Akt Isoforms: A Family Affair in Breast Cancer
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Akt, also known as protein kinase B (PKB), belongs to the AGC family of protein kinases. It acts downstream of the phosphatidylinositol 3-kinase (PI3K) and regulates diverse cellular processes, including cell proliferation, cell survival, metabolism, tumor growth and metastasis. The PI3K/Akt signaling pathway is frequently deregulated in breast cancer and plays an important role in the development and progression of breast cancer. There are three closely related members in the Akt family, namely Akt1(PKBα), Akt2(PKBβ) and Akt3(PKBγ). Although Akt isoforms share similar structures, they exhibit redundant, distinct as well as opposite functions. While the Akt signaling pathway is an important target for cancer therapy, an understanding of the isoform-specific function of Akt is critical to effectively target this pathway. However, our perception regarding how Akt isoforms contribute to the genesis and progression of breast cancer changes as we gain new knowledge. The purpose of this review article is to analyze current literatures on distinct functions of Akt isoforms in breast cancer.Keywords:
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Aberrant activation of fundamental cellular processes, such as proliferation, migration and survival, underlies the development of numerous human pathophysiologies, including cancer. One of the most frequently hyperactivated pathways in cancer is the phosphoinositide 3-kinase (PI3K)/Akt signalling cascade. Three isoforms of the serine/threonine protein kinase Akt (Akt1, Akt2 and Akt3) function to regulate cell survival, growth, proliferation and metabolism. Strikingly, non-redundant and even opposing functions of Akt isoforms in the regulation of phenotypes associated with malignancy in humans have been described. However, the mechanisms by which Akt isoform-specificity is conferred are largely unknown. In the present review, we highlight recent findings that have contributed to our understanding of the complexity of Akt isoform-specific signalling and discussed potential mechanisms by which this isoform-specificity is conferred. An understanding of the mechanisms of Akt isoform-specificity has important implications for the development of isoform-specific Akt inhibitors and will be critical to finding novel targets to treat disease.
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PKB (protein kinase B, also known as Akt) is a serine/threonine protein kinase that is important in various signalling cascades and acts as a major signal transducer downstream of activated phosphoinositide 3-kinase. There are three closely related isoforms of PKB in mammalian cells, PKBα (Akt1), PKBβ (Akt2) and PKBγ (Akt3), and this review discusses recent advances in our understanding of the functions of these isoforms in the regulation of adipocyte differentiation, glucose homoeostasis and tumour development.
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Akt, a known serine/threonine-protein kinase B has been revealed to be an imperative protein of the PI3K/Akt pathway. Akt is available in three isoforms, Akt1, Akt2, and Akt3. Ubiquitously expressed Akt1 & Akt2 are essential for cell survival and are believed to be involved in regulating glucose homeostasis. PI3K/Akt pathway has been evidenced to be associated with metabolic diseases viz. hypertension, dyslipidemia, and diabetes. Akt interacting proteins have been revealed to be scaffold proteins of the PI3K/Akt pathway. Notably, some protein-protein interactions are imperative for the inhibition or uncontrolled activation of these signaling pathways. For instance, Akt interacting protein binds with other protein namely, FOXO1 and mTOR, and play a key role in the onset and progression of metabolic syndrome (MS). The purpose of this review is to highlight the role of the PI3K/Akt pathway and associated protein-protein interactions which might serve as a valuable tool for investigators to develop some new promising therapeutic agents in the management of MS.
