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Critical role for PI 3-kinase in the control of erythropoietin-induced erythroid progenitor proliferation.

Authors
  • Didier Bouscary
  • Pene, Frédéric
  • Claessens, Yann-Erick
  • Muller, Odile
  • Chrétien, Stany
  • Fontenay-Roupie, Michaëla
  • Gisselbrecht, Sylvie
  • Patrick Mayeux
  • Lacombe, Catherine
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
May 28, 2003
Volume
101
Issue
9
Pages
3436–3443
Identifiers
DOI: 10.1182/blood-2002-07-2332
PMID: 12506011
Source
USPC - SET - SVS
License
Green

Abstract

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 SCF(SKP2), which, in turn, down-regulates p27(Kip1) cyclin-dependent kinase (CDK) inhibitor via proteasome degradation.

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