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Prepublished online as a Blood First Edition Paper on December 27, 2002; DOI 10.1182/blood-2002-07-2332. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-07-2332v1 101/9/3436    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Bouscary, D. Articles by Lacombe, C. Search for Related Content PubMed PubMed Citation Articles by Bouscary, D. Articles by Lacombe, C. Related Collections Hematopoiesis and Stem Cells Apoptosis Cell Cycle Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 May 2003, Vol. 101, No. 9, pp. 3436-3443 HEMATOPOIESIS Critical role for PI 3-kinase in the control of erythropoietin-induced erythroid progenitor proliferation Didier Bouscary, Frédéric Pene, Yann-Erick Claessens, Odile Muller, Stany Chrétien, Michaëla Fontenay-Roupie, Sylvie Gisselbrecht, Patrick Mayeux, and Catherine Lacombe From the Département d'Hématologie, Institut Cochin, Institut National de la Santé et de la Recherche Médicale (INSERM) U567, Centre National de la Recherche Scientifique (CNRS), UMR 8104, Université René Descartes, Paris, France; and Service d'Hématologie, AP-HP, Hôpital Cochin, Paris, France. The production of red blood cells is tightly regulated by erythropoietin (Epo). The phosphoinositide 3-kinase (PI 3-kinase) pathway was previously shown to be activated in response to Epo. We studied the role of this pathway in the control of Epo-induced survival and proliferation of primary human erythroid progenitors. We show that phosphoinositide 3 (PI 3)-kinase associates with 4 tyrosine-phosphorylated proteins in primary human erythroid progenitors, namely insulin receptor substrate-2 (IRS2), Src homology 2 domain-containing inositol 5'-phosphatase (SHIP), Grb2-associated binder-1 (Gab1), and the Epo receptor (EpoR). Using different in vitro systems, we demonstrate that 3 alternative pathways independently lead to Epo-induced activation of PI 3-kinase and phosphorylation of its downstream effectors, Akt, FKHRL1, and P70S6 kinase: through direct association of PI 3-kinase with the last tyrosine residue (Tyr479) of the Epo receptor (EpoR), through recruitment and phosphorylation of Gab proteins via either Tyr343 or Tyr401 of the EpoR, or through phosphorylation of IRS2 adaptor protein. The mitogen-activated protein (MAP) kinase pathway was also activated by Epo in erythroid progenitors, but we found that this process is independent of PI 3-kinase activation. In erythroid progenitors, the functional role of PI 3-kinase was both to prevent apoptosis and to stimulate cell proliferation in response to Epo stimulation. Finally, our results show that PI 3-kinase-mediated proliferation of erythroid progenitors in response to Epo occurs mainly through modulation of the E3 ligase SCFSKP2, which, in turn, down-regulates p27Kip1 cyclin-dependent kinase (CDK) inhibitor via proteasome degradation. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. Sulahian, O. Cleaver, and L. J.-s. Huang Ligand-induced EpoR internalization is mediated by JAK2 and p85 and is impaired by mutations responsible for primary familial and congenital polycythemia Blood, May 21, 2009; 113(21): 5287 - 5297. [Abstract] [Full Text] [PDF] P. Sathyanarayana, A. Dev, J. Fang, E. Houde, O. Bogacheva, O. Bogachev, M. Menon, S. Browne, A. Pradeep, C. Emerson, et al. EPO receptor circuits for primary erythroblast survival Blood, June 1, 2008; 111(11): 5390 - 5399. [Abstract] [Full Text] [PDF] K. Miyake, T. 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