Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not cell growth and proliferation in PTEN-null lymphocytes

In normal T cell progenitors, phosphoinositide-dependent kinase l (PDK1)–mediated phosphorylation and activation of protein kinase B (PKB) is essential for the phosphorylation and inactivation of Foxo family transcription factors, and also controls T cell growth and proliferation. The current study has characterized the role of PDK1 in the pathology caused by deletion of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN). PDK1 is shown to be essential for lymphomagenesis caused by deletion of PTEN in T cell progenitors. However, PTEN deletion bypasses the normal PDK1-controlled signaling pathways that determine thymocyte growth and proliferation. PDK1 does have important functions in PTEN-null thymocytes, notably to control the PKB–Foxo signaling axis and to direct the repertoire of adhesion and chemokine receptors expressed by PTEN-null T cells. The results thus provide two novel insights concerning pathological signaling caused by PTEN loss in lymphocytes. First, PTEN deletion bypasses the normal PDK1-controlled metabolic checkpoints that determine cell growth and proliferation. Second, PDK1 determines the cohort of chemokine and adhesion receptors expressed by PTEN-null cells, thereby controlling their migratory capacity.

[1]  M. Varella‐Garcia,et al.  Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation , 2008, Nature.

[2]  J. Mendell.  miRiad Roles for the miR-17-92 Cluster in Development and Disease , 2008, Cell.

[3]  J. Dixon,et al.  PTEN and myotubularin phosphatases: from 3-phosphoinositide dephosphorylation to disease. , 2002, Trends in cell biology.

[4]  M. Birnbaum,et al.  Akt1 and Akt2 are required for αβ thymocyte survival and differentiation , 2007, Proceedings of the National Academy of Sciences.

[5]  A. Ferrando,et al.  NOTCH1 extracellular juxtamembrane expansion mutations in T-ALL. , 2008, Blood.

[6]  M. Okabe,et al.  Functional competence of T cells in the absence of glycosylphosphatidylinositol‐anchored proteins caused by T cell‐specific disruption of the Pig‐agene , 1998, European journal of immunology.

[7]  Cornelis J. Weijer,et al.  PtdIns(3,4,5)P3-Dependent and -Independent Roles for PTEN in the Control of Cell Migration , 2007, Current Biology.

[8]  Lisa M. Ebert,et al.  Chemokine-mediated control of T cell traffic in lymphoid and peripheral tissues. , 2005, Molecular immunology.

[9]  B. Burgering,et al.  A brief introduction to FOXOlogy , 2008, Oncogene.

[10]  E. Wolf,et al.  CCR7 Coordinates the Primary Immune Response by Establishing Functional Microenvironments in Secondary Lymphoid Organs , 1999, Cell.

[11]  R. Lahesmaa,et al.  The RhoA transcriptional program in pre-T cells , 2007, FEBS letters.

[12]  D. Alessi,et al.  The serine kinase phosphoinositide-dependent kinase 1 (PDK1) regulates T cell development , 2004, Nature Immunology.

[13]  T. H. van der Kwast,et al.  Targeted biallelic inactivation of Pten in the mouse prostate leads to prostate cancer accompanied by increased epithelial cell proliferation but not by reduced apoptosis. , 2005, Cancer research.

[14]  C. Thompson,et al.  Akt-dependent transformation: there is more to growth than just surviving , 2005, Oncogene.

[15]  D. Alessi,et al.  Deficiency of PDK1 in cardiac muscle results in heart failure and increased sensitivity to hypoxia , 2003, The EMBO journal.

[16]  S. Morrison,et al.  Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells , 2006, Nature.

[17]  Jing Wang,et al.  Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes , 2008, Nature Immunology.

[18]  L. Cantley,et al.  New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Thijs J. Hagenbeek,et al.  The Loss of PTEN Allows TCR αβ Lineage Thymocytes to Bypass IL-7 and Pre-TCR–mediated Signaling , 2004, The Journal of experimental medicine.

[20]  David K. Finlay,et al.  Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking , 2008, Nature Immunology.

[21]  A. Berns,et al.  PTEN is essential for cell migration but not for fate determination and tumourigenesis in the cerebellum. , 2002, Development.

[22]  T. Ludwig,et al.  Unequal Contribution of Akt Isoforms in the Double-Negative to Double-Positive Thymocyte Transition1 , 2007, The Journal of Immunology.

[23]  R. Deberardinis,et al.  The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. , 2008, Cell metabolism.

[24]  C. Nobes,et al.  Phosphatidylinositol 3-kinase signals activate a selective subset of Rac/Rho-dependent effector pathways , 1996, Current Biology.

[25]  Kathryn A. O’Donnell,et al.  Activation of Transferrin Receptor 1 by c-Myc Enhances Cellular Proliferation and Tumorigenesis , 2006, Molecular and Cellular Biology.

[26]  V. Lazar,et al.  FOXO1 Regulates L-Selectin and a Network of Human T Cell Homing Molecules Downstream of Phosphatidylinositol 3-Kinase1 , 2008, The Journal of Immunology.

[27]  V. Stewart,et al.  RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement , 1992, Cell.

[28]  T. Sasaki,et al.  T cell-specific loss of Pten leads to defects in central and peripheral tolerance. , 2001, Immunity.

[29]  J. Mora,et al.  T-cell homing specificity and plasticity: new concepts and future challenges. , 2006, Trends in immunology.

