title: TGF-β regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion.
abstract: Recent studies implicate a role for cell mechanics in cancer progression. The epithelial-to-mesenchymal transition (EMT) regulates the detachment of cancer cells from the epithelium and facilitates their invasion into stromal tissue. Although classic EMT hallmarks include loss of cell-cell adhesions, morphology changes, and increased invasion capacity, little is known about the associated mechanical changes. Previously, force application on integrins has been shown to initiate cytoskeletal rearrangements that result in increased cell stiffness and a stiffening response. Here we demonstrate that transforming growth factor β (TGF-β)-induced EMT results in decreased stiffness and loss of the normal stiffening response to force applied on integrins. We find that suppression of the RhoA guanine nucleotide exchange factors (GEFs) LARG and GEF-H1 through TGF-β/ALK5-enhanced proteasomal degradation mediates these changes in cell mechanics and affects EMT-associated invasion. Taken together, our results reveal a functional connection between attenuated stiffness and stiffening response and the increased invasion capacity acquired after TGF-β-induced EMT.
authors.affiliation: Department of Physics and Astronomy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
authors.forename: Lukas D
authors.initials: LD
authors.lastname: Osborne
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710.
authors.forename: George Z
authors.initials: GZ
authors.lastname: Li
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710.
authors.forename: Tam
authors.initials: T
authors.lastname: How
authors.affiliation: Department of Physics and Astronomy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
authors.forename: E Tim
authors.initials: ET
authors.lastname: O'Brien
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710 karthike@mailbox.sc.edu rsuper@physics.unc.edu gerard.blobe@duke.edu.
authors.forename: Gerard C
authors.initials: GC
authors.lastname: Blobe
authors.affiliation: Department of Physics and Astronomy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 karthike@mailbox.sc.edu rsuper@physics.unc.edu gerard.blobe@duke.edu.
authors.forename: Richard
authors.initials: R
authors.lastname: Superfine
authors.affiliation: Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208 karthike@mailbox.sc.edu rsuper@physics.unc.edu gerard.blobe@duke.edu.
authors.forename: Karthikeyan
authors.initials: K
authors.lastname: Mythreye
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena / Q000235:genetics*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D051379:Mice; D009361:Neoplasm Invasiveness; D011312:Pressure; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology
chemical_list: C577222:ARHGEF12 protein, human; C577356:ARHGEF2 protein, human; D016023:Integrins; D064067:Rho Guanine Nucleotide Exchange Factors; D016212:Transforming Growth Factor beta