Rescue of tropomyosin deficiency in Drosophila and human cancer cells by synaptopodin reveals a role of tropomyosin α in RhoA stabilization

Jenny S. Wong, Elizabeth Iorns, Michelle N. Rheault, Toby M. Ward, Priyanka Rashmi, Ursula Weber, Marc E. Lippman, Christian Faul, Marek Mlodzik, Peter Mundel

Research output: Contribution to journalArticle

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1028-1040
Number of pages13
JournalEMBO Journal
Volume31
Issue number4
DOIs
StatePublished - Feb 15 2012

Keywords

  • actin filaments
  • cell migration
  • oskar mRNA
  • RhoA
  • Smurf1

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

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    Wong, J. S., Iorns, E., Rheault, M. N., Ward, T. M., Rashmi, P., Weber, U., Lippman, M. E., Faul, C., Mlodzik, M., & Mundel, P. (2012). Rescue of tropomyosin deficiency in Drosophila and human cancer cells by synaptopodin reveals a role of tropomyosin α in RhoA stabilization. EMBO Journal, 31(4), 1028-1040. https://doi.org/10.1038/emboj.2011.464