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TGF-β induces assembly of a Smad2–Smurf2 ubiquitin ligase complex that targets SnoN for degradation

Nature Cell Biology volume 3, pages 587–595 (2001)Cite this article

Abstract

The receptor-regulated Smad proteins are essential intracellular mediators of signal transduction by the transforming growth factor-β (TGF-β) superfamily of growth factors and are also important as regulators of gene transcription. Here we describe a new role for TGF-β-regulated Smad2 and Smad3 as components of a ubiquitin ligase complex. We show that in the presence of TGF-β signalling, Smad2 interacts through its proline-rich PPXY motif with the tryptophan-rich WW domains of Smurf2, a recently identified E3 ubiquitin ligases. TGF-β also induces the association of Smurf2 with the transcriptional co-repressor SnoN and we show that Smad2 can function to mediate this interaction. This allows Smurf2 HECT domain to target SnoN for ubiquitin-mediated degradation by the proteasome. Thus, stimulation by TGF-β can induce the assembly of a Smad2–Smurf2 ubiquitin ligase complex that functions to target substrates for degradation.

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Figure 1: TGF-β signalling induces association between Smurf2 and Smad2 or Smad3.
Figure 2: Smad2 is not a major target for Smurf2-dependent degradation.
Figure 3: Smad2 recruits Smurf2 into a complex with SnoN.
Figure 4: Smurf2 regulates levels of SnoN at steady state.
Figure 5: Smad2–Smurf2 complex targets SnoN for ubiquitination and degradation.
Figure 6: The Smad2 PY motif is required to recruit Smurf2 to SnoN.
Figure 7: Determinants on SnoN required for Smad2–Smurf2-dependent turnover and model depicting ubiquitin-mediated degradation of SnoN.

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Acknowledgements

We thank D. Bohmann for HA-ubiquitin, G. Stark for U4A/Jak1 cells and L. Attisano, C. LeRoy and Y. Wang for helpful discussions. This work was supported by grants to J.L.W. from the Canadian Institutes of Health Research and the National Cancer Institute of Canada with funds from the Terry Fox Run. C.G.C. is a Research Fellow of the National Cancer Institute of Canada with funds from the Terry Fox run, and J.L.W. is a Canadian Institutes of Health Research Investigator.

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Authors and Affiliations

  1. Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, M5G 1X5, Ontario, Canada

    Shirin Bonni, Hong-Rui Wang, Carrie G. Causing, Peter Kavsak & Jeffrey L. Wrana

  2. Department of Medical Genetics and Microbiology, University of Toronto, 1 King's College Circle, Toronto, M5S 1A8, Ontario, Canada

    Peter Kavsak & Jeffrey L. Wrana

  3. Life Sciences Division, Lawrence Berkeley National Laboratory and Department of Molecular and Cell Biology, University of California, 229 Stanley Hall, Berkeley, 94720, California, USA

    Shannon L. Stroschein, Kunxin Luo & Jeffrey L. Wrana

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Correspondence to Jeffrey L. Wrana.

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Bonni, S., Wang, HR., Causing, C. et al. TGF-β induces assembly of a Smad2–Smurf2 ubiquitin ligase complex that targets SnoN for degradation. Nat Cell Biol 3, 587–595 (2001). https://doi.org/10.1038/35078562

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