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The serine/threonine kinase Akt/PKB (protein kinase B) is key for mammalian cell growth, survival, metabolism and oncogenic transformation. The diverse level and tissue expression of its three isoforms, Akt1/PKBα, Akt2/PKBβ and Akt3/PKBγ, make it daunting to identify isoform-specific actions in vivo and even in isolated tissues/cells. To date, isoform-specific knockout and knockdown have been the best strategies to dissect their individual overall functions. In a recent article in the Biochemical Journal, Kajno et al. reported a new strategy to study isoform selectivity in cell lines. Individual Akt/PKB isoforms in 3T3-L1 pre-adipocytes are first silenced via shRNA and stable cellular clones lacking one or the other isoform are selected. The stably silenced isoform is then replaced by a mutant engineered to be refractory to inhibition by MK-2206 (Akt1W80A or Akt2W80A). Akt1W80A or Akt2W80A are functional and effectively recruited to the plasma membrane in response to insulin. The system affords the opportunity to acutely control the activity of the endogenous non-silenced isoform through timely addition of MK-2206. Using this approach, it is confirmed that Akt1/PKBα is the preferred isoform sustaining adipocyte differentiation, but both Akt1/PKBα and Akt2/PKBβ can indistinctly support insulin-dependent FoxO1 (forkhead box O1) nuclear exclusion. Surprisingly, either isoform can also support insulin-dependent glucose transporter (GLUT) 4 translocation to the membrane, in contrast with the preferential role of Akt2/PKBβ assessed by knockdown studies. The new strategy should allow analysis of the plurality of Akt/PKB functions in other cells and in response to other stimuli. It should also be amenable to high-throughput studies to speed up advances in signal transmission by this pivotal kinase.
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Akt/PKB is a serine/threonine protein kinase that functions as a critical regulator of cell survival and proliferation. Akt/PKB family comprises three highly homologous members known as PKBα/Akt1, PKBβ/Akt2 and PKBγ/Akt3 in mammalian cells. Similar to many other protein kinases, Akt/PKB contains a conserved domain structure including a specific PH domain, a central kinase domain and a carboxyl-terminal regulatory domain that mediates the interaction between signaling molecules. Akt/PKB plays important roles in the signaling pathways in response to growth factors and other extracellular stimuli to regulate several cellular functions including nutrient metabolism, cell growth, apoptosis and survival. This review surveys recent developments in understanding the molecular mechanisms of Akt/PKB activation and its roles in cell survival in normal and cancer cells.
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The serine/threonine protein kinase AKT is frequently over-activated in cancer and is associated with poor prognosis. As a central node in the PI3K/AKT/mTOR pathway, which regulates various processes considered to be hallmarks of cancer, this kinase has become a prime target for cancer therapy. However, AKT has proven to be a highly complex target as it comes in three isoforms (AKT1, AKT2 and AKT3) which are highly homologous, yet non-redundant. The isoform-specific functions of the AKT kinases can be dependent on context (i.e. different types of cancer) and even opposed to one another. To date, there is no isoform-specific inhibitor available and no alternative to genetic approaches to study the function of a single AKT isoform. We have developed and characterized nanobodies that specifically interact with the AKT1 or AKT2 isoforms. These new tools should enable future studies of AKT1 and AKT2 isoform-specific functions. Furthermore, for both isoforms we obtained a nanobody that interferes with the AKT-PIP3-interaction, an essential step in the activation of the kinase. The nanobodies characterized in this study are a new stepping stone towards unravelling AKT isoform-specific signalling.
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Abstract Background The serine/threonine protein kinase AKT is frequently over-activated in cancer and is associated with poor prognosis. As a central node in the PI3K/AKT/mTOR pathway, which regulates various processes considered to be hallmarks of cancer, this kinase has become a prime target for cancer therapy. However, AKT has proven to be a highly complex target as it comes in three isoforms (AKT1, AKT2 and AKT3) which are highly homologous, yet non-redundant. The isoform-specific functions of the AKT kinases can be dependent on context (i.e. different types of cancer) and even opposed to one another. To date, there is no isoform-specific inhibitor available and no alternative to genetic approaches to study the function of a single AKT isoform. Results We have developed and characterized nanobodies that specifically interact with the AKT1 or AKT2 isoforms. These new tools should enable future studies of AKT1 and AKT2 isoform-specific functions. Furthermore, for both isoforms we obtained a nanobody that interferes with the AKT-PIP3-interaction, an essential step in the activation of the kinase. Conclusions The nanobodies characterized in this study, which can be expressed in mammalian cells, are a new stepping stone towards unravelling AKT isoform-specific signalling and can lead to the first isoform-specific AKT inhibitor.
