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    The tumour suppressor HACE1 controls cell migration by regulating Rac1 degradation.

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    Authors
    Castillo-Lluva, Sonia
    Tan, C-T
    Daugaard, M
    Sorensen, P H B
    Malliri, Angeliki
    Affiliation
    Cell Signalling Group, Cancer Research UK Paterson Institute for Cancer Research, The University of Manchester, Manchester, UK.
    Issue Date
    2012-05-21
    
    Metadata
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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.Oncogene advance online publication, 21 May 2012; doi:10.1038/onc.2012.189.
    Citation
    The tumour suppressor HACE1 controls cell migration by regulating Rac1 degradation. 2012:Oncogene
    Journal
    Oncogene
    URI
    http://hdl.handle.net/10541/251602
    DOI
    10.1038/onc.2012.189
    PubMed ID
    22614015
    Type
    Article
    Language
    en
    ISSN
    1476-5594
    ae974a485f413a2113503eed53cd6c53
    10.1038/onc.2012.189
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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