[30]  H. Degrendele,et al.  Requirement for CD44 in activated T cell extravasation into an inflammatory site. , 1997, Science.

[31]  J. Cyster,et al.  Finding a way out: lymphocyte egress from lymphoid organs , 2007, Nature Immunology.

[32]  J. Rathmell,et al.  Glucose Uptake Is Limiting in T Cell Activation and Requires CD28-Mediated Akt-Dependent and Independent Pathways1 , 2008, The Journal of Immunology.

[33]  D. Alessi,et al.  New anti-cancer role for PDK1 inhibitors: preventing resistance to tamoxifen. , 2009, The Biochemical journal.

[34]  S. Armstrong,et al.  FoxOs Are Critical Mediators of Hematopoietic Stem Cell Resistance to Physiologic Oxidative Stress , 2007, Cell.

[35]  E. Sebzda,et al.  Transcription factor KLF2 regulates the migration of naive T cells by restricting chemokine receptor expression patterns , 2008, Nature Immunology.

[36]  J. Dick,et al.  Targeting of CD44 eradicates human acute myeloid leukemic stem cells , 2006, Nature Medicine.

[37]  L. Cantley,et al.  PI3K pathway alterations in cancer: variations on a theme , 2008, Oncogene.

[38]  Corey M. Carlson,et al.  Kruppel-like factor 2 regulates thymocyte and T-cell migration , 2006, Nature.

[39]  A. Hall,et al.  Regulation of Cell Migration by the C2 Domain of the Tumor Suppressor PTEN , 2004, Science.

[40]  W. Sellers,et al.  Drug discovery approaches targeting the PI3K/Akt pathway in cancer , 2008, Oncogene.

[41]  R. Parsons,et al.  Hypomorphic Mutation of PDK1 Suppresses Tumorigenesis in PTEN+/− Mice , 2005, Current Biology.

[42]  B. Hemmings,et al.  Deletion of PKBα/Akt1 Affects Thymic Development , 2007, PloS one.

[43]  S. Ward.  Faculty Opinions recommendation of Phosphatidylinositol 3-kinase regulates thymic exit. , 2005 .

[44]  C. Thompson,et al.  Activated Akt promotes increased resting T cell size, CD28‐independent T cell growth, and development of autoimmunity and lymphoma , 2003, European journal of immunology.

[45]  Yonghong Xiao,et al.  FoxOs Are Lineage-Restricted Redundant Tumor Suppressors and Regulate Endothelial Cell Homeostasis , 2007, Cell.

[46]  J. Cyster,et al.  Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. , 2005, Annual review of immunology.

[47]  W. Paul,et al.  Neonates support "homeostatic" proliferation. , 2002, Advances in experimental medicine and biology.

[48]  T. Mak,et al.  Normal development is an integral part of tumorigenesis in T cell-specific PTEN-deficient mice , 2008, Proceedings of the National Academy of Sciences.

[49]  Ximing J. Yang,et al.  The deficiency of Akt1 is sufficient to suppress tumor development in Pten mice , 2006 .

[50]  M. Birnbaum,et al.  Akt1 and Akt2 are required for alphabeta thymocyte survival and differentiation. , 2007, Proceedings of the National Academy of Sciences of the United States of America.

[51]  R. A. Etten,et al.  Requirement for CD44 in homing and engraftment of BCR-ABL–expressing leukemic stem cells , 2006, Nature Medicine.

[52]  L. Turka,et al.  Cutting Edge: T Cell Requirement for CD28 Costimulation Is Due to Negative Regulation of TCR Signals by PTEN1 , 2006, The Journal of Immunology.

[53]  Thijs J. Hagenbeek,et al.  T-cell lymphomas in T-cell-specific Pten-deficient mice originate in the thymus , 2008, Leukemia.

[54]  K. Ley,et al.  Lymphocyte homing and leukocyte rolling and migration are impaired in L-selectin-deficient mice. , 1994, Immunity.

[55]  K. Okkenhaug,et al.  PI3K-signalling in B- and T-cells: insights from gene-targeted mice. , 2001, Biochemical Society transactions.

[56]  R. Mamillapalli,et al.  Genetic deletion of the Pten tumor suppressor gene promotes cell motility by activation of Rac1 and Cdc42 GTPases , 2000, Current Biology.

[57]  David K. Finlay,et al.  Notch-induced T cell development requires phosphoinositide-dependent kinase 1 , 2007, The EMBO journal.

[58]  D. Cantrell,et al.  Inhibition of Rho at different stages of thymocyte development gives different perspectives on Rho function , 1999, Current Biology.

[59]  Jianzhu Chen,et al.  Krüppel-Like Factor 2 Controls T Cell Trafficking by Activating L-Selectin (CD62L) and Sphingosine-1-Phosphate Receptor 1 Transcription1 , 2007, The Journal of Immunology.

[60]  Ximing J. Yang,et al.  The deficiency of Akt1 is sufficient to suppress tumor development in Pten+/- mice. , 2006, Genes & development.

[61]  Linda V. Sinclair,et al.  Differential regulation of T-cell growth by IL-2 and IL-15. , 2006, Blood.

[62]  Daniel R. Beisner,et al.  Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor , 2009, Nature Immunology.

[63]  M. Ciofani,et al.  Notch promotes survival of pre–T cells at the β-selection checkpoint by regulating cellular metabolism , 2005, Nature Immunology.

[64]  T. Mak,et al.  Portrait of PTEN: Messages from mutant mice , 2008, Cancer science.