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. Author manuscript; available in PMC: 2010 Dec 6.
Published in final edited form as: Cell Cycle. 2009 Aug 23;8(16):2502–2508. doi: 10.4161/cc.8.16.9335

The Akt kinases: isoform specificity in metabolism and cancer

Eva Gonzalez 1, Timothy E McGraw 1,*
PMCID: PMC2997486  NIHMSID: NIHMS254555  PMID: 19597332

Abstract

The Akt (PKB) protein kinases are critical regulators of human physiology that control an impressive array of diverse cellular functions, including the modulation of growth, survival, proliferation and metabolism. The Akt kinase family is comprised of three highly homologous isoforms: Akt1 (PKBα), Akt2 (PKBβ) and Akt3 (PKBγ). Phenotypic analyses of Akt isoform knockout mice documented Akt isoform specific functions in the regulation of cellular growth, glucose homeostasis and neuronal development. Those studies establish that the functions of the different Akt kinases are not completely overlapping and that isoform-specific signaling contributes to the diversity of Akt activities. However, despite these important advances, a thorough understanding about the specific roles of Akt family members and the molecular mechanisms that determine Akt isoform functional specificity will be essential to elucidate the complexity of Akt regulated cellular processes and how Akt isoform-specific deregulation might contribute to disease states. Here, we summarize recent advances in understanding the roles of Akt isoforms in the regulation of metabolism and cancer, and possible mechanisms contributing to Akt isoform functional specificity.

Keywords: Akt, isoforms, metabolism, cancer, glucose homeostasis, GLUT4, signaling specificity, cellular growth, Akt1, Akt2

Akt activation by extracellular stimuli

The serine/threonine protein kinase Akt is one of the most versatile kinases in the human kinome. Work from numerous laboratories over the last 10 years has elucidated the basic mechanisms underlying the activation of the Akt kinase and has identified a number of substrates that mediate Akt action (for review see references1, 2). Akt activity is modulated downstream of phosphatidylinositol 3 (PI3) kinase in response to extracellular stimuli following a multistep process (Fig 1A). Akt, by virtue of an amino-terminal pleckstrin homology (PH) domain, is recruited to sites of the plasma membrane containing increased PI(3,4,5)P3 or PI(3,4)P2 produced by PI3-kinase. Once recruited to the plasma membrane, Akt is phosphorylated at two sites, one within the T-loop of the catalytic domain (Thr308, Akt1 residue) by the phosphoinositide-dependent kinase 1 (PDK1) and within the carboxyl terminal hydrophobic domain (Ser473, Akt1 residue) by the mammalian target of rapamycin complex 2 (mTORC2)3, 4. Targeting of Akt to the plasma membrane, independent of external stimuli (or PI3 kinase activity), results in Akt activation, strongly suggesting that activation is limited predominantly by recruitment to the plasma membrane rather than the direct modulation of PDK1 and/or mTORC2 activities. Akt is transiently localized to the plasma membrane during activation 5, 6 and once activated, Akt phosphorylates substrates distributed throughout the cell to regulate multiple cellular functions (Fig 1A)(see reference 2 for review).

Figure 1.

Figure 1

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Regulation of Akt signaling. A. Growth factor-mediated Akt activation. In response to numerous growth factors and cytokines Akt is activated downstream of PI3-kinase following a multistep mechanism. Activated PI3-kinase converts PIP2 into PIP3 providing sites of recruitment at the plasma membrane of proteins containing PH domains, including Akt and PDK1 kinases. Upon translocation to the plasma membrane Akt is phosphorylated by PDK1 within the catalytic domain and mTORC2 within the hydrophobic motif, which renders Akt catalytically active. Activated Akt, trough the phosphorylation of numerous downstream targets located throughout the cell, regulates a wide array of cellular functions. B. Overlapping and specific functions of the Akt family members. Summarized are common and distinct Akt isoform functions elucidated from the phenotypic analysis of single and double Akt isoform knockout mice. C. Potential mechanisms dictating Akt isoform functional specificity.

Akt isoform-specific signaling

Akt kinases control an array of diverse functions including cell growth, survival, proliferation and metabolism, and one critical unresolved question is how Akt activity is specified to discrete cellular functions in response to extracellular stimulus. Recent studies of Akt isoform-specific knockout mice suggest that Akt signaling diversity might in part be due to different functions of the three Akt family members Akt1, Akt2 and Akt3 7 (Fig 1B). Akt1 knockout mice are smaller than their wild-type counterparts and Akt1-null cells display higher rates of apoptosis, indicating a critical role for Akt1 in cell survival 8, 9. Akt2 knockout mice develop a type 2 diabetes-like phenotype, and cells derived from those mice show impaired glucose utilization 9, 10, suggesting a central role for Akt2 in the maintenance of glucose homeostasis. A role for Akt3 in brain development has been proposed based on the fact that Akt3 knockout mice display impaired brain development11. Although those data strongly support the hypothesis that different cellular processes are primarily under the control of the different Akt isoforms, phenotypic analyses of double Akt isoform knockout mice reveal some overlap (or compensation) among the isoforms. Simultaneous deletion of Akt1 and Akt2 causes lethality shortly after birth 12, Akt1 and Akt3 double knockout mice are embryonic lethal 13, whereas mice with a single functional allele of Akt1 (Akt1+/−Akt2−/−Akt3−/−) are viable despite reduced body weight and insulin and glucose intolerance 14. All together, these studies provide genetic evidence for overlapping as well as specific roles of the Akt family members. Further studies of Akt isoform conditional and tissue specific knockout mice, as well as in vitro studies of Akt isoform function in different cell types will be required to develop a complete and integrated understanding of the spectrum of common and isoform specific roles of Akt kinases.

The striking observation that despite their high homology, Akt isoforms regulate distinct physiological functions leads to the critical question of how Akt isoform-specific signaling is achieved. A priori, different mechanisms could dictate or contribute to Akt isoform function distinctions (Fig 1C). Those modes of regulation might include:

  1. Distinct tissue distribution of the Akt isoforms.

  2. Differential activation of the Akt isoforms by extracellular stimuli (that is, cues like the amplitude or timing of PI3 kinase activity triggered by different stimuli could be translated into differential activation/regulation of the Akt isoforms).

