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Tumor suppressor Fbxw7 regulates TGFβ signaling by targeting TGIF1 for degradation

Oncogene volume 29, pages 5322–5328 (2010)Cite this article

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Abstract

Transforming growth factor-β (TGFβ) signaling regulates multiple cellular processes, including extracellular matrix production, cell growth, apoptosis and differentiation. Dysfunction of TGFβ signaling has been implicated in various human disorders ranging from vascular diseases to cancer. TGFβ signaling is negatively regulated by the transcriptional repressor TGFβ-induced factor 1 (TGIF1). The tumor suppressor Fbxw7 is the substrate-recognition factor of a ubiquitin ligase that targets multiple proteins for degradation, including c-Myc, cyclin E, c-Jun and Notch. Here, we describe that TGIF1 is targeted for degradation by Fbxw7 in a phosphorylation-dependent manner. Inactivation of Fbxw7 results in the accumulation of phosphorylated TGIF1 molecules and repression of TGFβ-dependent transcription. Cancer cell lines with inactivating mutations in Fbxw7 show enhanced levels of TGIF1 and attenuated TGFβ-dependent signaling. Importantly, inactivation of Fbxw7 attenuates TGFβ-dependent regulation of cell growth and migration. Taken together, our results suggest that Fbxw7 is a novel regulator of TGFβ signaling.

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Acknowledgements

We thank Ulla Engström for peptide synthesis and antibody purification, and Aris Moustakas, Lars van der Heide and Peter Lönn for plasmids, antibodies and advice. This work was supported by a grant from the Ludwig Institute for Cancer Research Ltd. JE is the recipient of a Science Foundation Ireland Stokes Professorship Award (07/SK/B1242b).

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  1. School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland

    M T Bengoechea-Alonso & J Ericsson

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  1. M T Bengoechea-Alonso
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Correspondence to J Ericsson.

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Bengoechea-Alonso, M., Ericsson, J. Tumor suppressor Fbxw7 regulates TGFβ signaling by targeting TGIF1 for degradation. Oncogene 29, 5322–5328 (2010). https://doi.org/10.1038/onc.2010.278

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