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Nat Cell Biol. 2015 Jan;17(1):68-80. doi: 10.1038/ncb3083. Epub 2014 Dec 22.

STRIPAK components determine mode of cancer cell migration and metastasis.

Author information

1
1] Tumour Cell Biology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields London WC2A 3LY, UK [2] Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5 2200 Copenhagen N, Denmark.
2
Tumour Cell Biology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields London WC2A 3LY, UK.
3
Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields London WC2A 3LY, UK.
4
Lymphocyte Interaction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields London WC2A 3LY, UK.
5
Epithelial Biology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields London, WC2A 3LY, UK.
6
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5 2200 Copenhagen N, Denmark.

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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PMID:
25531779
PMCID:
PMC5354264
DOI:
10.1038/ncb3083
[Indexed for MEDLINE]
Free PMC Article

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