  3. Distinct intrinsic catalytic activity of the Akt isoforms to phosphorylate substrates.

  4. Cell context-specific factors. Examples of this mode of regulation include isoform specific subcellular compartmentalization that determines access to substrates and/or specific adaptor proteins that confer specificity to substrate selection.

Elucidating the individual and combinatorial contributions of these mechanisms to Akt isoform functional specificity will be required to understand the complexity of Akt-mediated signaling and to facilitate the development of therapeutic approaches directed to interfere with Akt isoform-specific functions. Akt signaling is at the center of growth and metabolic control, and alterations of Akt signaling are underlying causes of two of the most prominent diseases in developed countries, cancer and type 2 diabetes. Here we focus on these disease models to summarize some of the recent advances and remaining challenges regarding the roles and regulation of Akt isoform-specific signaling.

Akt isoform-specific signaling in metabolism

To date, the regulation of glucose homeostasis is one of the best-characterized Akt-mediated processes with strong isoform specificity. Insulin regulates whole body glucose homeostasis by inducing the uptake of glucose into muscle and fat cells and by inhibiting hepatic glucose output, both of which are under the regulation of Akt signaling 15. To regulate glucose disposal insulin-induces the redistribution of the GLUT4 glucose transporter from intracellular compartments to the plasma membrane of fat and muscle cells 16. The increase in plasma membrane GLUT4 promotes increased flux of glucose into those cells in a concentration dependent manner. As noted above, targeted deletion of Akt2 in mice, but not Akt1 or Akt3, results in fasting hyperglycemia, hyperinsulinimia, glucose intolerance and impaired glucose uptake by fat and muscle cells 10, 17. Consistent with a requirement for Akt2 in control of glucose metabolism, a mutation in the catalytic domain of Akt2 causes severe insulin resistance and diabetes in humans 18. In vitro studies showed that transient siRNA-mediated down-regulation of Akt2 inhibits insulin-induced GLUT4 translocation to the plasma membrane of 3T3-L1 adipocytes 19–21, suggesting that impaired glucose transport in Akt2-null adipocytes is at least in part explained by defective regulation of GLUT4 trafficking in those cells.

How is this Akt2 isoform signaling specificity achieved?

Two of the most likely mechanisms, tissue-specific isoform expression and isoform-specific activation, do not account for the selective requirement for Akt2 in the control of GLUT4 trafficking to the plasma membrane. Overexpression of Akt1 in Akt2-deficient brown fat adipocytes did not rescue the impairment in insulin-mediated glucose transport 22 nor does over-expression of Akt1 rescue defects in GLUT4 translocation to the plasma membrane of adipocytes induced by siRNA knockdown of Akt2 21. Those findings strongly argue that the distinct functional role for Akt1 and Akt2 in the regulation of glucose transport in fat cells is not determined by selective expression of Akt isoforms. Insulin activates both Akt1 and Akt2 in 3T3-L1 and primary rat adipocytes 21, 23, demonstrating that the failure of Akt1 to regulate GLUT4 translocation to the plasma membrane is not due to differential activation of the Akt isoforms by insulin. Thus, differences in Akt isoform-specific regulation of glucose transport in fat cells are determined post Akt activation, at the step of substrate selection/phosphorylation.

How is this substrate selectivity achieved?

One possibility is that Akt isoform substrate specificity is determined by cell context-specific factors. For example, isoform-specific subcellular compartmentalization could determine access to substrates. The first hints that differential localization might have a role in controlling isoform specific signaling were provided by biochemical fractionation of adipocytes in which Akt2 but not Akt1 was found associated with GLUT4 vesicles 24, 25. Recent studies in intact cells provide compelling evidence that differences in subcellular localization are primary in determining Akt2-specific control of GLUT4 trafficking in fat cells (Fig 2). Using fluorescence reporters and total internal reflection fluorescence microscopy, we have observed that insulin induces a preferential accumulation of Akt2, relative to Akt1, at the plasma membrane of adipocytes. Changes that reduce the accumulation of the Akt2 kinase domain at the plasma membrane of insulin-stimulated adipocytes without affecting kinase activation, interrupted signaling to GLUT4, indicating that the selectivity is not intrinsic to the Akt2 kinase domain 21. These data suggest that the greater accumulation of Akt2 at the plasma membrane is a contributing factor to isoform – specific signaling to GLUT4. In support of that hypothesis, expression of an Akt1 mutant with enhanced plasma membrane association, Akt1E17K 26, was sufficient to induce GLUT4 translocation and overcome Akt isoform specificity in the regulation of GLUT4 trafficking 21. These findings document that Akt1 can regulate substrates involved in GLUT4 translocation when it accumulates at the plasma membrane to a similar degree as Akt2, and thereby establish that stimulus-controlled differences in subcellular localization of Akt isoforms contribute to Akt isoform-specific signaling. Importantly, aberrant Akt subcellular localization, such as this caused by the E17K point mutation, can confer Akt2-like signaling to Akt1 resulting in the loss of isoform-specific signaling. These conclusions are in agreement with previous work in which Akt1 engineered to be constitutively targeted to membranes via addition of a myristoyl group 27 was shown to induce GLUT4 translocation.

Figure 2.

Figure 2

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Akt2 signaling specificity in insulin-mediated glucose uptake. Insulin binding to the insulin receptor at the surface of adipocytes leads the activation and the autophosphorylation of the receptor, followed by recruitment and phosphorylation of insulin receptor substrate proteins (IRS). Phosphorylated IRS create docking sites for the recruitment of PI3-kinase which converts PIP2 into PIP3, providing sites for the recruitment of Akt kinases to the plasma membrane. Both Akt1 and Akt2 translocate to the plasma membrane in response to PI3-kinase activation and both kinases are activated by phosphorylation trough PDK1 and the mTORC2. Using Akt1 and Akt2 reporters and total internal reflection fluorescence (TIRF) microscopy we found that upon insulin stimulation Akt2 accumulates at the plasma membrane environment (TIRF zone) to a larger degree than Akt1. This distinct subcellular distribution facilitates Akt2 phosphorylation and inactivation of the Rab GAP AS160 possibly located on GLUT4 containing vesicles. Inactivation of AS160 allows the subsequent docking and fusion of GLUT4 vesicles with the plasma, and consequently the entrance of glucose into the cells.

