Cargando…
Rho GTPase–independent regulation of mitotic progression by the RhoGEF Net1
Neuroepithelial transforming gene 1 (Net1) is a RhoA-subfamily–specific guanine nucleotide exchange factor that is overexpressed in multiple human cancers and is required for proliferation. Molecular mechanisms underlying its role in cell proliferation are unknown. Here we show that overexpression o...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2013
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756918/ https://www.ncbi.nlm.nih.gov/pubmed/23864709 http://dx.doi.org/10.1091/mbc.E13-01-0061 |
_version_ | 1782282136847384576 |
---|---|
author | Menon, Sarita Oh, Wonkyung Carr, Heather S. Frost, Jeffrey A. |
author_facet | Menon, Sarita Oh, Wonkyung Carr, Heather S. Frost, Jeffrey A. |
author_sort | Menon, Sarita |
collection | PubMed |
description | Neuroepithelial transforming gene 1 (Net1) is a RhoA-subfamily–specific guanine nucleotide exchange factor that is overexpressed in multiple human cancers and is required for proliferation. Molecular mechanisms underlying its role in cell proliferation are unknown. Here we show that overexpression or knockdown of Net1 causes mitotic defects. Net1 is required for chromosome congression during metaphase and generation of stable kinetochore microtubule attachments. Accordingly, inhibition of Net1 expression results in spindle assembly checkpoint activation. The ability of Net1 to control mitosis is independent of RhoA or RhoB activation, as knockdown of either GTPase does not phenocopy effects of Net1 knockdown on nuclear morphology, and effects of Net1 knockdown are effectively rescued by expression of catalytically inactive Net1. We also observe that Net1 expression is required for centrosomal activation of p21-activated kinase and its downstream kinase Aurora A, which are critical regulators of centrosome maturation and spindle assembly. These results identify Net1 as a novel regulator of mitosis and indicate that altered expression of Net1, as occurs in human cancers, may adversely affect genomic stability. |
format | Online Article Text |
id | pubmed-3756918 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-37569182013-11-16 Rho GTPase–independent regulation of mitotic progression by the RhoGEF Net1 Menon, Sarita Oh, Wonkyung Carr, Heather S. Frost, Jeffrey A. Mol Biol Cell Articles Neuroepithelial transforming gene 1 (Net1) is a RhoA-subfamily–specific guanine nucleotide exchange factor that is overexpressed in multiple human cancers and is required for proliferation. Molecular mechanisms underlying its role in cell proliferation are unknown. Here we show that overexpression or knockdown of Net1 causes mitotic defects. Net1 is required for chromosome congression during metaphase and generation of stable kinetochore microtubule attachments. Accordingly, inhibition of Net1 expression results in spindle assembly checkpoint activation. The ability of Net1 to control mitosis is independent of RhoA or RhoB activation, as knockdown of either GTPase does not phenocopy effects of Net1 knockdown on nuclear morphology, and effects of Net1 knockdown are effectively rescued by expression of catalytically inactive Net1. We also observe that Net1 expression is required for centrosomal activation of p21-activated kinase and its downstream kinase Aurora A, which are critical regulators of centrosome maturation and spindle assembly. These results identify Net1 as a novel regulator of mitosis and indicate that altered expression of Net1, as occurs in human cancers, may adversely affect genomic stability. The American Society for Cell Biology 2013-09-01 /pmc/articles/PMC3756918/ /pubmed/23864709 http://dx.doi.org/10.1091/mbc.E13-01-0061 Text en © 2013 Menon et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology. |
spellingShingle | Articles Menon, Sarita Oh, Wonkyung Carr, Heather S. Frost, Jeffrey A. Rho GTPase–independent regulation of mitotic progression by the RhoGEF Net1 |
title | Rho GTPase–independent regulation of mitotic progression by the RhoGEF Net1 |
title_full | Rho GTPase–independent regulation of mitotic progression by the RhoGEF Net1 |
title_fullStr | Rho GTPase–independent regulation of mitotic progression by the RhoGEF Net1 |
title_full_unstemmed | Rho GTPase–independent regulation of mitotic progression by the RhoGEF Net1 |
title_short | Rho GTPase–independent regulation of mitotic progression by the RhoGEF Net1 |
title_sort | rho gtpase–independent regulation of mitotic progression by the rhogef net1 |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756918/ https://www.ncbi.nlm.nih.gov/pubmed/23864709 http://dx.doi.org/10.1091/mbc.E13-01-0061 |
work_keys_str_mv | AT menonsarita rhogtpaseindependentregulationofmitoticprogressionbytherhogefnet1 AT ohwonkyung rhogtpaseindependentregulationofmitoticprogressionbytherhogefnet1 AT carrheathers rhogtpaseindependentregulationofmitoticprogressionbytherhogefnet1 AT frostjeffreya rhogtpaseindependentregulationofmitoticprogressionbytherhogefnet1 |