SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on December 27, 2002; DOI 10.1182/blood-2002-07-2332. This Article 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 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. Social Bookmarking                   What's this? Submitted July 31, 2002 Accepted December 12, 2002 Critical role for PI 3-kinase in the control of erythropoietin-induced erythroid progenitor proliferation Didier Bouscary, Frederic Pene, Yann-Erick Claessens, Odile Muller, Stany Chretien, Michaela Fontenay-Roupie, Sylvie Gisselbrecht, Patrick Mayeux, and Catherine Lacombe* Departement d'Hematologie, Institut Cochin, INSERM U567, CNRS UMR 8104, Universite Rene Descartes, Hopital Cochin, Paris, France Service d'Hematologie, AP-HP, Hopital Cochin, Paris, France * Corresponding author; email: lacombe{at}cochin.inserm.fr. 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 erythropoietin (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 PI 3-kinase associates with four tyrosine phosphorylated proteins in primary human erythroid progenitors, namely IRS2, SHIP, Gab1 and the Epo receptor (EpoR). Using different in vitro systems, we demonstrate that three alternative pathways independently lead to Epo-induced activation of PI 3-kinase and its downstream effectors, Akt, FKHRL1 and P70S6 kinase: through direct association of PI 3-kinase to the last tyrosine residue (Tyr 479) of the Epo receptor (EpoR), through recruitment and phosphorylation of Gab proteins via either Tyr 343 or Tyr 401 of the EpoR or through phosphorylation of IRS2 adaptor protein. The 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 mainly occurs through modulation of the E3 ligase SCFSKP2 which, in turn downregulates p27Kip1 CDK inhibitor via proteasome degradation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: 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. Utsugisawa, J. Flygare, T. Kiefer, I. Hamaguchi, J. Richter, and S. Karlsson Ribosomal Protein S19 Deficiency Leads to Reduced Proliferation and Increased Apoptosis but Does Not Affect Terminal Erythroid Differentiation in a Cell Line Model of Diamond-Blackfan Anemia Stem Cells, February 1, 2008; 26(2): 323 - 329. [Abstract] [Full Text] [PDF] J. Fang, M. Menon, W. Kapelle, O. Bogacheva, O. Bogachev, E. Houde, S. Browne, P. Sathyanarayana, and D. M. Wojchowski EPO modulation of cell-cycle regulatory genes, and cell division, in primary bone marrow erythroblasts Blood, October 1, 2007; 110(7): 2361 - 2370. [Abstract] [Full Text] [PDF] R. Zhande and A. Karsan Erythropoietin promotes survival of primary human endothelial cells through PI3K-dependent, NF-{kappa}B-independent upregulation of Bcl-xL Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2467 - H2474. [Abstract] [Full Text] [PDF] E. Ingley, J. R. Schneider, C. J. Payne, D. J. McCarthy, K. W. Harder, M. L. Hibbs, and S. P. Klinken Csk-binding Protein Mediates Sequential Enzymatic Down-regulation and Degradation of Lyn in Erythropoietin-stimulated Cells J. Biol. Chem., October 20, 2006; 281(42): 31920 - 31929. [Abstract] [Full Text] [PDF] N. Gude, J. Muraski, M. Rubio, J. Kajstura, E. Schaefer, P. Anversa, and M. A. Sussman Akt Promotes Increased Cardiomyocyte Cycling and Expansion of the Cardiac Progenitor Cell Population Circ. Res., August 18, 2006; 99(4): 381 - 388. [Abstract] [Full Text] [PDF] F. Verdier, S. Gomez, C. Lacombe, P. Mayeux, S. Elliott, A. M. Sinclair, and C. G. Begley Selected anti-Epo receptor antibodies predict Epo receptor expression Blood, August 1, 2006; 108(3): 1106 - 1107. [Full Text] [PDF] Y.-E. Claessens, M. Fontenay, F. Pene, J.-D. Chiche, M. Guesnu, C. Hababou, N. Casadevall, J.-F. Dhainaut, J.