The increased accumulation of Akt2 at the plasma membrane correlates with Akt2-specific substrate selection/phosphorylation. The best characterized downstream effector of Akt required for regulation of GLUT4 trafficking to the plasma membrane is the RabGAP AS160 (also known as TBCD1D4) 28–30. Phosphorylation by Akt leads to inhibition of the AS160 GAP activity towards Rab proteins, including Rab8, Rab10, and Rab14 31. The subsequent activation of these Rab proteins facilitates the translocation of GLUT4 to the plasma membrane of adipocytes and muscle cells 32, 33. siRNA-mediated Akt isoform specific down-regulation revealed a preferential role for Akt2 in the phosphorylation of AS160 in response to insulin, both in adipocytes 21 and muscle cells 34. Furthermore, Akt2 but not Akt1 localizes at the plasma membrane with AS160, indicating that this might be the site of AS160 regulation by Akt2 in insulin-stimulated cells 21.

The requirement for Akt activity at the plasma membrane to regulate glucose transport is consistent with previous studies that proposed a role for Akt in the regulation of the late stages of GLUT4 vesicle exocytosis, including the docking and fusion of GLUT4 vesicles with the plasma membrane 35–37. Although AS160 is the best characterized Akt substrate involved in GLUT4 trafficking, the phosphorylation of at least two other substrates believed to have roles in GLUT4 trafficking, Myosin Va and the syntaxin interacting protein Synip, have also been linked specifically to Akt2 38 39.

The molecular determinants of Akt2 preferential accumulation at the plasma membrane have not been elucidated. Akt plasma membrane targeting is mediated through interactions of its PH domain with PI(3,4,5)P3 and PI(3,4)P2 generated by PI3kinase. However, exchange of Akt1 PH domain by that of Akt2, does not confer Akt1 enhanced plasma membrane association, documenting that distinct insulin-induced Akt2 plasma membrane accumulation does not rely solely on Akt2 PH domain 21. It is possible that differences in post-translational modifications in the Akt isoforms might contribute to the differences in compartmentalization. This type of regulation contributes to the discrete subcellular localization and functional specificity of the Ras isoforms and members of the Src family of kinases 40, 41. However, to date Akt isoform-specific posttranslational modifications have not been described.

A growing number of proteins that interact with and regulate Akt function are being described (for review see references 42, 43). However, Akt isoform specific binding partners that regulate subcellular location and substrate recognition are almost unknown. Schenck and colleagues 44 reported that Akt interaction with the Rab5 effector APPL1 regulates the activity of Akt and its downstream signaling specificity from an endosomal compartment with implications in vertebrate development. Interestingly, APPL1 interacts with Akt2 in unstimulated adipocytes, and down-regulation of APPL1 in adipocytes impairs insulin-induced GLUT4 translocation and glucose transport, indicating that APPL1 might facilitate Akt2 signaling to GLUT4 45. However, whether APPL1 also regulates Akt1-mediated signaling in adipocytes and muscle cells, and the mechanism by which APPL1 regulates Akt2-mediated GLUT4 translocation are unknown. Recently Ding and colleagues identified ClipR-59, a member of the Clip-170 family, as a scaffolding protein that interacts with Akt and stabilizes it at the plasma membrane of insulin-stimulated adipocytes 46. ClipR-59 preferentially binds to Akt2, and down-regulation of ClipR-59 impairs insulin-induced GLUT4 translocation and Akt-mediated phosphorylation of AS160. These studies, together with our recent observations underscore the role of insulin-mediated Akt2 plasma membrane accumulation in GLUT4 regulation and suggest ClipR-59 as a putative regulator of Akt isoform functional specificity in insulin-regulated glucose uptake.

These recent studies have started to uncover the molecular mechanisms that determine Akt isoform signaling specificity in the regulation of glucose homeostasis. The availability of cell-lines derived from mice lacking individual Akt isoforms, combined with the use of siRNA, proteomics, mass spectrometry and live-cell fluorescence microscopy techniques will facilitate the identification of Akt isoform-specific binding partners and signaling networks that regulate Akt-isoform signaling diversity in glucose homeostasis. Whether these modes of regulation will also function in non-insulin responsive cells or in response to other physiological stimulus will also need to be addressed. Due to the intricate relationship between insulin-responsive tissues in the maintenance of glucose homeostasis, the future development of tissue specific Akt isoform knock-ins and knock-outs will also be required to evaluate the contribution of Akt isoform signaling in different tissues to the systemic regulation of glucose homeostasis and insulin sensitivity.

Akt isoform-specific signaling in cancer

Akt is one of most frequently hyperactivated kinases in human cancers 47, which perhaps is not unexpected considering that Akt modulates cell proliferation, survival, intermediate metabolism, growth, invasiveness and angiogenesis, all of which are hallmarks of cancer. Interestingly, there is evidence for hyperactivation of specific Akt isoforms in certain tumors, suggesting that in some cases there is Akt isoform-specificity to cell transformation. Aberrant activation of Akt can occur by different mechanisms including amplifications, overexpression, mutations in Akt genes, and/or alterations in Akt upstream regulators 48, and as briefly discussed below, there are examples of all these modes of Akt hyperactivation in tumors.

Activation of specific Akt isoforms in cancer

The Akts are produced from three distinct genes and therefore one mechanism for isoform-specific increased expression is gene amplification. AKT2 gene amplification has been reported in ovarian and pancreatic cancers 49, 50, AKT1 amplification has been reported in gastric cancers 51, and AKT3 amplification in melanoma 52. Overexpression of specific Akt isoforms independent of gene amplification has also been found to differ among different cancers. For example, Akt2 has been found to be upregulated in hepatocellular carcinomas and colorectal cancers 53, 54, Akt1 in breast cancers 55 and Akt3 mRNA has been shown to be upregulated in estrogen receptor-negative breast tumors 56 and melanoma 52. Recently, a somatic activating mutation in Akt1 PH domain was identified in human ovarian, breast and colorectal cancers, in that study no changes in Akt2 or Akt3 were found 26; however an equivalent mutation in Akt3 has recently been described in human melanoma cancers 57. The correlation between specific tumors and the hyperactivation of specific Akt isoforms raises the possibility that Akt isoform-specific signaling might contribute to the development of certain tumors; however, additional studies are required to test this hypothesis.

