title: LKB1 kinase-dependent and -independent defects disrupt polarity and adhesion signaling to drive collagen remodeling during invasion.
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.
authors: 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.
authors: Jessica
authors: J
authors: Konen
authors: 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.
authors: Scott
authors: S
authors: Wilkinson
authors: Department of Mathematics and Statistics, Georgia State University, Atlanta, GA 30302.
authors: Byoungkoo
authors: B
authors: Lee
authors: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA 30322 Department of Pharmacology, Emory University, Atlanta, GA 30322.
authors: Haian
authors: H
authors: Fu
authors: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA 30322.
authors: Wei
authors: W
authors: Zhou
authors: Department of Mathematics and Statistics, Georgia State University, Atlanta, GA 30302.
authors: Yi
authors: Y
authors: Jiang
authors: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA 30322 aimarcu@emory.edu.
authors: Adam I
authors: AI
authors: Marcus
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D002448:Cell Adhesion; D016764:Cell Polarity; D003094:Collagen / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D017368:Protein Prenylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein
chemical_list: D003094:Collagen; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D020742:rhoA GTP-Binding Protein