Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor (original) (raw)

1. Akiko Hata1,3,
2. Giorgio Lagna2,3,
3. Joan Massagué1,4, and
4. Ali Hemmati-Brivanlou2,4
5. 1Cell Biology Program, Howard Hughes Medical Institute and The Sloan-Kettering Division of the Cornell University Graduate School of Medical Sciences, Memorial Sloan-Kettering Cancer Center;2Laboratory of Molecular Embryology, The Rockefeller University, New York, NY 10021

Abstract

Bone morphogenetic protein (BMP) receptors signal by phosphorylating Smad1, which then associates with Smad4; this complex moves into the nucleus and activates transcription. Here we report the existence of a natural inhibitor of this process, Smad6, a longer version of the previously reported JV15-1. In Xenopus embryos and in mammalian cells, Smad6 specifically blocks signaling by the BMP/Smad1 pathway. Smad6 inhibits BMP/Smad1 signaling without interfering with receptor-mediated phosphorylation of Smad1. Smad6 specifically competes with Smad4 for binding to receptor-activated Smad1, yielding an apparently inactive Smad1–Smad6 complex. Therefore, Smad6 selectively antagonizes BMP-activated Smad1 by acting as a Smad4 decoy.

• Smad proteins
• BMP receptors
• TGFβ
• Xenopus
• antagonist
• mammalian cells

Footnotes

• ↵3 These authors contributed equally to this work.

• ↵4 Corresponding authors.

• E-MAIL j-massague{at}ski.mskcc.org; FAX (212) 717-3298. E-MAILbrvnlou{at}rockvax.rockefeller.edu; FAX (212) 327-8656.

• • Received October 3, 1997.
  • Accepted November 19, 1997.

• Cold Spring Harbor Laboratory Press

•