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The tumour suppressor HACE1 controls cell migration by regulating Rac1 degradation

Oncogene volume 32, pages 1735–1742 (2013)Cite this article

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Abstract

The small GTPase Rac1 is a key regulator of cell motility. Multiple mechanisms regulate Rac1 activity including its ubiquitylation and subsequent degradation. Here, we identify the tumour suppressor HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1) as an E3 ubiquitin ligase responsible for Rac1 degradation following activation by a migration stimulus. We show that HACE1 and Rac1 interaction is enhanced by hepatocyte growth factor (HGF) signalling, a Rac activator and potent stimulus of cell migration. Furthermore, HACE1 catalyses the poly-ubiquitylation of Rac1 at lysine 147 following its activation by HGF, resulting in its proteasomal degradation. This negative feedback mechanism likely restricts cell motility. Consistent with this, HACE1 depletion is accompanied by increased total Rac1 levels and accumulation of Rac1 in membrane ruffles. Moreover, HACE1-depletion enhances cell migration independently of growth factor stimulation, which may have significance for malignant conversion. A non-ubiquitylatable Rac1 rescues the migration defect of Rac1-null cells to a greater extent than wild-type Rac1. These findings identify HACE1 as an antagonist of cell migration through its ability to degrade active Rac1.

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Acknowledgements

This work was supported by Cancer Research UK grant number C147/A12328 and the Association for International Cancer Research grant number 12-0037 to AM. SCL was additionally supported by an EMBO long-term fellowship. Also this work was supported in part by funds to PHBS from the British Columbia Cancer Foundation through generous donations from Team Finn and other riders in the Ride to Conquer Cancer. MD was supported by The Danish Cancer Society Scientific Committee (grant number R2-A189-B146). We thank Dr Trusolino, Dr Sánchez-Madrid and Dr Vidali for reagents, Dr Hurlstone and Dr Wilkinson for critical reading of the manuscript.

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Authors and Affiliations

  1. Cell Signalling Group, Cancer Research UK Paterson Institute for Cancer Research, The University of Manchester, Manchester, UK

    S Castillo-Lluva, C-T Tan & A Malliri

  2. Department of Molecular Oncology, BC Cancer Research Centre and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, V6T 1Z4, British Columbia, Canada

    M Daugaard & P H B Sorensen

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  1. S Castillo-Lluva
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  2. C-T Tan
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  3. M Daugaard
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Correspondence to A Malliri.

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Castillo-Lluva, S., Tan, CT., Daugaard, M. et al. The tumour suppressor HACE1 controls cell migration by regulating Rac1 degradation. Oncogene 32, 1735–1742 (2013). https://doi.org/10.1038/onc.2012.189

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