Abstract
Members of the transforming growth factor β (TGF-β) family regulate fundamental physiological processes, such as cell growth, differentiation and apoptosis, in almost all cell types1. As a result, defects in TGF-β signalling pathways have been linked to uncontrolled cellular proliferation and carcinogenesis1. Here, we explored the signal transduction mechanisms downstream of the activin/TGF-β receptors that result in cell growth arrest and apoptosis. We show that in haematopoietic cells, TGF-β family members regulate apoptosis through expression of the inositol phosphatase SHIP (Src homology 2 (SH2) domain-containing 5′ inositol phosphatase), a central regulator of phospholipid metabolism2. We also demonstrated that the Smad pathway is required in the transcriptional regulation of the SHIP gene. Activin/TGF-β-induced expression of SHIP results in intracellular changes in the pool of phospholipids, as well as in inhibition of both Akt/PKB (protein kinase B) phosphorylation and cell survival. Our results link phospholipid metabolism to activin/TGF-β-mediated apoptosis and define TGF-β family members as potent inducers of SHIP expression.
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Acknowledgements
The authors are thankful to Y. Eto and Ajinomoto Co. Inc. for activin, J. Wrana and L. Attisano for ARE-Lux and ΔN-Smad2, H. Lodish for ΔN-Smad3, C. Sirard for the Smad4 −/− embryonic fibroblast cells, J.V. Ravetch for the DT-40 SHIP −/− and DT-40 SHP1 −/− cells, M. Rauh for preparing the SHIP +/+ and SHIP −/− bone-marrow-derived macrophages and B. Morin for the human lymphocytes preparation. H. Valderrama is supported by a fellowship from Consejo Nacional de Cienca Tecnologia, Mexico. S. Ali is a National Cancer Institute of Canada (NCIC) scholar and J. J. Lebrun is a Canadian Institute for Health Research (CIHR) scholar. This work was supported by grants from the CIHR (to J.J.L. and to S.A.), from the NCIC with core support from the British Columbia Cancer Foundation and the British Columbia Cancer Agency (to G.K.), from the Leukemia Research Funds of Canada (to J.J.L.) and from the Anemia Institute for Research and Education (to J.J.L.).
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Fig.S1 Activin and TGFβ induce apoptosis in hematopoietic cells. (PDF 37 kb)
Fig.S2 Activin-induced SHIP expression in B9 cells antagonizes AKT phosphorylation in response to IL-6 on both Thr308 and Ser 473.
Fig.S3 Inhibition of expression of the lipid phosphatase SHIP prevents TGFβ- induced apoptosis.
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Valderrama-Carvajal, H., Cocolakis, E., Lacerte, A. et al. Activin/TGF-β induce apoptosis through Smad-dependent expression of the lipid phosphatase SHIP. Nat Cell Biol 4, 963–969 (2002). https://doi.org/10.1038/ncb885
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DOI: https://doi.org/10.1038/ncb885
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