title: A small molecule inhibitor of tropomyosin dissociates actin binding from tropomyosin-directed regulation of actin dynamics.
abstract: The tropomyosin family of proteins form end-to-end polymers along the actin filament. Tumour cells rely on specific tropomyosin-containing actin filament populations for growth and survival. To dissect out the role of tropomyosin in actin filament regulation we use the small molecule TR100 directed against the C terminus of the tropomyosin isoform Tpm3.1. TR100 nullifies the effect of Tpm3.1 on actin depolymerisation but surprisingly Tpm3.1 retains the capacity to bind F-actin in a cooperative manner. In vivo analysis also confirms that, in the presence of TR100, fluorescently tagged Tpm3.1 recovers normally into stress fibers. Assembling end-to-end along the actin filament is thereby not sufficient for tropomyosin to fulfil its function. Rather, regulation of F-actin stability by tropomyosin requires fidelity of information communicated at the barbed end of the actin filament. This distinction has significant implications for perturbing tropomyosin-dependent actin filament function in the context of anti-cancer drug development.
authors.affiliation: School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
authors.forename: Teresa T
authors.initials: TT
authors.lastname: Bonello
authors.affiliation: School of Medical Sciences and ARC Centre of Excellence in Advanced Molecular Imaging, University of New South Wales, Sydney, NSW, 2052, Australia.
authors.forename: Miro
authors.initials: M
authors.lastname: Janco
authors.affiliation: School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
authors.forename: Jeff
authors.initials: J
authors.lastname: Hook
authors.affiliation: School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
authors.forename: Alex
authors.initials: A
authors.lastname: Byun
authors.affiliation: School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Appaduray
authors.affiliation: School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
authors.forename: Irina
authors.initials: I
authors.lastname: Dedova
authors.affiliation: Pathology &Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hitchcock-DeGregori
authors.affiliation: School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
authors.forename: Edna C
authors.initials: EC
authors.lastname: Hardeman
authors.affiliation: School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
authors.forename: Justine R
authors.initials: JR
authors.lastname: Stehn
authors.affiliation: School of Medical Sciences and ARC Centre of Excellence in Advanced Molecular Imaging, University of New South Wales, Sydney, NSW, 2052, Australia.
authors.forename: Till
authors.initials: T
authors.lastname: Böcking
authors.affiliation: School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Gunning
mesh_terms: D008841:Actin Cytoskeleton / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D055503:Protein Multimerization / Q000187:drug effects; D011817:Rabbits; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D014335:Tropomyosin / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D054852:Small Molecule Libraries; D014335:Tropomyosin