akt by PHLPP1 and PHLPP2 was a groundbreaking discovery, and further research in defining the mechanisms of action and regulation of these two phosphatases is warranted. An exciting and promising line of research involves the development of Akt isoform-specific small molecule inhibitors. Some inhibitors exert their effects by preventing Akt from being activated due to changes in ternary structure. For instance, an Akt-specific inhibitor commonly referred to as “Akti-1/2” has recently been developed that can bind to the PH domain and/or hinge region on Akt1 or Akt2 thereby preventing activation ( 76 ). This inhibitor can also bind to activated Akt and inhibit phosphorylation of substrates. However, Akti-1/2 can also inhibit Akt3 in 3T3-L1 adipocytes and L6 myotubes ( 77 ), as well as in C2C12 myoblasts (Matheny and Adamo, unpublished observations) at micromolar concentrations. Although Akti-1/2 is not specific for Akt isoforms in some cell lines at specific concentrations, this compound still possesses great potential under conditions where all three Akt isoforms can act in a redundant manner. In any case, intense research in the development of Akt isoform-specific inhibitory compounds is ongoing ( 78 ). In conclusion, Akt is at the crossroads of a number of intracellular pathways and is a key signaling intermediate in growth and survival. Much has been learned thus far with respect to regulation and signaling of Akt, yet much remains to be discovered; specifically, the localization of Akt isoforms in response to various stimuli in different tissues, as well as isoform-specific actions of Akt on target substrates. Figure 1. Comparison of human Akt isoform domain structures. Three isoforms of Akt exist in man that share approximately 80% amino acid sequence homology. Additionally, an alternative splice variant of Akt3 with a truncated hydrophobic domain (designated “Akt3-(γ1)” in this figure) has been identified (see text). All Akt isoforms possess an N-terminal PH domain responsible for phospholipid binding that is tethered to a catalytic region containing a threonine residue (T308 in Akt1) critical for activation of the enzyme. A C-terminal hydrophobic domain (designated “HD” in this figure) follows the catalytic domain and contains a serine residue (S473 in Akt1) important for full activation. Phosphorylation of a threonine residue in the turn motif (T450 in Akt1) by mTORC2 contributes to stability of the molecule. Numbers to the immediate left of the images designate the first amino acid, and numbers to the immediate right of the images represent the number of the most C-terminal residue as determined by comparative sequence analysis. A color version of this figure is available in the online journal. Figure 2. Regulation of Akt activation. Tyrosine kinase growth factor receptor - induced activation of Akt is initiated upon growth factor (GF) ligand binding to its cognate receptor. Recruitment of PI3K (p85 regulatory subunit complexed with p110 catalytic subunit) to the receptor at the membrane occurs after binding of adaptor molecules, including IRS docking proteins, to the intracellular subunits of receptors. PI3K, in close proximity to PI(4,5)P2 (PIP 2 ) then phosphorylates the D3 position of the inositol ring generating PI(3,4,5)P3 (PIP 3 ). PIP 3 then recruits PH-domain-containing molecules including PDK1 and Akt to the lipid bilayer (Akt recruitment not shown for clarity), allowing for binding to PIP 3 , and phosphorylation of Akt at the A-loop (T308 in Akt1) by PDK1. Reconversion of PIP 3 to PIP 2 is promoted by PTEN, which reduces available PIP 3 for PDK1 and Akt binding, thus terminating growth factor signals. Phosphorylation of Akt at the HD (S473 in Akt1) occurs through the actions of the mTORC2 complex, which contains Rictor, SIN1, and mTOR. Activated Akt can then act on substrates in the cytosol to promote survival, growth and energy homeostasis, or translocate to the nucleus and phosphorylate target molecules such as FoxO3a. A color version of this figure is available in the online journal. This work was supported by NIA grant R01AG026012 to MLA. RWM was supported by pre-doctoral award from NIA training grant T32 AG021890-08. 1 Staal SP, Hartley JW, Rowe WP. Isolation of transforming murine leukemia viruses from mice with a high incidence of spontaneous lymphoma. Proc Natl Acad Sci U S A 74 : 3065 –3067, 1977 . 2 Staal SP. Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Proc Natl Acad Sci U S A 84 : 5034 –5037, 1987 . 3 Vanhaesebroeck B, Waterfield MD. 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PY - 2009/11
Y1 - 2009/11
N2 - The serine/threonine kinase Akt is an effector of PI3K-generated phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P3] and is a principle mediator of growth factor-induced signal transduction. Akt is activated through phosphorylation by specific kinases, and its activity is reduced directly by phosphorylation-site-specific phosphatases. In addition, Akt activity is effectively reduced by the action of phosphatases which dephosphorylate PI(3,4,5)P3, thereby reducing the levels of the essential lipid activators of PDK1 and Akt. The functions of Akt are pleiotropic and include regulation of cellular proliferation, differentiation, protein synthesis, and survival. Akt stimulates protein synthesis through actions on mTOR/p70S6K, and promotes survival by phosphorylating and inactivating pro-apoptotic molecules such as Ask1, Bad, Bax, and FoxO3a. Furthermore, loss of Akt decreases the intracellular ATP:AMP ratio, thus establishing a role for Akt in energy regulation. Three isoforms of Akt have been identified, and although redundant functions between isoforms exist, recent investigations have enumerated unique functions for each. Therefore, targeting specific Akt isozymes in a tissue- and context-specific fashion may lead to a greater understanding of Akt-mediated processes.
AB - The serine/threonine kinase Akt is an effector of PI3K-generated phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P3] and is a principle mediator of growth factor-induced signal transduction. Akt is activated through phosphorylation by specific kinases, and its activity is reduced directly by phosphorylation-site-specific phosphatases. In addition, Akt activity is effectively reduced by the action of phosphatases which dephosphorylate PI(3,4,5)P3, thereby reducing the levels of the essential lipid activators of PDK1 and Akt. The functions of Akt are pleiotropic and include regulation of cellular proliferation, differentiation, protein synthesis, and survival. Akt stimulates protein synthesis through actions on mTOR/p70S6K, and promotes survival by phosphorylating and inactivating pro-apoptotic molecules such as Ask1, Bad, Bax, and FoxO3a. Furthermore, loss of Akt decreases the intracellular ATP:AMP ratio, thus establishing a role for Akt in energy regulation. Three isoforms of Akt have been identified, and although redundant functions between isoforms exist, recent investigations have enumerated unique functions for each. Therefore, targeting specific Akt isozymes in a tissue- and context-specific fashion may lead to a greater understanding of Akt-mediated processes.
KW - Akt
KW - Apoptosis
KW - Growth
UR - http://www.scopus.com/inward/record.url?scp=70350560575&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70350560575&partnerID=8YFLogxK
U2 - 10.3181/0904-MR-138
DO - 10.3181/0904-MR-138
M3 - Short survey
C2 - 19596822
AN - SCOPUS:70350560575
VL - 234
SP - 1264
EP - 1270
JO - Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N. Y.)
JF - Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N. Y.)
SN - 1535-3702
IS - 11