title: TEM4 is a junctional Rho GEF required for cell-cell adhesion, monolayer integrity and barrier function.
abstract: Signaling events mediated by Rho family GTPases orchestrate cytoskeletal dynamics and cell junction formation. The activation of Rho GTPases is tightly regulated by guanine-nucleotide-exchange factors (GEFs). In this study, we identified a novel Rho-specific GEF called TEM4 (tumor endothelial marker 4) that associates with multiple members of the cadherin-catenin complex and with several cytoskeleton-associated proteins. Depending on confluence, TEM4 localized to either actin stress fibers or areas of cell-cell contact. The junctional localization of TEM4 was independent of actin binding. Depletion of endogenous TEM4 by shRNAs impaired Madin-Darby canine kidney (MDCK) and human umbilical vein endothelial cell (HUVEC) cell junctions, disrupted MDCK acini formation in 3D culture and negatively affected endothelial barrier function. Taken together, our findings implicate TEM4 as a novel and crucial junctional Rho GEF that regulates cell junction integrity and epithelial and endothelial cell function.
authors.affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Griffin Cancer Research Building, Room 307, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Siu P
authors.initials: SP
authors.lastname: Ngok
authors.forename: Rory
authors.initials: R
authors.lastname: Geyer
authors.forename: Antonis
authors.initials: A
authors.lastname: Kourtidis
authors.forename: Natalia
authors.initials: N
authors.lastname: Mitin
authors.forename: Ryan
authors.initials: R
authors.lastname: Feathers
authors.forename: Channing
authors.initials: C
authors.lastname: Der
authors.forename: Panos Z
authors.initials: PZ
authors.lastname: Anastasiadis
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology*; D003599:Cytoskeleton / Q000378:metabolism*; D004285:Dogs; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C577226:ARHGEF17 protein, human; D020662:Guanine Nucleotide Exchange Factors; D064067:Rho Guanine Nucleotide Exchange Factors
keywords: Catenin; Cell adhesion; Cell junction; Guanine nucleotide exchange factor; RhoA; TEM4