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      Akt and mTOR in B Cell Activation and Differentiation

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          Abstract

          Activation of phosphoinositide 3-kinase (PI3K) is required for B cell proliferation and survival. PI3K signaling also controls key aspects of B cell differentiation. Upon engagement of the B cell receptor (BCR), PI3K activation promotes Ca 2+ mobilization and activation of NFκB-dependent transcription, events which are essential for B cell proliferation. PI3K also initiates a distinct signaling pathway involving the Akt and mTOR serine/threonine kinases. It has been generally assumed that activation of Akt and mTOR downstream of PI3K is essential for B cell function. However, Akt and mTOR have complex roles in B cell fate decisions and suppression of this pathway can enhance certain B cell responses while repressing others. In this review we will discuss genetic and pharmacological studies of Akt and mTOR function in normal B cells, and in malignancies of B cell origin.

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          Most cited references88

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          DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival.

          The mTORC1 and mTORC2 pathways regulate cell growth, proliferation, and survival. We identify DEPTOR as an mTOR-interacting protein whose expression is negatively regulated by mTORC1 and mTORC2. Loss of DEPTOR activates S6K1, Akt, and SGK1, promotes cell growth and survival, and activates mTORC1 and mTORC2 kinase activities. DEPTOR overexpression suppresses S6K1 but, by relieving feedback inhibition from mTORC1 to PI3K signaling, activates Akt. Consistent with many human cancers having activated mTORC1 and mTORC2 pathways, DEPTOR expression is low in most cancers. Surprisingly, DEPTOR is highly overexpressed in a subset of multiple myelomas harboring cyclin D1/D3 or c-MAF/MAFB translocations. In these cells, high DEPTOR expression is necessary to maintain PI3K and Akt activation and a reduction in DEPTOR levels leads to apoptosis. Thus, we identify a novel mTOR-interacting protein whose deregulated overexpression in multiple myeloma cells represents a mechanism for activating PI3K/Akt signaling and promoting cell survival.
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            Membrane recognition by phospholipid-binding domains.

            Many different globular domains bind to the surfaces of cellular membranes, or to specific phospholipid components in these membranes, and this binding is often tightly regulated. Examples include pleckstrin homology and C2 domains, which are among the largest domain families in the human proteome. Crystal structures, binding studies and analyses of subcellular localization have provided much insight into how members of this diverse group of domains bind to membranes, what features they recognize and how binding is controlled. A full appreciation of these processes is crucial for understanding how protein localization and membrane topography and trafficking are regulated in cells.
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              Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks.

              The ribosomal protein S6K (S6 kinase) represents an extensively studied effector of the TORC1 [TOR (target of rapamycin) complex 1], which possesses important yet incompletely defined roles in cellular and organismal physiology. TORC1 functions as an environmental sensor by integrating signals derived from diverse environmental cues to promote anabolic and inhibit catabolic cellular functions. mTORC1 (mammalian TORC1) phosphorylates and activates S6K1 and S6K2, whose first identified substrate was rpS6 (ribosomal protein S6), a component of the 40S ribosome. Studies over the past decade have uncovered a number of additional S6K1 substrates, revealing multiple levels at which the mTORC1-S6K1 axis regulates cell physiology. The results thus far indicate that the mTORC1-S6K1 axis controls fundamental cellular processes, including transcription, translation, protein and lipid synthesis, cell growth/size and cell metabolism. In the present review we summarize the regulation of S6Ks, their cellular substrates and functions, and their integration within rapidly expanding mTOR (mammalian TOR) signalling networks. Although our understanding of the role of mTORC1-S6K1 signalling in physiology remains in its infancy, evidence indicates that this signalling axis controls, at least in part, glucose homoeostasis, insulin sensitivity, adipocyte metabolism, body mass and energy balance, tissue and organ size, learning, memory and aging. As dysregulation of this signalling axis contributes to diverse disease states, improved understanding of S6K regulation and function within mTOR signalling networks may enable the development of novel therapeutics.
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                Author and article information

                Journal
                Front Immunol
                Front Immunol
                Front. Immun.
                Frontiers in Immunology
                Frontiers Research Foundation
                1664-3224
                25 May 2012
                06 August 2012
                2012
                : 3
                : 228
                Affiliations
                [1] 1simpleDepartment of Molecular Biology and Biochemistry, Institute for Immunology, University of California Irvine Irvine, CA, USA
                Author notes

                Edited by: Klaus Okkenhaug, Babraham Institute, UK

                Reviewed by: Michael R. Gold, The University of British Columbia, Canada; John D. Colgan, University of Iowa, USA; David Nemazee, The Scripps Research Institute, USA

                *Correspondence: David A. Fruman, Department of Molecular Biology and Biochemistry, University of California Irvine, 3242 McGaugh Hall, Irvine, CA 92697-3900, USA. e-mail: dfruman@ 123456uci.edu

                This article was submitted to Frontiers in B Cell Biology, a specialty of Frontiers in Immunology.

                Article
                10.3389/fimmu.2012.00228
                3412259
                22888331
                f331691d-5ab7-41c7-a124-1d69e36337f2
                Copyright © 2012 Limon and Fruman.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                History
                : 01 May 2012
                : 14 July 2012
                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 121, Pages: 12, Words: 10714
                Categories
                Immunology
                Review Article

                Immunology
                akt,proliferation,antibody,differentiation,kinase,pi3k,mtor,b cells
                Immunology
                akt, proliferation, antibody, differentiation, kinase, pi3k, mtor, b cells

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