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Distinct effects of thrombopoietin depending on a threshold level of activated Mpl in BaF-3 cells

Gaël A Millot1, William Vainchenker, Dominique Duménil

  • 1INSERM U362, Laboratoire Hématopoïèse et Cellules Souches, Institut Gustave Roussy, 39 rue Camille Desmoulins, Villejuif, France. millot@ijm.jussieu.fr

Journal of Cell Science
|May 15, 2002
PubMed

Insights

Thrombopoietin (TPO) signaling via Mpl receptor impacts cell fate. TPO drives proliferation at high Mpl levels but only survival at low levels, dependent on PI3K/AKT pathways.

Area of Science:

  • Hematology
  • Cell Biology
  • Molecular Biology

Background:

  • Thrombopoietin (TPO) is crucial for megakaryopoiesis, regulating blood platelet production.
  • TPO exerts its effects by binding to the Mpl receptor, activating intracellular signaling pathways like PI3K and MAPK.
  • The precise roles of these pathways in TPO-mediated cell proliferation, survival, and differentiation remain incompletely understood.

Purpose of the Study:

  • To investigate how varying Mpl receptor expression levels influence TPO-induced biological responses in BaF-3 cells.
  • To elucidate the specific roles of phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways in TPO-driven cell proliferation and survival.

Main Methods:

  • Utilized Mpl-transduced BaF-3 cells with differing Mpl surface densities.
  • Employed kinase inhibitors PD98059 (MAPK inhibitor) and LY294002 (PI3K inhibitor) to assess pathway involvement.
  • Analyzed cell proliferation, survival, and the phosphorylation status of key proteins like BAD and expression of Bcl-X(L).

Main Results:

  • TPO induced proliferation in cells with high Mpl density, but only survival (without proliferation) in cells with low Mpl density.
  • Proliferative effects were dependent on the activation levels of both PI3K and MAPK p42/44 pathways.
  • Survival effects in low Mpl-expressing cells were primarily dependent on PI3K/AKT pathway activation, correlating with BAD phosphorylation but not Bcl-X(L) expression.
  • PI3K inhibition did not increase apoptosis during TPO-induced proliferation, suggesting compensatory signaling mechanisms.

Conclusions:

  • Mpl receptor density dictates TPO's biological outcome, modulating proliferation versus survival.
  • The PI3K and MAPK pathways play distinct, dose-dependent roles in TPO signaling.
  • PI3K/AKT signaling is critical for TPO-mediated survival in Mpl-low cells, while compensatory mechanisms exist during proliferation.

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