Akt activity can also be altered by changes in upstream regulatory proteins. Examples include hyperactivation of the PIK3CA gene (which encodes a catalytic subunit of PI3-kinase), loss/down regulation of phosphatase and tensin homolog (PTEN, a lipid phosphatase that counteracts PI3-kinase activity), up-regulation of growth factor receptors or activation of Ras. These changes would/should result in activation of all three Akt isoforms, therefore it is unknown whether they will translate to different contributions of the Akt isoforms to tumorigenesis. Interestingly, it has recently been shown that deficiency of Akt1 is sufficient to inhibit endometrial and prostate neoplasia in PTEN+/− mice 58, suggesting a predominant role of Akt1 in these cancers. Whether a similar Akt isoform dependency exists in PI3-kinase and/or Ras induced tumors is largely unknown.

How could differential activation of Akt isoforms contribute to tumorigenesis?

Although our understanding of the distinct roles of Akt isoforms in tumor formation, development and invasiveness is still limited, several studies have begun to address the differential roles for Akt1 and Akt2 in the regulation of cell cycle progression and cell migration. A series of recent studies provide compelling evidence for isoform-specific functions of Akt kinases in the regulation of cell migration (reviewed in reference59). In vivo and in vitro studies support that Akt1 attenuates while Akt2 enhances cancer cell migration. On the contrary Akt1 specifically promotes migration of non-transformed cells in certain cellular contexts 60, indicating that isoform specific regulation of cellular migration exist both in transformed and non-transformed cells although it might be dictated by distinct mechanisms. Several mechanisms have been proposed for Akt1-mediated inhibition of cancer cell migration including negative regulation of the extracellular-signal regulated kinase pathway 61, the tumor suppressor tuberous sclerosis complex 2 (TCS2) 62 and the nuclear factor of activated T cells (NFAT) a pro-migratory and pro-invasive transcription factor in breast cells 63. Akt1 down-regulation also caused phenotypic changes characteristic of an epithelial-mesenchymal transition in IGF-IR stimulated breast cancer cells, a phenotype inhibited by down-regulation of Akt2 61. Contrary to Akt1, overexpression of Akt2 promoted adhesion and invasion in eight human breast cancer cell lines that correlated with upregulation of β1 integrins 64.

Studies of transgenic mice further support Akt isoform-specific roles in tumor development and metastasis. Coordinated overexpression of activated Akt1 and ErbB-2 in the mammary gland of transgenic mice accelerated the appearance of multifocal mammary tumors and decreased the incidence of metastatic lesions compared to tumors initiated by ErbB-2 alone 65. Interestingly, coexpression of Akt2 with activated ErbB-2 in the mammary gland did not affect the latency of tumor development, but markedly increased the incidence of pulmonary metastases 66. Consistent with those findings, ablation of Akt1 delayed mammary adenocarcinoma induction by polyoma middle T (PyMT) and Neu transgenes in mice, while ablation of Akt2 accelerates this process 67.

Apart from differences in cell migration, a differential role for Akt isoforms in cell cycle control has also been reported. Silencing Akt1 but not Akt2, in non-transformed mammalian cells results in reduction of cyclin A levels and S-phase entry, while over expression of Akt2 hindered cell cycle progression in M-G1 with increased nuclear p21 68. Analysis of Akt isoform function in early stages of oncogenesis showed that the number of mammary epithelial cells expressing cyclin D1 in PyMT/Akt1−/−mice is lower than in the wild type mice, while PyMT/Akt2−/−mice revealed a higher number of cyclin D1– expressing cellsin lesions than PyMT/wild type mice 67. This work reveals differences in the regulation of the cell cycle progression by the Akt isoforms both in non-transformed and transformed mammalian cells.

Together these studies strongly suggest distinct functions of the Akt family members in the regulation of cell cycle progression, migration and invasion that might translate into differential roles in the modulation of tumor development and metastasis. Although the molecular mechanisms dictating Akt isoform specificity in these settings are largely unknown, some of the mechanisms identified in other cellular contexts, such as the regulation of glucose transport, could potentially be applied in these Akt-regulated processes. Investigating how these modes of regulation contribute to Akt isoform specific signaling in cell growth, survival and migration, and their relevance in distinct types of tumors would provide the basis to understand the pluripotent role of Akt kinases in human tumorigenesis and determine how Akt inhibitors could be used most efficiently to treat human cancer.

Akt signaling in the metabolic reprogramming of cancer cells

Although the regulation of metabolism and cancer by the Akt kinases are very active areas of study, we still have a very limited understanding about the integration of these two processes by the Akt family members. High proliferating rates characteristic of cancer cells require the efficient conversion of nutrients into biomass. Indeed it is known for many years that cancer cells display a distinct intermediate metabolism from most normal tissues, favoring glycolysis and the production of high concentrations of lactate versus metabolizing glucose to carbon dioxide in the mitochondrial tricarboxylic acid (TCA) cycle as most differentiated cells. Although aerobic glycolysis is less efficient in terms of ATP production than oxidative phosphorylation, it provides cancer cells with an advantage in terms of production of ribose-5 phosphate, acetyl-CoA and NADPH required for macromolecular synthesis (reviewed in reference 69).

