Activin/TGF-beta induce apoptosis through Smad-dependent expression of the lipid phosphatase SHIP.
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.
Valderrama-Carvajal
Hector
H
Molecular Endocrinology Laboratory, McGill University, Department of Medicine, Royal Victoria Hospital, 687 Pine Avenue West, H3A 1A1, Montreal, Canada.
Cocolakis
Eftihia
E
Lacerte
Annie
A
Lee
Eun-Hye
EH
Krystal
Gerald
G
Ali
Suhad
S
Lebrun
Jean-Jacques
JJ
D028341:Activins / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D006410:Hematopoiesis / Q000502:physiology; D006801:Humans; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*
D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D028341:Activins; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases