title: The actin crosslinking protein palladin modulates force generation and mechanosensitivity of tumor associated fibroblasts.
abstract: Cells organize actin filaments into higher-order structures by regulating the composition, distribution and concentration of actin crosslinkers. Palladin is an actin crosslinker found in the lamellar actin network and stress fibers, which are critical for mechanosensing of the environment. Palladin also serves as a molecular scaffold for α-actinin, another key actin crosslinker. By virtue of its close interactions with actomyosin structures in the cell, palladin may play an important role in cell mechanics. However, the role of palladin in cellular force generation and mechanosensing has not been studied. Here, we investigate the role of palladin in regulating the plasticity of the actin cytoskeleton and cellular force generation in response to alterations in substrate stiffness. Traction force microscopy revealed that tumor-associated fibroblasts generate larger forces on substrates of increased stiffness. Contrary to expectations, knocking down palladin increased the forces generated by cells and inhibited their ability to sense substrate stiffness for very stiff gels. This was accompanied by significant differences in actin organization, adhesion dynamics and altered myosin organization in palladin knock-down cells. Our results suggest that actin crosslinkers such as palladin and myosin motors coordinate for optimal cell function and to prevent aberrant behavior as in cancer metastasis.
authors.affiliation: Department of Physics, University of Maryland, College Park MD 20742, USA.
authors.forename: Mikheil
authors.initials: M
authors.lastname: Azatov
authors.affiliation: Department of Biological Sciences, University of Toledo, Toledo, Ohio, 43606, USA.
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Goicoechea
authors.affiliation: Department of Cell Biology and Physiology and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Otey
authors.affiliation: Department of Physics, University of Maryland, College Park MD 20742, USA.|Institute for Physical Science and Technology, University of Maryland, College Park, MD 20742, USA.
authors.forename: Arpita
authors.initials: A
authors.lastname: Upadhyaya
mesh_terms: D000199:Actins / Q000378:metabolism; D000072645:Cancer-Associated Fibroblasts / Q000187:drug effects / Q000502:physiology*; D002448:Cell Adhesion; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000502:physiology*; D022001:Focal Adhesions / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D040542:Mechanotransduction, Cellular; D010750:Phosphoproteins / Q000502:physiology*
chemical_list: D000199:Actins; D003598:Cytoskeletal Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; C412722:PALLD protein, human; D010750:Phosphoproteins; C472645:blebbistatin