Akt signaling is at the crossroads of growth control and glucose metabolism. Akt regulates protein and long chain fatty acid synthesis via modulation of mTOR 70 and fatty acid synthase 71 respectively. The role of Akt in the modulation of glucose uptake into insulin-responsive tissues has been discussed above, however non-insulin responsive tissues also rely on Akt activity for glucose uptake and utilization. Growth factor-mediated Akt activation induces increased expression of the glucose transporter GLUT1 as well as an increase of GLUT1 in the plasma membrane 72, 73. Both of these changes promote enhanced glucose flux into the cells. Akt also increases metabolism of glucose by modulating hexokinase association with mitochondria, thereby increasing the efficiency of glucose-6-phosphate production, and Akt stimulates phosphofructokinase activity increasing glycolysis 74, 75. As a consequence, alterations in the PI3-kinase/Akt pathway leading to enhanced Akt activity correlate with the high glycolytic rates characteristic of cancer cells 76, 77. Due to this metabolic reprogramming, glucose withdrawal induces cell death in a manner similar to that of growth factor withdrawal 78. Indeed, glucose uptake by tumors containing mutations in PIK3CA is inhibited by small molecule inhibitors of PI3-kinase and mTOR, and correlates with tumor regression 79, documenting the role of the PI3-kinase/Akt signaling pathway in the control of glucose metabolism in cancer cells.

The role of the distinct Akt family members in the “glucose addiction” of cancer cells is an exciting and largely unexplored area of study. Although specific functions for these kinases might exist, it is also possible that under deregulation of Akt signaling, as in the presence of activating mutations of PI3-kinase or loss of PTEN, Akt isoform functional specificity might also be lost. Indeed, our recent data suggest that overexpression of Akt1E17K, an Akt mutant with enhanced plasma membrane association identified in human cancers, is sufficient to induce GLUT4 translocation to the plasma membrane of adipocytes, a process that is under specific regulation of Akt2 21.. Therefore, even if Akt isoforms have a distinct contribution to the regulation of glucose metabolism in “non-insulin responsive cells”, that specificity could be overridden by oncogenic mutations. Indeed, oncogenic transformation has been described by overexpression of all 3 myristoylated Akt isoforms 80. Consequently, it is tempting to speculate that the loss of Akt isoform functional restrictions might further contribute to cellular transformation. The current effort to develop small molecule Akt inhibitors with high potency, improved pharmacokinetics, and isoform selectivity will certainly help to answer these questions.

Perspectives

The development of Akt isoform-specific null mice has proven a functional diversity within the Akt family of kinases in physiology and disease. Work over the last few years has begun to dissect specific roles of these kinases; however, we still have a limited knowledge about the cellular and molecular mechanisms that determine Akt isoform functional specificity. Exploring the contribution of differential expression patterns, substrate specificity, binding partners and subcellular localization to Akt functional specificity through the combination of genetic models, proteomics and live cell microscopy will be required in order to define Akt isoform specific regulatory and signaling networks. A challenge ahead is to understand how/if deregulation of specific Akt isoforms contributes to the development of disease such as cancer and type 2 diabetes. The answers to these questions will provide the basis for the development of efficient and selective pharmacological interventions of Akt function in disease states without globally perturbing the cellular functions modulated by Akt signaling.

Acknowledgments

We thank members of the McGraw laboratory for critical reading of our manuscript. We apologize to all those colleagues whose contributions could not be mentioned due to space limitations. TEM is funded by NIH grants RO1 DK52852, DK069982 and Robert Pollock and Ahn-Tuyet Nguyen Charitable Trust. EG is a recipient of an American Heart Association postdoctoral fellowship.

