FAST-2 Is a Mammalian Winged-Helix Protein Which Mediates Transforming Growth Factor β Signals

Abstract

The mechanisms by which transforming growth factor β (TGF-β) and related ligands regulate transcription remain poorly understood. The winged-helix (WH) transcription factor fork head activin signal transducer 1 (FAST-1) was identified as a mediator of activin signaling in Xenopus embryos (X. Chen, M. J. Rubock, and M. Whitman, Nature 383:691–696, 1996). We have cloned a novel WH gene from the mouse which shares many properties with FAST-1. We find that this gene, which we call FAST-2, is able to mediate transcriptional activation by TGF-β. FAST-2 also interacts directly with Smad2, a cytoplasmic protein which is translocated to the nucleus in response to TGF-β, and forms a multimeric complex with Smad2 and Smad4 on the activin response element, a high-affinity binding site for FAST-1. Analysis of the sequences of FAST-1 and FAST-2 reveals substantial protein sequence divergence compared to known vertebrate orthologs in the WH family. This suggests that FAST-2 represents a new WH gene related to FAST-1, which functions to mediate TGF-β signals in mammals. We have also examined the structure of the FAST-2 gene and find that it overlaps with a kinesin motor protein gene. The genes are transcribed in opposite orientations, and their transcripts overlap in the 3′ untranslated region.

ACKNOWLEDGMENTS

We thank Dana Benhaim, Chetna Thayyulathil, Yasmin Khakoo, and Robert Johnson for technical assistance. We are grateful to Joan Massague for Smad constructs and the A3-luc reporter and to Malcolm Whitman for Myc–FAST-1. We thank Suzanne Li, Fang Liu, and J. Massague for helpful discussions and critical comments on the manuscript.

B. Liu and C.-L. Dou contributed equally to this work.

This work was supported by National Institutes of Health grants HD29584 (E.L.), F32NS10035 (B.L.), and F32NS10313 (C.-L.D.) and a Cancer Center Support Grant to MSKCC.