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Molecular and Cellular Biology, November 2008, p. 6889-6902, Vol. 28, No. 22
0270-7306/08/$08.00+0     doi:10.1128/MCB.01192-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Transforming Growth Factor β-Induced Smad1/5 Phosphorylation in Epithelial Cells Is Mediated by Novel Receptor Complexes and Is Essential for Anchorage-Independent Growth {triangledown} ,{dagger}

Amanda C. Daly,{ddagger} Rebecca A. Randall, and Caroline S. Hill*

Laboratory of Developmental Signalling, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom

Received 29 July 2008/ Returned for modification 20 August 2008/ Accepted 9 September 2008

Transforming growth factor β (TGF-β) signals predominantly through a receptor complex comprising ALK5 and TβRII to activate receptor-regulated Smads (R-Smads) Smad2 and Smad3. In endothelial cells, however, TGF-β can additionally activate Smad1 and Smad5. Here, we report that TGF-β also strongly induces phosphorylation of Smad1/5 in many different normal epithelial cells, epithelium-derived tumor cells, and fibroblasts. We demonstrate that TβRII and ALK5, as well as ALK2 and/or ALK3, are required for TGF-β-induced Smad1/5 phosphorylation. We show that the simultaneous activation of the R-Smads Smad2/3 and Smad1/5 by TGF-β results in the formation of mixed R-Smad complexes, containing, for example, phosphorylated Smad1 and Smad2. The prevalence of these mixed R-Smad complexes explains why TGF-β-induced Smad1/5 phosphorylation does not result in transcriptional activation via bone morphogenetic protein (BMP)-responsive elements, which bind activated Smad1/5-Smad4 complexes that are induced by BMP stimulation. Thus, TGF-β induces two parallel pathways: one signaling via Smad2-Smad4 or Smad3-Smad4 complexes and the other signaling via mixed R-Smad complexes. Finally, we assess the function of the novel arm of TGF-β signaling and show that TGF-β-induced Smad1/5 activation is not required for the growth-inhibitory effects of TGF-β but is specifically required for TGF-β-induced anchorage-independent growth.

* Corresponding author. Mailing address: Laboratory of Developmental Signalling, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom. Phone: 44-20-7269-2941. Fax: 44-20-7269-3093. E-mail: caroline.hill{at}cancer.org.uk

{triangledown} Published ahead of print on 15 September 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.

Molecular and Cellular Biology, November 2008, p. 6889-6902, Vol. 28, No. 22
0270-7306/08/$08.00+0     doi:10.1128/MCB.01192-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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