title: Coordinated cell motility is regulated by a combination of LKB1 farnesylation and kinase activity.
abstract: Cell motility requires the precise coordination of cell polarization, lamellipodia formation, adhesion, and force generation. LKB1 is a multi-functional serine/threonine kinase that associates with actin at the cellular leading edge of motile cells and suppresses FAK. We sought to understand how LKB1 coordinates these multiple events by systematically dissecting LKB1 protein domain function in combination with live cell imaging and computational approaches. We show that LKB1-actin colocalization is dependent upon LKB1 farnesylation leading to RhoA-ROCK-mediated stress fiber formation, but membrane dynamics is reliant on LKB1 kinase activity. We propose that LKB1 kinase activity controls membrane dynamics through FAK since loss of LKB1 kinase activity results in morphologically defective nascent adhesion sites. In contrast, defective farnesylation mislocalizes nascent adhesion sites, suggesting that LKB1 farnesylation serves as a targeting mechanism for properly localizing adhesion sites during cell motility. Together, we propose a model where coordination of LKB1 farnesylation and kinase activity serve as a multi-step mechanism to coordinate cell motility during migration.
authors.affiliation: Winship Cancer Institute of Emory University, Department of Hematology and Medical Oncology, Atlanta, GA, USA.|Graduate Program in Cancer Biology, Emory University, Atlanta, GA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Wilkinson
authors.affiliation: Winship Cancer Institute of Emory University, Department of Hematology and Medical Oncology, Atlanta, GA, USA.|Department of Biomedical Informatics, Emory University, Atlanta, GA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Winship Cancer Institute of Emory University, Department of Hematology and Medical Oncology, Atlanta, GA, USA.|Graduate Program in Cancer Biology, Emory University, Atlanta, GA, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Zoine
authors.affiliation: Department of Biomedical Informatics, Stony Brook University, Stony Brook, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Saltz
authors.affiliation: Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Winship Cancer Institute of Emory University, Department of Hematology and Medical Oncology, Atlanta, GA, USA.|Department of Biomedical Informatics, Emory University, Atlanta, GA, USA.
authors.forename: L A D
authors.initials: LA
authors.lastname: Cooper
authors.affiliation: Winship Cancer Institute of Emory University, Department of Hematology and Medical Oncology, Atlanta, GA, USA.
authors.forename: A I
authors.initials: AI
authors.lastname: Marcus
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000199:Actins / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D002448:Cell Adhesion; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D016297:Mutagenesis, Site-Directed; D054876:Prenylation; D000072417:Protein Domains; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D000577:Amides; D007211:Indoles; C527797:N-methyl-N-(3-((2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino)-methyl)-pyridin-2-yl)-methanesulfonamide; D011725:Pyridines; D013449:Sulfonamides; C108830:Y 27632; D051417:Focal Adhesion Kinase 1; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D020742:rhoA GTP-Binding Protein