References

  • 1.Hanada M, Feng J, Hemmings BA. Structure, regulation and function of PKB/AKT--a major therapeutic target. Biochim Biophys Acta. 2004;1697:3–16. doi: 10.1016/j.bbapap.2003.11.009. [DOI] [PubMed] [Google Scholar]
  • 2.Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261–74. doi: 10.1016/j.cell.2007.06.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol. 1997;7:261–9. doi: 10.1016/s0960-9822(06)00122-9. [DOI] [PubMed] [Google Scholar]
  • 4.Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307:1098–101. doi: 10.1126/science.1106148. [DOI] [PubMed] [Google Scholar]
  • 5.Bellacosa A, Chan TO, Ahmed NN, Datta K, Malstrom S, Stokoe D, et al. Akt activation by growth factors is a multiple-step process: the role of the PH domain. Oncogene. 1998;17:313–25. doi: 10.1038/sj.onc.1201947. [DOI] [PubMed] [Google Scholar]
  • 6.Ananthanarayanan B, Ni Q, Zhang J. Signal propagation from membrane messengers to nuclear effectors revealed by reporters of phosphoinositide dynamics and Akt activity. Proc Natl Acad Sci U S A. 2005;102:15081–6. doi: 10.1073/pnas.0502889102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Dummler B, Hemmings BA. Physiological roles of PKB/Akt isoforms in development and disease. Biochem Soc Trans. 2007;35:231–5. doi: 10.1042/BST0350231. [DOI] [PubMed] [Google Scholar]
  • 8.Chen WS, Xu PZ, Gottlob K, Chen ML, Sokol K, Shiyanova T, et al. Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene. Genes Dev. 2001;15:2203–8. doi: 10.1101/gad.913901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Cho H, Thorvaldsen JL, Chu Q, Feng F, Birnbaum MJ. Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem. 2001;276:38349–52. doi: 10.1074/jbc.C100462200. [DOI] [PubMed] [Google Scholar]
  • 10.Garofalo RS, Orena SJ, Rafidi K, Torchia AJ, Stock JL, Hildebrandt AL, et al. Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. J Clin Invest. 2003;112:197–208. doi: 10.1172/JCI16885. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Tschopp O, Yang ZZ, Brodbeck D, Dummler BA, Hemmings-Mieszczak M, Watanabe T, et al. Essential role of protein kinase B gamma (PKB gamma/Akt3) in postnatal brain development but not in glucose homeostasis. Development. 2005;132:2943–54. doi: 10.1242/dev.01864. [DOI] [PubMed] [Google Scholar]
  • 12.Peng XD, Xu PZ, Chen ML, Hahn-Windgassen A, Skeen J, Jacobs J, et al. Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2. Genes Dev. 2003;17:1352–65. doi: 10.1101/gad.1089403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Yang ZZ, Tschopp O, Di-Poi N, Bruder E, Baudry A, Dummler B, et al. Dosage-dependent effects of Akt1/protein kinase Balpha (PKBalpha) and Akt3/PKBgamma on thymus, skin, and cardiovascular and nervous system development in mice. Mol Cell Biol. 2005;25:10407–18. doi: 10.1128/MCB.25.23.10407-10418.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Dummler B, Tschopp O, Hynx D, Yang ZZ, Dirnhofer S, Hemmings BA. Life with a single isoform of Akt: mice lacking Akt2 and Akt3 are viable but display impaired glucose homeostasis and growth deficiencies. Mol Cell Biol. 2006;26:8042–51. doi: 10.1128/MCB.00722-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Whiteman EL, Cho H, Birnbaum MJ. Role of Akt/protein kinase B in metabolism. Trends Endocrinol Metab. 2002;13:444–51. doi: 10.1016/s1043-2760(02)00662-8. [DOI] [PubMed] [Google Scholar]
  • 16.Huang S, Czech MP. The GLUT4 glucose transporter. Cell Metab. 2007;5:237–52. doi: 10.1016/j.cmet.2007.03.006. [DOI] [PubMed] [Google Scholar]
  • 17.Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw EB, 3rd, et al. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta) Science. 2001;292:1728–31. doi: 10.1126/science.292.5522.1728. [DOI] [PubMed] [Google Scholar]
  • 18.George S, Rochford JJ, Wolfrum C, Gray SL, Schinner S, Wilson JC, et al. A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science. 2004;304:1325–8. doi: 10.1126/science.1096706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Jiang ZY, Zhou QL, Coleman KA, Chouinard M, Boese Q, Czech MP. Insulin signaling through Akt/protein kinase B analyzed by small interfering RNA-mediated gene silencing. Proc Natl Acad Sci U S A. 2003;100:7569–74. doi: 10.1073/pnas.1332633100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Katome T, Obata T, Matsushima R, Masuyama N, Cantley LC, Gotoh Y, et al. Use of RNA interference-mediated gene silencing and adenoviral overexpression to elucidate the roles of AKT/protein kinase B isoforms in insulin actions. J Biol Chem. 2003;278:28312–23. doi: 10.1074/jbc.M302094200. [DOI] [PubMed] [Google Scholar]
  • 21.Gonzalez E, McGraw TE. Insulin-modulated Akt subcellular localization determines Akt isoform-specific signaling. Proc Natl Acad Sci U S A. 2009;106:7004–9. doi: 10.1073/pnas.0901933106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Bae SS, Cho H, Mu J, Birnbaum MJ. Isoform-specific regulation of insulin-dependent glucose uptake by Akt/protein kinase B. J Biol Chem. 2003;278:49530–6. doi: 10.1074/jbc.M306782200. [DOI] [PubMed] [Google Scholar]
  • 23.Kim YB, Peroni OD, Franke TF, Kahn BB. Divergent regulation of Akt1 and Akt2 isoforms in insulin target tissues of obese Zucker rats. Diabetes. 2000;49:847–56. doi: 10.2337/diabetes.49.5.847. [DOI] [PubMed] [Google Scholar]
  • 24.Calera MR, Martinez C, Liu H, Jack AK, Birnbaum MJ, Pilch PF. Insulin increases the association of Akt-2 with Glut4-containing vesicles. J Biol Chem. 1998;273:7201–4. doi: 10.1074/jbc.273.13.7201. [DOI] [PubMed] [Google Scholar]
  • 25.Hill MM, Clark SF, Tucker DF, Birnbaum MJ, James DE, Macaulay SL. A role for protein kinase Bbeta/Akt2 in insulin-stimulated GLUT4 translocation in adipocytes. Mol Cell Biol. 1999;19:7771–81. doi: 10.1128/mcb.19.11.7771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature. 2007;448:439–44. doi: 10.1038/nature05933. [DOI] [PubMed] [Google Scholar]
  • 27.Kohn AD, Summers SA, Birnbaum MJ, Roth RA. Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation. J Biol Chem. 1996;271:31372–8. doi: 10.1074/jbc.271.49.31372. [DOI] [PubMed] [Google Scholar]
