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


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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    • "Fish & Shellfish Immunology angiogenesis and migration [3] [5] [17]. Akt has been highly conserved during evolution, and its homologs have been identified in detail in both mammals and invertebrates , including Drosophila melanogaster and Caenorhabditis elegans [18]. "
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    ABSTRACT: G-protein-coupled receptors (GPCRs) are the largest class of cell-surface receptors and play crucial roles in virtually every organ system. As one of the major downstream effectors of GPCRs, Akt can acquire information from the receptors and coordinate intracellular responses for many signalling pathways, through which the serine/threonine kinase masters numerous aspects of biological processes, such as cell survival, growth, proliferation, migration, angiogenesis, and metabolism. In the present study, we have characterized the first Akt1 ortholog in mollusks using the Hong Kong oyster, Crassostrea hongkongensis (designed ChAkt1). The full-length cDNA is 2,223 bp and encodes a putative protein of 493 amino acids that contains an amino-terminal pleckstin homology (PH) domain, a central catalytic domain, and a carboxy-terminal regulatory domain. Quantitative real-time PCR analysis showed that ChAkt1 mRNA is broadly expressed in various tissues and during different stages of the oyster's embryonic and larval development. Upon exposure to two stressors (microbial infection and heat shock), the expression level of ChAkt1 mRNA increases significantly. Furthermore, ChAkt1 is located in the cytoplasm in HEK293T cells, where the over-expression of ChAkt1 regulates the transcriptional activities of NF-κB and p53 reporter genes. Taken together, our results indicate that ChAkt1 most likely plays a central role in response to various stimuli in oysters and has a particular response to microbial pathogens and high temperature.
    Fish &amp Shellfish Immunology 11/2015; 47(2). DOI:10.1016/j.fsi.2015.11.009 · 2.67 Impact Factor
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    • "Throughout these dynamic phases, preservation of the simple epithelial structure of the mammary ducts is essential for lactation, and more importantly , it is essential for preventing mammary tumorigenesis (McCaffrey and Macara, 2011). The tumor suppressor phosphatase and tensin homolog (PTEN) plays a central role in regulating organ growth and development (Manning and Cantley, 2007; Song et al., 2012). PTEN dephosphorylates phosphatidylinositol 3,4,5-triphosphate (PIP3), the product of phosphatidylinositol kinase 3 (PI3K), thereby attenuating the nutrient-and growth factor-sensing PI3K pathway. "
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    ABSTRACT: In the mammary gland, PTEN loss in luminal and basal epithelial cells results in differentiation defects and enhanced proliferation, leading to the formation of tumors with basal epithelial characteristics. In breast cancer, PTEN loss is associated with a hormone receptor-negative, basal-like subtype that is thought to originate in a luminal epithelial cell. Here, we show that luminal-specific PTEN loss results in distinct effects on epithelial homeostasis and mammary tumor formation. Luminal PTEN loss increased proliferation of hormone receptor-negative cells, thereby decreasing the percentage of hormone receptor-positive cells. Moreover, luminal PTEN loss led to misoriented cell divisions and mislocalization of cells to the intraluminal space of mammary ducts. Despite their elevated levels of activated AKT, Pten-null intraluminal cells showed increased levels of apoptosis. One year after Pten deletion, the ducts had cleared and no palpable mammary tumors were detected. These data establish PTEN as a critical regulator of luminal epithelial homeostasis and integrity in the adult mammary gland, and further show that luminal PTEN loss alone is not sufficient to promote the progression of mammary tumorigenesis.
    Developmental Biology 11/2015; DOI:10.1016/j.ydbio.2015.10.023 · 3.55 Impact Factor
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    • "The protein kinase Akt is one of the most critical and versatile protein kinases in higher eukaryotes. Numerous Akt substrates have been identified in relation to metabolism, cell survival, proliferation , and cell migration (Manning and Cantley, 2007). In addition, Akt may play a role in regulating the IFN pathway. "
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    ABSTRACT: Upon DNA stimulation, cyclic GMP-AMP synthase (cGAS) synthesizes the second messenger cyclic GMP-AMP (cGAMP) that binds to the STING, triggering antiviral interferon-β (IFN-β) production. However, it has remained undetermined how hosts regulate cGAS enzymatic activity after the resolution of DNA immunogen. Here, we show that Akt kinase plays a negative role in cGAS-mediated anti-viral immune response. Akt phosphorylated the S291 or S305 residue of the enzymatic domain of mouse or human cGAS, respectively, and this phosphorylation robustly suppressed its enzymatic activity. Consequently, expression of activated Akt led to the reduction of cGAMP and IFN-β production and the increase of herpes simplex virus 1 replication, whereas treatment with Akt inhibitor augmented cGAS-mediated IFN-β production. Furthermore, expression of the phosphorylation-resistant cGAS S291A mutant enhanced IFN-β production upon DNA stimulation, HSV-1 infection, and vaccinia virus infection. Our study identifies an Akt kinase-mediated checkpoint to fine-tune hosts’ immune responses to DNA stimulation.
    Cell Reports 10/2015; 13(2). DOI:10.1016/j.celrep.2015.09.007 · 8.36 Impact Factor
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