title: Rescue of tropomyosin deficiency in Drosophila and human cancer cells by synaptopodin reveals a role of tropomyosin α in RhoA stabilization.
abstract: Tropomyosins are widespread actin-binding proteins that influence numerous cellular functions including actin dynamics, cell migration, tumour suppression, and Drosophila oocyte development. Synaptopodin is another actin-binding protein with a more restricted expression pattern in highly dynamic cell compartments such as kidney podocyte foot processes, where it promotes RhoA signalling by blocking the Smurf1-mediated ubiquitination of RhoA. Here, we show that synaptopodin has a shorter half-life but shares functional properties with the highly stable tropomyosin. Transgenic expression of synaptopodin restores oskar mRNA localization in Drosophila oocytes mutant for TmII, thereby rescuing germline differentiation and fertility. Synaptopodin restores stress fibres in tropomyosin-deficient human MDA-MB 231 breast cancer cells and TPMα-depleted fibroblasts. Gene silencing of TPMα but not TPMβ causes loss of stress fibres by promoting Smurf1-mediated ubiquitination and proteasomal degradation of RhoA. Functionally, overexpression of synaptopodin or RhoA(K6,7R) significantly reduces MDA-MB 231 cell migration. Our findings elucidate RhoA stabilization by structurally unrelated actin-binding proteins as a conserved mechanism for regulation of stress fibre dynamics and cell motility in a cell type-specific fashion.
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Jenny S
authors.initials: JS
authors.lastname: Wong
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Iorns
authors.forename: Michelle N
authors.initials: MN
authors.lastname: Rheault
authors.forename: Toby M
authors.initials: TM
authors.lastname: Ward
authors.forename: Priyanka
authors.initials: P
authors.lastname: Rashmi
authors.forename: Ursula
authors.initials: U
authors.lastname: Weber
authors.forename: Marc E
authors.initials: ME
authors.lastname: Lippman
authors.forename: Christian
authors.initials: C
authors.lastname: Faul
authors.forename: Marek
authors.initials: M
authors.lastname: Mlodzik
authors.forename: Peter
authors.initials: P
authors.lastname: Mundel
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000502:physiology*; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D014335:Tropomyosin / Q000235:genetics* / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000502:physiology*
chemical_list: D008840:Microfilament Proteins; C503967:SYNPO protein, human; D014335:Tropomyosin; D020742:rhoA GTP-Binding Protein