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LKB1 kinase-dependent and -independent defects disrupt polarity and adhesion signaling to drive collagen remodeling during invasion

LKB1 is a serine/threonine kinase and a commonly mutated gene in lung adenocarcinoma. The majority of LKB1 mutations are truncations that disrupt its kinase activity and remove its C-terminal domain (CTD). Because LKB1 inactivation drives cancer metastasis in mice and leads to aberrant cell invasion...

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Autores principales: Konen, Jessica, Wilkinson, Scott, Lee, Byoungkoo, Fu, Haian, Zhou, Wei, Jiang, Yi, Marcus, Adam I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814216/
https://www.ncbi.nlm.nih.gov/pubmed/26864623
http://dx.doi.org/10.1091/mbc.E15-08-0569
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author Konen, Jessica
Wilkinson, Scott
Lee, Byoungkoo
Fu, Haian
Zhou, Wei
Jiang, Yi
Marcus, Adam I.
author_facet Konen, Jessica
Wilkinson, Scott
Lee, Byoungkoo
Fu, Haian
Zhou, Wei
Jiang, Yi
Marcus, Adam I.
author_sort Konen, Jessica
collection PubMed
description LKB1 is a serine/threonine kinase and a commonly mutated gene in lung adenocarcinoma. The majority of LKB1 mutations are truncations that disrupt its kinase activity and remove its C-terminal domain (CTD). Because LKB1 inactivation drives cancer metastasis in mice and leads to aberrant cell invasion in vitro, we sought to determine how compromised LKB1 function affects lung cancer cell polarity and invasion. Using three-dimensional models, we show that LKB1 kinase activity is essential for focal adhesion kinase–mediated cell adhesion and subsequent collagen remodeling but not cell polarity. Instead, cell polarity is overseen by the kinase-independent function of its CTD and more specifically its farnesylation. This occurs through a mesenchymal-amoeboid morphological switch that signals through the Rho-GTPase RhoA. These data suggest that a combination of kinase-dependent and -independent defects by LKB1 inactivation creates a uniquely invasive cell with aberrant polarity and adhesion signaling that drives invasion into the microenvironment.
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spelling pubmed-48142162016-06-16 LKB1 kinase-dependent and -independent defects disrupt polarity and adhesion signaling to drive collagen remodeling during invasion Konen, Jessica Wilkinson, Scott Lee, Byoungkoo Fu, Haian Zhou, Wei Jiang, Yi Marcus, Adam I. Mol Biol Cell Articles LKB1 is a serine/threonine kinase and a commonly mutated gene in lung adenocarcinoma. The majority of LKB1 mutations are truncations that disrupt its kinase activity and remove its C-terminal domain (CTD). Because LKB1 inactivation drives cancer metastasis in mice and leads to aberrant cell invasion in vitro, we sought to determine how compromised LKB1 function affects lung cancer cell polarity and invasion. Using three-dimensional models, we show that LKB1 kinase activity is essential for focal adhesion kinase–mediated cell adhesion and subsequent collagen remodeling but not cell polarity. Instead, cell polarity is overseen by the kinase-independent function of its CTD and more specifically its farnesylation. This occurs through a mesenchymal-amoeboid morphological switch that signals through the Rho-GTPase RhoA. These data suggest that a combination of kinase-dependent and -independent defects by LKB1 inactivation creates a uniquely invasive cell with aberrant polarity and adhesion signaling that drives invasion into the microenvironment. The American Society for Cell Biology 2016-04-01 /pmc/articles/PMC4814216/ /pubmed/26864623 http://dx.doi.org/10.1091/mbc.E15-08-0569 Text en © 2016 Konen, Wilkinson, 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 for Cell Biology.
spellingShingle Articles
Konen, Jessica
Wilkinson, Scott
Lee, Byoungkoo
Fu, Haian
Zhou, Wei
Jiang, Yi
Marcus, Adam I.
LKB1 kinase-dependent and -independent defects disrupt polarity and adhesion signaling to drive collagen remodeling during invasion
title LKB1 kinase-dependent and -independent defects disrupt polarity and adhesion signaling to drive collagen remodeling during invasion
title_full LKB1 kinase-dependent and -independent defects disrupt polarity and adhesion signaling to drive collagen remodeling during invasion
title_fullStr LKB1 kinase-dependent and -independent defects disrupt polarity and adhesion signaling to drive collagen remodeling during invasion
title_full_unstemmed LKB1 kinase-dependent and -independent defects disrupt polarity and adhesion signaling to drive collagen remodeling during invasion
title_short LKB1 kinase-dependent and -independent defects disrupt polarity and adhesion signaling to drive collagen remodeling during invasion
title_sort lkb1 kinase-dependent and -independent defects disrupt polarity and adhesion signaling to drive collagen remodeling during invasion
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814216/
https://www.ncbi.nlm.nih.gov/pubmed/26864623
http://dx.doi.org/10.1091/mbc.E15-08-0569
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