Smad7 and protein phosphatase 1α are critical determinants in the duration of TGF-β/ALK1 signaling in endothelial cells

• Main Authors: Heldin Carl-Henrik, Itoh Susumu, Itoh Fumiko, Goumans Marie-José, Valdimarsdottir Gudrun, Dijke Peter
• Format: Article
• Language: English
• Published: BMC 2006-03-01
• Series: BMC Cell Biology
• Online Access: http://www.biomedcentral.com/1471-2121/7/16

<p>Abstract</p> <p>Background</p> <p>In endothelial cells (EC), transforming growth factor-β (TGF-β) can bind to and transduce signals through ALK1 and ALK5. The TGF-β/ALK5 and TGF-β/ALK1 pathways have opposite effects on EC behaviour. Besides differential receptor binding, the duration of TGF-β signaling is an important specificity determinant for signaling responses. TGF-β/ALK1-induced Smad1/5 phosphorylation in ECs occurs transiently.</p> <p>Results</p> <p>The temporal activation of TGF-β-induced Smad1/5 phosphorylation in ECs was found to be affected by <it>de novo </it>protein synthesis, and ALK1 and Smad5 expression levels determined signal strength of TGF-β/ALK1 signaling pathway. Smad7 and protein phosphatase 1α (PP1α) mRNA expression levels were found to be specifically upregulated by TGF-β/ALK1. Ectopic expression of Smad7 or PP1α potently inhibited TGF-β/ALK1-induced Smad1/5 phosphorylation in ECs. Conversely, siRNA-mediated knockdown of Smad7 or PP1α enhanced TGF-β/ALK1-induced signaling responses. PP1α interacted with ALK1 and this association was further potentiated by Smad7. Dephosphorylation of the ALK1, immunoprecipitated from cell lysates, was attenuated by a specific PP1 inhibitor.</p> <p>Conclusion</p> <p>Our results suggest that upon its induction by the TGF-β/ALK1 pathway, Smad7 may recruit PP1α to ALK1, and thereby control TGF-β/ALK1-induced Smad1/5 phosphorylation.</p>