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Molecular and Cellular Biology, February 2004, p. 1106-1121, Vol. 24, No. 3
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.3.1106-1121.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Recognition of Phosphorylated-Smad2-Containing Complexes by a Novel Smad Interaction Motif

Rebecca A. Randall,1 Michael Howell,1 Christopher S. Page,2 Amanda Daly,1 Paul A. Bates,2 and Caroline S. Hill1*

Laboratory of Developmental Signalling,1 Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, London WC2A 3PX, United Kingdom2

Received 31 July 2003/ Returned for modification 5 September 2003/ Accepted 29 October 2003

Transforming growth factor ß (TGF-ß) superfamily members signal via complexes of activated Smads, comprising phosphorylated receptor-regulated Smads, such as Smad2 and Smad3, and Smad4. These complexes are recruited to DNA by specific transcription factors. The forkhead/winged-helix transcription factors, XFast-1/XFoxH1a and XFast-3/XFoxH1b, bind an activated Smad heterotrimer comprising two Smad2s and one Smad4. Here we identify a novel Smad2 interaction motif, the Fast/FoxH1 motif (FM), present in all known Fast/FoxH1 family members, N-terminal to the common Smad interaction motif (SIM). The FM is necessary and sufficient to bind active Smad2/Smad4 complexes. The FM differs from the SIM since it discriminates between Smad2 and Smad3, and moreover only binds phosphorylated Smad2 in the context of activated Smad complexes. It is the first Smad interaction motif with this property. Site-directed mutagenesis indicates that the binding site for the FM on a Smad2/Smad4 heterotrimer is a hydrophobic pocket that incorporates the Smad/Smad interface. We demonstrate that the presence of an FM and SIM in the Fast/FoxH1 proteins allows them to compete efficiently for activated Smad2/Smad4 complexes with transcription factors such as Mixer that only contain a SIM. This establishes a hierarchy of Smad-interacting transcription factors, determined by their affinity for active Smad complexes.

* 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 (0)20 7269 2941. Fax: 44 (0)20 7269 3093. E-mail: caroline.hill{at}cancer.org.uk.

Molecular and Cellular Biology, February 2004, p. 1106-1121, Vol. 24, No. 3
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.3.1106-1121.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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