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The type I TGF-β receptor is covalently modified and regulated by sumoylation

Nature Cell Biology volume 10, pages 654–664 (2008)Cite this article

Abstract

Post-translational sumoylation, the covalent attachment of a small ubiquitin-like modifier (SUMO), regulates the functions of proteins engaged in diverse processes. Often associated with nuclear and perinuclear proteins, such as transcription factors, it is not known whether SUMO can conjugate to cell-surface receptors for growth factors to regulate their functions. Here we show that the type I transforming growth factor-β (TGF-β) receptor, TβRI, is sumoylated in response to TGF-β and that its sumoylation requires the kinase activities of both TβRI and the type II TGF-β receptor, TβRII. Sumoylation of TβRI enhances receptor function by facilitating the recruitment and phosphorylation of Smad3, consequently regulating TGF-β-induced transcription and growth inhibition. TβRI sumoylation modulates the dissemination of transformed cells in a mouse model of TβRI-stimulated metastasis. TβRI sumoylation therefore controls responsiveness to TGF-β, with implications for tumour progression. Sumoylation of cell-surface receptors may regulate other growth factor responses.

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Figure 1: The type I TGF-β receptor TβRI is sumoylated.
Figure 2: The kinase activities of TβRI and TβRII are required for TβRI sumoylation.
Figure 3: The TβRI receptor is sumoylated on Lys 389.
Figure 4: TβRI sumoylation regulates Smad activation and TGF-β responses.
Figure 5: Lack of TβRI sumoylation decreases TGF-β-regulated invasion and metastasis.
Figure 6: The Ser385Tyr mutation impairs TβRI sumoylation and function.

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Acknowledgements

This research was supported by grants RO1-CA63101 and R21-CA125190 to R.D. and PO1 AR050440 and RO1s CA116019 and HL078564 to R.J.A. from the National Institutes of Health, and a Scientist Development grant 0630322N to J.S.K. from the American Heart Association.

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Authors and Affiliations

  1. Department of Cell and Tissue Biology, Program in Cell Biology, University of California – San Francisco, San Francisco, 94143, California, USA

    Jong Seok Kang & Rik Derynck

  2. Cancer Research Institute, University of California – San Francisco, San Francisco, 94143, California, USA

    Elise F. Saunier & Rosemary J. Akhurst

  3. Department of Anatomy, University of California – San Francisco, San Francisco, 94143, California, USA

    Rosemary J. Akhurst & Rik Derynck

  4. Program In Human Genetics, University of California – San Francisco, San Francisco, 94143, California, USA

    Rosemary J. Akhurst

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  1. Jong Seok Kang
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J.S.K., R.J.A. and R.D. conceived and designed the studies; J.S.K. and E.F.S. performed the experiments; J.S.K., E.F.S., R.J.A. and R.D. prepared the manuscript.

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Correspondence to Rik Derynck.

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Kang, J., Saunier, E., Akhurst, R. et al. The type I TGF-β receptor is covalently modified and regulated by sumoylation. Nat Cell Biol 10, 654–664 (2008). https://doi.org/10.1038/ncb1728

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