-P. Mira, and A. Cariou Erythropoiesis Abnormalities Contribute to Early-Onset Anemia in Patients with Septic Shock Am. J. Respir. Crit. Care Med., July 1, 2006; 174(1): 51 - 57. [Abstract] [Full Text] [PDF] Y. Liu, R. Pop, C. Sadegh, C. Brugnara, V. H. Haase, and M. Socolovsky Suppression of Fas-FasL coexpression by erythropoietin mediates erythroblast expansion during the erythropoietic stress response in vivo Blood, July 1, 2006; 108(1): 123 - 133. [Abstract] [Full Text] [PDF] B. Li, N. Jia, R. Kapur, and K. T. Chun Cul4A targets p27 for degradation and regulates proliferation, cell cycle exit, and differentiation during erythropoiesis Blood, June 1, 2006; 107(11): 4291 - 4299. [Abstract] [Full Text] [PDF] K. Kaushansky Lineage-specific hematopoietic growth factors. N. Engl. J. Med., May 11, 2006; 354(19): 2034 - 2045. [Full Text] [PDF] M. P. Menon, J. Fang, and D. M. Wojchowski Core erythropoietin receptor signals for late erythroblast development Blood, April 1, 2006; 107(7): 2662 - 2672. [Abstract] [Full Text] [PDF] T. Buchse, H. Prietzsch, T. Sasse, S. Korbel, G. Stigge, S. Bogdanow, J. Brock, and T. Bittorf Profiling of Early Gene Expression Induced by Erythropoietin Receptor Structural Variants J. Biol. Chem., March 24, 2006; 281(12): 7697 - 7707. [Abstract] [Full Text] [PDF] S. Ghaffari, C. Kitidis, W. Zhao, D. Marinkovic, M. D. Fleming, B. Luo, J. Marszalek, and H. F. Lodish AKT induces erythroid-cell maturation of JAK2-deficient fetal liver progenitor cells and is required for Epo regulation of erythroid-cell differentiation Blood, March 1, 2006; 107(5): 1888 - 1891. [Abstract] [Full Text] [PDF] W. Zhao, C. Kitidis, M. D. Fleming, H. F. Lodish, and S. Ghaffari Erythropoietin stimulates phosphorylation and activation of GATA-1 via the PI3-kinase/AKT signaling pathway Blood, February 1, 2006; 107(3): 907 - 915. [Abstract] [Full Text] [PDF] T. Montoye, I. Lemmens, D. Catteeuw, S. Eyckerman, and J. Tavernier A systematic scan of interactions with tyrosine motifs in the erythropoietin receptor using a mammalian 2-hybrid approach Blood, June 1, 2005; 105(11): 4264 - 4271. [Abstract] [Full Text] [PDF] C. Recher, O. Beyne-Rauzy, C. Demur, G. Chicanne, C. Dos Santos, V. M.-D. Mas, D. Benzaquen, G. Laurent, F. Huguet, and B. Payrastre Antileukemic activity of rapamycin in acute myeloid leukemia Blood, March 15, 2005; 105(6): 2527 - 2534. [Abstract] [Full Text] [PDF] P. Walrafen, F. Verdier, Z. Kadri, S. Chretien, C. Lacombe, and P. Mayeux Both proteasomes and lysosomes degrade the activated erythropoietin receptor Blood, January 15, 2005; 105(2): 600 - 608. [Abstract] [Full Text] [PDF] S.-J. Lu, F. Li, L. Vida, and G. R. Honig CD34+CD38- hematopoietic precursors derived from human embryonic stem cells exhibit an embryonic gene expression pattern Blood, June 1, 2004; 103(11): 4134 - 4141. [Abstract] [Full Text] [PDF] J. H. Weishaupt, G. Rohde, E. Polking, A.-L. Siren, H. Ehrenreich, and M. Bahr Effect of Erythropoietin Axotomy-Induced Apoptosis in Rat Retinal Ganglion Cells Invest. Ophthalmol. Vis. Sci., May 1, 2004; 45(5): 1514 - 1522. [Abstract] [Full Text] [PDF] S. Chu, M. Holtz, M. Gupta, and R. Bhatia BCR/ABL kinase inhibition by imatinib mesylate enhances MAP kinase activity in chronic myelogenous leukemia CD34+ cells Blood, April 15, 2004; 103(8): 3167 - 3174. [Abstract] [Full Text] [PDF] K. Li, M. P. Menon, V. G. Karur, S. Hegde, and D. M. Wojchowski Attenuated signaling by a phosphotyrosine-null Epo receptor form in primary erythroid progenitor cells Blood, November 1, 2003; 102(9): 3147 - 3153. [Abstract] [Full Text] [PDF] K. Li, C. Miller, S. Hegde, and D. Wojchowski Roles for an Epo Receptor Tyr-343 Stat5 Pathway in Proliferative Co-signaling with Kit J. Biol. Chem., October 17, 2003; 278(42): 40702 - 40709. [Abstract] [Full Text] [PDF]

	Copyright © 2002 by American Society of Hematology         Online ISSN: 1528-0020