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Cell Rep. 2015 Jan 6;10(1):88-102. doi: 10.1016/j.celrep.2014.12.012. Epub 2014 Dec 24.

HUWE1 ubiquitylates and degrades the RAC activator TIAM1 promoting cell-cell adhesion disassembly, migration, and invasion.

Author information

1
Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
2
Faculty of Life Sciences, The University of Manchester, Oxford Road, Manchester M13 9PT, UK.
3
Department of Histopathology, The Christie Hospital and Institute of Cancer Sciences, The University of Manchester, Manchester M20 4BX, UK.
4
Biological Mass Spectrometry, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
5
Respiratory Research Group, Institute of Inflammation and Repair, The University of Manchester and North West Lung Centre, University Hospital of South Manchester, Manchester M23 9LT, UK.
6
Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK. Electronic address: angeliki.malliri@cruk.manchester.ac.uk.

Abstract

The E3 ubiquitin ligase HUWE1, deregulated in carcinoma, has been implicated in tumor formation. Here, we uncover a role for HUWE1 in cell migration and invasion through degrading the RAC activator TIAM1, implying an additional function in malignant progression. In MDCKII cells in response to HGF, HUWE1 catalyzes TIAM1 ubiquitylation and degradation predominantly at cell-cell adhesions, facilitating junction disassembly, migration, and invasion. Depleting HUWE1 or mutating the TIAM1 ubiquitylation site prevents TIAM1 degradation, antagonizing scattering, and invasion. Moreover, simultaneous depletion of TIAM1 restores migration and invasion in HUWE1-depleted cells. Significantly, we show that HUWE1 stimulates human lung cancer cell invasion through regulating TIAM1 stability. Finally, we demonstrate that HUWE1 and TIAM1 protein levels are inversely correlated in human lung carcinomas. Thus, we elucidate a critical role for HUWE1 in regulating epithelial cell-cell adhesion and provide additional evidence that ubiquitylation contributes to spatiotemporal control of RAC.

PMID:
25543140
PMCID:
PMC4542307
DOI:
10.1016/j.celrep.2014.12.012
[Indexed for MEDLINE]
Free PMC Article

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