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Recent studies indicate that dysregulation of the Akt/PKB family of serine/threonine kinases is a prominent feature of many human cancers. The Akt/PKB family is composed of three members termed Akt1/PKBalpha, Akt2/PKBbeta, and Akt3/PKBgamma. It is currently not known to what extent there is functional overlap between these family members. We have recently identified small molecule inhibitors of Akt. These compounds have pleckstrin homology domain-dependent, isozyme-specific activity. In this report, we present data showing the relative contribution that inhibition of the different isozymes has on the apoptotic response of tumor cells to a variety of chemotherapies. In multiple cell backgrounds, maximal induction of caspase-3 activity is achieved when both Akt1 and Akt2 are inhibited. This induction is not reversed by overexpression of functionally active Akt3. The level of caspase-3 activation achieved under these conditions is equivalent to that observed with the phosphatidylinositol-3-kinase inhibitor LY294002. We also show that in different tumor cell backgrounds inhibition of mammalian target of rapamycin, a downstream substrate of Akt, is less effective in inducing caspase-3 activity than inhibition of Akt1 and Akt2. This shows that the survival phenotype conferred by Akt can be mediated by signaling pathways independent of mammalian target of rapamycin in some tumor cell backgrounds. Finally, we show that inhibition of both Akt1 and Akt2 selectively sensitizes tumor cells, but not normal cells, to apoptotic stimuli.
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Protein kinase B (PKB/Akt) belongs to a subfamily of serine/threonine protein kniases called AGC protein kinases. Homologues of PKB can be found in worms, flies and mammals. Three isoforms of PKB, termed PKBα/Akt1, PKBβ/Akt2 and PKBγ/Akt3 that are encoded by three distinct genes, have been identified in mammals like mice and humans. PKB can be activated by numerous growth factors, hormones, cytokines and other stimuli through a phosphatidylinositol 3-kinase (PI3K)-dependent manner. The signaling pathway of PI3K/PKB/Akt has been established and the significance of this pathway for numerous cellular and physiological processes has been recognized and widely accepted. The understanding of developmental principles in mouse is a big challenge. How PKB contributes to mouse development and why three isoforms exist in mice have been wondering researchers in this field since the identification of these proteins in this animal. Early mouse work using northern blotting and in situ hybridization showed expression of PKB/Akt in mouse embryos with isoform- and tissue-specific properties. Thus, PKB/Akt may play important roles in mouse development. In addition, the distinct tissue distribution patterns of the three isoforms suggest that these proteins have different functions. To address these questions, we generated mouse mutant for each isoform by homologous recombination. Characterization and analyses of these mice have provided new insights into the functions of PKB/Akt in mouse development. We found that PKBα/Akt1 was the predominant isoform in placenta. PKBα/Akt1 mutant mice were born small with increased neonatal mortality. The mutant placenta displayed reduced size and impaired development and glycogen-containing spongiotrophoblast cells are
rare. More significant is a decrease in vascularization of the mutant placenta. As the
size and structure of the placenta determines the growth of the fetus, we conclude that
PKBα/Akt1 modulates placental development and, thus, fetal growth.
In contrast to PKBα/Akt1 mutant mice, PKBγ/Akt3 mutant mice did not show
increased postnatal mortality and and grew normally. However, these mice displayed a
reduced brain size by 25% after birth. This indicates that PKBγ/Akt3 is an important
modulator of postnatal brain growth.
We crossed PKBα/Akt1 mutant mice with PKBγ/Akt3 mutant mice to produce
compound knockout mice and found that the two proteins have different roles in the
maintenance of animal survival. While Pkbα+/−Pkbγ −/− (Akt1+/-Akt3 -/-) mice survived
normally, almost all Pkbα -/-Pkbγ +/-(Akt1-/- Akt3+/-) mice died at an early age with
multiple pathologies. PKBα/γ (Akt1/3) double knockout mice were embryonic lethal at
around E12. The development of these mice was severely impaired, including the
branchial arch arteries, the brain and the placenta. We conclude that PKBα/Akt1 is
more important than PKBγ/Akt3 for animal survival but both are required for mouse
development.
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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.
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