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Activin/TGF-beta induce apoptosis through Smad-dependent expression of the lipid phosphatase SHIP
Hector Valderrama-Carvajal1, Eftihia Cocolakis, Annie Lacerte
1Molecular Endocrinology Laboratory, McGill University, Department of Medicine, Royal Victoria Hospital, 687 Pine Avenue West, H3A 1A1, Montreal, Canada.
Abstract:
Members of the transforming growth factor beta (TGF-beta) family regulate fundamental physiological processes, such as cell growth, differentiation and apoptosis, in almost all cell types. As a result, defects in TGF-beta signalling pathways have been linked to uncontrolled cellular proliferation and carcinogenesis. Here, we explored the signal transduction mechanisms downstream of the activin/TGF-beta receptors that result in cell growth arrest and apoptosis. We show that in haematopoietic cells, TGF-beta 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 metabolism. We also demonstrated that the Smad pathway is required in the transcriptional regulation of the SHIP gene. Activin/TGF-beta-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-beta-mediated apoptosis and define TGF-beta family members as potent inducers of SHIP expression.
Insights
Transforming growth factor beta (TGF-beta) signaling regulates cell death via the inositol phosphatase SHIP. This pathway impacts phospholipid metabolism, controlling cell survival and apoptosis in hematopoietic cells.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Transforming growth factor beta (TGF-beta) family members are crucial regulators of cell growth, differentiation, and apoptosis.
- Dysregulation of TGF-beta signaling pathways is implicated in uncontrolled cell proliferation and carcinogenesis.
- Understanding downstream signal transduction is key to deciphering TGF-beta's role in cell fate.
Purpose of the Study:
- To investigate the signal transduction mechanisms of activin/TGF-beta receptors leading to cell growth arrest and apoptosis.
- To identify key molecular players involved in TGF-beta-mediated apoptosis in hematopoietic cells.
- To elucidate the role of phospholipid metabolism in TGF-beta signaling.
Main Methods:
- Analysis of signal transduction pathways downstream of activin/TGF-beta receptors.
- Investigated the role of inositol phosphatase SHIP in TGF-beta-induced apoptosis.
- Examined the involvement of the Smad pathway in the transcriptional regulation of the SHIP gene.
- Assessed changes in phospholipid pools and Akt/PKB phosphorylation.
Main Results:
- TGF-beta family members induce apoptosis in hematopoietic cells through the expression of inositol phosphatase SHIP (Src homology 2 domain-containing 5' inositol phosphatase).
- The Smad pathway is essential for the transcriptional regulation of the SHIP gene.
- Activin/TGF-beta-induced SHIP expression alters intracellular phospholipid pools.
- SHIP expression inhibits Akt/PKB (protein kinase B) phosphorylation, leading to reduced cell survival.
Conclusions:
- TGF-beta family members are potent inducers of SHIP expression.
- SHIP links phospholipid metabolism to TGF-beta-mediated apoptosis.
- The findings define a novel mechanism by which TGF-beta controls cell survival and apoptosis via SHIP and phospholipid metabolism.