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STRIPAK components determine mode of cancer cell migration and metastasis

Madsen, Chris D LU ; Hooper, Steven; Tozluoglu, Melda; Bruckbauer, Andreas; Fletcher, Georgina; Erler, Janine T; Bates, Paul A; Thompson, Barry and Sahai, Erik (2015) In Nature Cell Biology 17(1). p.68-80
Abstract

The contractile actomyosin cytoskeleton and its connection to the plasma membrane are critical for control of cell shape and migration. We identify three STRIPAK complex components, FAM40A, FAM40B and STRN3, as regulators of the actomyosin cortex. We show that FAM40A negatively regulates the MST3 and MST4 kinases, which promote the co-localization of the contractile actomyosin machinery with the Ezrin/Radixin/Moesin family proteins by phosphorylating the inhibitors of PPP1CB, PPP1R14A-D. Using computational modelling, in vitro cell migration assays and in vivo breast cancer metastasis assays we demonstrate that co-localization of contractile activity and actin-plasma membrane linkage reduces cell speed on planar surfaces, but favours... (More)

The contractile actomyosin cytoskeleton and its connection to the plasma membrane are critical for control of cell shape and migration. We identify three STRIPAK complex components, FAM40A, FAM40B and STRN3, as regulators of the actomyosin cortex. We show that FAM40A negatively regulates the MST3 and MST4 kinases, which promote the co-localization of the contractile actomyosin machinery with the Ezrin/Radixin/Moesin family proteins by phosphorylating the inhibitors of PPP1CB, PPP1R14A-D. Using computational modelling, in vitro cell migration assays and in vivo breast cancer metastasis assays we demonstrate that co-localization of contractile activity and actin-plasma membrane linkage reduces cell speed on planar surfaces, but favours migration in confined environments similar to those observed in vivo. We further show that FAM40B mutations found in human tumours uncouple it from PP2A and enable it to drive a contractile phenotype, which may underlie its role in human cancer.

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@article{8710b31d-2914-4a89-ac9f-a5b6dabfb03e,
  abstract     = {<p>The contractile actomyosin cytoskeleton and its connection to the plasma membrane are critical for control of cell shape and migration. We identify three STRIPAK complex components, FAM40A, FAM40B and STRN3, as regulators of the actomyosin cortex. We show that FAM40A negatively regulates the MST3 and MST4 kinases, which promote the co-localization of the contractile actomyosin machinery with the Ezrin/Radixin/Moesin family proteins by phosphorylating the inhibitors of PPP1CB, PPP1R14A-D. Using computational modelling, in vitro cell migration assays and in vivo breast cancer metastasis assays we demonstrate that co-localization of contractile activity and actin-plasma membrane linkage reduces cell speed on planar surfaces, but favours migration in confined environments similar to those observed in vivo. We further show that FAM40B mutations found in human tumours uncouple it from PP2A and enable it to drive a contractile phenotype, which may underlie its role in human cancer.</p>},
  author       = {Madsen, Chris D and Hooper, Steven and Tozluoglu, Melda and Bruckbauer, Andreas and Fletcher, Georgina and Erler, Janine T and Bates, Paul A and Thompson, Barry and Sahai, Erik},
  issn         = {1465-7392},
  keyword      = {Actin Cytoskeleton,Actomyosin,Animals,Apoptosis Regulatory Proteins,Autoantigens,Breast Neoplasms,Calmodulin-Binding Proteins,Carrier Proteins,Cell Line, Tumor,Cell Movement,Computational Biology,Cytoskeletal Proteins,Drosophila melanogaster,Female,Humans,Membrane Proteins,Microfilament Proteins,Neoplasm Metastasis,Phosphoprotein Phosphatases,Phosphorylation,Protein Phosphatase 1,Protein Phosphatase 2,Protein-Serine-Threonine Kinases,Proto-Oncogene Proteins,RNA Interference,RNA, Small Interfering,Signal Transduction,rho-Associated Kinases,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {1},
  pages        = {68--80},
  publisher    = {Nature Publishing Group},
  series       = {Nature Cell Biology},
  title        = {STRIPAK components determine mode of cancer cell migration and metastasis},
  url          = {http://dx.doi.org/10.1038/ncb3083},
  volume       = {17},
  year         = {2015},
}