STRIPAK components determine mode of cancer cell migration and metastasis

Chris D Madsen; Steven Hooper; Melda Tozluoglu; Andreas Bruckbauer; Georgina Fletcher; Janine Terra Erler; Paul A Bates; Barry Thompson; Erik Sahai

doi:10.1038/ncb3083

STRIPAK components determine mode of cancer cell migration and metastasis

Chris D Madsen, Steven Hooper, Melda Tozluoglu, Andreas Bruckbauer, Georgina Fletcher, Janine Terra Erler, Paul A Bates, Barry Thompson, Erik Sahai

89 Citations (Scopus)

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 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.

Original language	English
Journal	Nature Cell Biology
Volume	17
Issue number	1
Pages (from-to)	68-80
Number of pages	13
ISSN	1465-7392
DOIs	https://doi.org/10.1038/ncb3083
Publication status	Published - 1 Jan 2015

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title = "STRIPAK components determine mode of cancer cell migration and metastasis",

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 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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T1 - STRIPAK components determine mode of cancer cell migration and metastasis

AU - Madsen, Chris D

AU - Hooper, Steven

AU - Tozluoglu, Melda

AU - Bruckbauer, Andreas

AU - Fletcher, Georgina

AU - Erler, Janine Terra

AU - Bates, Paul A

AU - Thompson, Barry

AU - Sahai, Erik

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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.

AB - 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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DO - 10.1038/ncb3083

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VL - 17

SP - 68

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JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 1

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STRIPAK components determine mode of cancer cell migration and metastasis

Abstract

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