  • 28.Bruss MD, Arias EB, Lienhard GE, Cartee GD. Increased phosphorylation of Akt substrate of 160 kDa (AS160) in rat skeletal muscle in response to insulin or contractile activity. Diabetes. 2005;54:41–50. doi: 10.2337/diabetes.54.1.41. [DOI] [PubMed] [Google Scholar]
  • 29.Sano H, Kane S, Sano E, Miinea CP, Asara JM, Lane WS, et al. Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J Biol Chem. 2003;278:14599–602. doi: 10.1074/jbc.C300063200. [DOI] [PubMed] [Google Scholar]
  • 30.Eguez L, Lee A, Chavez JA, Miinea CP, Kane S, Lienhard GE, et al. Full intracellular retention of GLUT4 requires AS160 Rab GTPase activating protein. Cell Metab. 2005;2:263–72. doi: 10.1016/j.cmet.2005.09.005. [DOI] [PubMed] [Google Scholar]
  • 31.Miinea CP, Sano H, Kane S, Sano E, Fukuda M, Peranen J, et al. AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain. Biochem J. 2005;391:87–93. doi: 10.1042/BJ20050887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Sano H, Eguez L, Teruel MN, Fukuda M, Chuang TD, Chavez JA, et al. Rab10, a target of the AS160 Rab GAP, is required for insulin-stimulated translocation of GLUT4 to the adipocyte plasma membrane. Cell Metab. 2007;5:293–303. doi: 10.1016/j.cmet.2007.03.001. [DOI] [PubMed] [Google Scholar]
  • 33.Ishikura S, Klip A. Muscle cells engage Rab8A and myosin Vb in insulin-dependent GLUT4 translocation. Am J Physiol Cell Physiol. 2008;295:C1016–25. doi: 10.1152/ajpcell.00277.2008. [DOI] [PubMed] [Google Scholar]
  • 34.Bouzakri K, Zachrisson A, Al-Khalili L, Zhang BB, Koistinen HA, Krook A, et al. siRNA-based gene silencing reveals specialized roles of IRS-1/Akt2 and IRS-2/Akt1 in glucose and lipid metabolism in human skeletal muscle. Cell Metab. 2006;4:89–96. doi: 10.1016/j.cmet.2006.04.008. [DOI] [PubMed] [Google Scholar]
  • 35.Huang S, Lifshitz LM, Jones C, Bellve KD, Standley C, Fonseca S, et al. Insulin stimulates membrane fusion and GLUT4 accumulation in clathrin coats on adipocyte plasma membranes. Mol Cell Biol. 2007;27:3456–69. doi: 10.1128/MCB.01719-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Gonzalez E, McGraw TE. Insulin signaling diverges into Akt-dependent and -independent signals to regulate the recruitment/docking and the fusion of GLUT4 vesicles to the plasma membrane. Mol Biol Cell. 2006;17:4484–93. doi: 10.1091/mbc.E06-07-0585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Bai L, Wang Y, Fan J, Chen Y, Ji W, Qu A, et al. Dissecting multiple steps of GLUT4 trafficking and identifying the sites of insulin action. Cell Metab. 2007;5:47–57. doi: 10.1016/j.cmet.2006.11.013. [DOI] [PubMed] [Google Scholar]
  • 38.Yoshizaki T, Imamura T, Babendure JL, Lu JC, Sonoda N, Olefsky JM. Myosin 5a is an insulin-stimulated Akt2 (protein kinase Bbeta) substrate modulating GLUT4 vesicle translocation. Mol Cell Biol. 2007;27:5172–83. doi: 10.1128/MCB.02298-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Yamada E, Okada S, Saito T, Ohshima K, Sato M, Tsuchiya T, et al. Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4-containing vesicles. J Cell Biol. 2005;168:921–8. doi: 10.1083/jcb.200408182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Hancock JF. Ras proteins: different signals from different locations. Nat Rev Mol Cell Biol. 2003;4:373–84. doi: 10.1038/nrm1105. [DOI] [PubMed] [Google Scholar]
  • 41.Resh MD. Palmitoylation of ligands, receptors, and intracellular signaling molecules. Sci STKE. 2006;2006:re14. doi: 10.1126/stke.3592006re14. [DOI] [PubMed] [Google Scholar]
  • 42.Du K, Tsichlis PN. Regulation of the Akt kinase by interacting proteins. Oncogene. 2005;24:7401–9. doi: 10.1038/sj.onc.1209099. [DOI] [PubMed] [Google Scholar]
  • 43.Brazil DP, Park J, Hemmings BA. PKB binding proteins. Getting in on the Akt. Cell. 2002;111:293–303. doi: 10.1016/s0092-8674(02)01083-8. [DOI] [PubMed] [Google Scholar]
  • 44.Schenck A, Goto-Silva L, Collinet C, Rhinn M, Giner A, Habermann B, et al. The endosomal protein Appl1 mediates Akt substrate specificity and cell survival in vertebrate development. Cell. 2008;133:486–97. doi: 10.1016/j.cell.2008.02.044. [DOI] [PubMed] [Google Scholar]
  • 45.Saito T, Jones CC, Huang S, Czech MP, Pilch PF. The interaction of Akt with APPL1 is required for insulin-stimulated Glut4 translocation. J Biol Chem. 2007;282:32280–7. doi: 10.1074/jbc.M704150200. [DOI] [PubMed] [Google Scholar]
  • 46.Ding J, Du K. ClipR-59 interacts with Akt and regulates Akt cellular compartmentalization. Mol Cell Biol. 2009;29:1459–71. doi: 10.1128/MCB.00754-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene. 2005;24:7455–64. doi: 10.1038/sj.onc.1209085. [DOI] [PubMed] [Google Scholar]
  • 48.Bellacosa A, Kumar CC, Di Cristofano A, Testa JR. Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res. 2005;94:29–86. doi: 10.1016/S0065-230X(05)94002-5. [DOI] [PubMed] [Google Scholar]
  • 49.Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK, et al. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci U S A. 1996;93:3636–41. doi: 10.1073/pnas.93.8.3636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Cheng JQ, Godwin AK, Bellacosa A, Taguchi T, Franke TF, Hamilton TC, et al. AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. Proc Natl Acad Sci U S A. 1992;89:9267–71. doi: 10.1073/pnas.89.19.9267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.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. 1987;84:5034–7. doi: 10.1073/pnas.84.14.5034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Stahl JM, Sharma A, Cheung M, Zimmerman M, Cheng JQ, Bosenberg MW, et al. Deregulated Akt3 activity promotes development of malignant melanoma. Cancer Res. 2004;64:7002–10. doi: 10.1158/0008-5472.CAN-04-1399. [DOI] [PubMed] [Google Scholar]
  • 53.Roy HK, Olusola BF, Clemens DL, Karolski WJ, Ratashak A, Lynch HT, et al. AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. Carcinogenesis. 2002;23:201–5. doi: 10.1093/carcin/23.1.201. [DOI] [PubMed] [Google Scholar]
  • 54.Xu X, Sakon M, Nagano H, Hiraoka N, Yamamoto H, Hayashi N, et al. Akt2 expression correlates with prognosis of human hepatocellular carcinoma. Oncol Rep. 2004;11:25–32. [PubMed] [Google Scholar]
