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Mol Biol Cell. 2016 Apr 1;27(7):1069-84. doi: 10.1091/mbc.E15-08-0569. Epub 2016 Feb 10.

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

Author information

1
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA 30322 Graduate Program in Cancer Biology, Emory University, Atlanta, GA 30322.
2
Department of Mathematics and Statistics, Georgia State University, Atlanta, GA 30302.
3
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA 30322 Department of Pharmacology, Emory University, Atlanta, GA 30322.
4
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA 30322.
5
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA 30322 aimarcu@emory.edu.

Abstract

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.

PMID:
26864623
PMCID:
PMC4814216
DOI:
10.1091/mbc.E15-08-0569
[Indexed for MEDLINE]
Free PMC Article

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