Activin/TGF-β induce apoptosis through Smad-dependent expression of the lipid phosphatase SHIP

Publisher Website
Google Scholar
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.