  • 55.Stal O, Perez-Tenorio G, Akerberg L, Olsson B, Nordenskjold B, Skoog L, et al. Akt kinases in breast cancer and the results of adjuvant therapy. Breast Cancer Res. 2003;5:R37–44. doi: 10.1186/bcr569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Nakatani K, Thompson DA, Barthel A, Sakaue H, Liu W, Weigel RJ, et al. Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer lines. J Biol Chem. 1999;274:21528–32. doi: 10.1074/jbc.274.31.21528. [DOI] [PubMed] [Google Scholar]
  • 57.Davies MA, Stemke-Hale K, Tellez C, Calderone TL, Deng W, Prieto VG, et al. A novel AKT3 mutation in melanoma tumours and cell lines. Br J Cancer. 2008;99:1265–8. doi: 10.1038/sj.bjc.6604637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Chen ML, Xu PZ, Peng XD, Chen WS, Guzman G, Yang X, et al. The deficiency of Akt1 is sufficient to suppress tumor development in Pten+/- mice. Genes Dev. 2006;20:1569–74. doi: 10.1101/gad.1395006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Stambolic V, Woodgett JR. Functional distinctions of protein kinase B/Akt isoforms defined by their influence on cell migration. Trends Cell Biol. 2006;16:461–6. doi: 10.1016/j.tcb.2006.07.001. [DOI] [PubMed] [Google Scholar]
  • 60.Zhou GL, Tucker DF, Bae SS, Bhatheja K, Birnbaum MJ, Field J. Opposing roles for Akt1 and Akt2 in Rac/Pak signaling and cell migration. J Biol Chem. 2006;281:36443–53. doi: 10.1074/jbc.M600788200. [DOI] [PubMed] [Google Scholar]
  • 61.Irie HY, Pearline RV, Grueneberg D, Hsia M, Ravichandran P, Kothari N, et al. Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition. J Cell Biol. 2005;171:1023–34. doi: 10.1083/jcb.200505087. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Liu H, Radisky DC, Nelson CM, Zhang H, Fata JE, Roth RA, et al. Mechanism of Akt1 inhibition of breast cancer cell invasion reveals a protumorigenic role for TSC2. Proc Natl Acad Sci U S A. 2006;103:4134–9. doi: 10.1073/pnas.0511342103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Yoeli-Lerner M, Yiu GK, Rabinovitz I, Erhardt P, Jauliac S, Toker A. Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT. Mol Cell. 2005;20:539–50. doi: 10.1016/j.molcel.2005.10.033. [DOI] [PubMed] [Google Scholar]
  • 64.Arboleda MJ, Lyons JF, Kabbinavar FF, Bray MR, Snow BE, Ayala R, et al. Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells. Cancer Res. 2003;63:196–206. [PubMed] [Google Scholar]
  • 65.Hutchinson JN, Jin J, Cardiff RD, Woodgett JR, Muller WJ. Activation of Akt-1 (PKB-alpha) can accelerate ErbB-2-mediated mammary tumorigenesis but suppresses tumor invasion. Cancer Res. 2004;64:3171–8. doi: 10.1158/0008-5472.can-03-3465. [DOI] [PubMed] [Google Scholar]
  • 66.Dillon RL, Marcotte R, Hennessy BT, Woodgett JR, Mills GB, Muller WJ. Akt1 and Akt2 Play Distinct Roles in the Initiation and Metastatic Phases of Mammary Tumor Progression. Cancer Res. 2009 doi: 10.1158/0008-5472.CAN-08-4287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Maroulakou IG, Oemler W, Naber SP, Tsichlis PN. Akt1 ablation inhibits, whereas Akt2 ablation accelerates, the development of mammary adenocarcinomas in mouse mammary tumor virus (MMTV)-ErbB2/neu and MMTV-polyoma middle T transgenic mice. Cancer Res. 2007;67:167–77. doi: 10.1158/0008-5472.CAN-06-3782. [DOI] [PubMed] [Google Scholar]
  • 68.Heron-Milhavet L, Franckhauser C, Rana V, Berthenet C, Fisher D, Hemmings BA, et al. Only Akt1 is required for proliferation, while Akt2 promotes cell cycle exit through p21 binding. Mol Cell Biol. 2006;26:8267–80. doi: 10.1128/MCB.00201-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33. doi: 10.1126/science.1160809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Gingras AC, Kennedy SG, O'Leary MA, Sonenberg N, Hay N. 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev. 1998;12:502–13. doi: 10.1101/gad.12.4.502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Wang D, Sul HS. Insulin stimulation of the fatty acid synthase promoter is mediated by the phosphatidylinositol 3-kinase pathway. Involvement of protein kinase B/Akt. J Biol Chem. 1998;273:25420–6. doi: 10.1074/jbc.273.39.25420. [DOI] [PubMed] [Google Scholar]
  • 72.Wofford JA, Wieman HL, Jacobs SR, Zhao Y, Rathmell JC. IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival. Blood. 2008;111:2101–11. doi: 10.1182/blood-2007-06-096297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Wieman HL, Wofford JA, Rathmell JC. Cytokine stimulation promotes glucose uptake via phosphatidylinositol-3 kinase/Akt regulation of Glut1 activity and trafficking. Mol Biol Cell. 2007;18:1437–46. doi: 10.1091/mbc.E06-07-0593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Majewski N, Nogueira V, Bhaskar P, Coy PE, Skeen JE, Gottlob K, et al. Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol Cell. 2004;16:819–30. doi: 10.1016/j.molcel.2004.11.014. [DOI] [PubMed] [Google Scholar]
  • 75.Deprez J, Vertommen D, Alessi DR, Hue L, Rider MH. Phosphorylation and activation of heart 6-phosphofructo-2-kinase by protein kinase B and other protein kinases of the insulin signaling cascades. J Biol Chem. 1997;272:17269–75. doi: 10.1074/jbc.272.28.17269. [DOI] [PubMed] [Google Scholar]
  • 76.Buzzai M, Bauer DE, Jones RG, Deberardinis RJ, Hatzivassiliou G, Elstrom RL, et al. The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid beta-oxidation. Oncogene. 2005;24:4165–73. doi: 10.1038/sj.onc.1208622. [DOI] [PubMed] [Google Scholar]
  • 77.DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008;7:11–20. doi: 10.1016/j.cmet.2007.10.002. [DOI] [PubMed] [Google Scholar]
  • 78.Vander Heiden MG, Plas DR, Rathmell JC, Fox CJ, Harris MH, Thompson CB. Growth factors can influence cell growth and survival through effects on glucose metabolism. Mol Cell Biol. 2001;21:5899–912. doi: 10.1128/MCB.21.17.5899-5912.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med. 2008;14:1351–6. doi: 10.1038/nm.1890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Mende I, Malstrom S, Tsichlis PN, Vogt PK, Aoki M. Oncogenic transformation induced by membrane-targeted Akt2 and Akt3. Oncogene. 2001;20:4419–23. doi: 10.1038/sj.onc.1204486. [DOI] [PubMed] [Google Scholar]

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