STRIPAK components determine mode of cancer cell migration and metastasis
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Chris D Madsen Steven Hooper Melda Tozluoglu Andreas Bruckbauer Georgina Fletcher Janine T Erler Paul Bates Barry Thompson Erik SahaiAbstract
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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Journal Nature Cell Biology
Volume 17
Issue number 1
Pages 68-80
Available online
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Publisher website (DOI) 10.1038/ncb3083
Europe PubMed Central 25531779
Pubmed 25531779
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