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dc.contributor.authorCastillo-Lluva, Sonia
dc.contributor.authorTan, C-T
dc.contributor.authorDaugaard, M
dc.contributor.authorSorensen, P H B
dc.contributor.authorMalliri, Angeliki
dc.date.accessioned2012-11-09T14:27:44Z
dc.date.available2012-11-09T14:27:44Z
dc.date.issued2012-05-21
dc.identifier.citationThe tumour suppressor HACE1 controls cell migration by regulating Rac1 degradation. 2012:Oncogeneen_GB
dc.identifier.issn1476-5594
dc.identifier.pmid22614015
dc.identifier.doi10.1038/onc.2012.189
dc.identifier.urihttp://hdl.handle.net/10541/251602
dc.description.abstractThe 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.
dc.languageENG
dc.language.isoenen
dc.rightsArchived with thanks to Oncogeneen_GB
dc.titleThe tumour suppressor HACE1 controls cell migration by regulating Rac1 degradation.en
dc.typeArticleen
dc.contributor.departmentCell Signalling Group, Cancer Research UK Paterson Institute for Cancer Research, The University of Manchester, Manchester, UK.en_GB
dc.identifier.journalOncogeneen_GB
html.description.abstractThe 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.


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