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.
authors.affiliation: 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.
authors.forename: Chris D
authors.initials: CD
authors.lastname: Madsen
authors.affiliation: Tumour Cell Biology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields London WC2A 3LY, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Hooper
authors.affiliation: Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields London WC2A 3LY, UK.
authors.forename: Melda
authors.initials: M
authors.lastname: Tozluoglu
authors.affiliation: Lymphocyte Interaction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields London WC2A 3LY, UK.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bruckbauer
authors.affiliation: Epithelial Biology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields London, WC2A 3LY, UK.
authors.forename: Georgina
authors.initials: G
authors.lastname: Fletcher
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5 2200 Copenhagen N, Denmark.
authors.forename: Janine T
authors.initials: JT
authors.lastname: Erler
authors.affiliation: Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields London WC2A 3LY, UK.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bates
authors.affiliation: Epithelial Biology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields London, WC2A 3LY, UK.
authors.forename: Barry
authors.initials: B
authors.lastname: Thompson
authors.affiliation: Tumour Cell Biology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields London WC2A 3LY, UK.
authors.forename: Erik
authors.initials: E
authors.lastname: Sahai
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000205:Actomyosin / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D019295:Computational Biology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004331:Drosophila melanogaster; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism; D009124:Muscle Proteins; D009362:Neoplasm Metastasis; D028044:Phosphate-Binding Proteins; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D054460:rho-Associated Kinases / Q000378:metabolism; D000099149:Ezrin; D000099317:Hippo Kinases
chemical_list: D000205:Actomyosin; D051017:Apoptosis Regulatory Proteins; D001324:Autoantigens; D002148:Calmodulin-Binding Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; D028044:Phosphate-Binding Proteins; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D054460:rho-Associated Kinases; D000099149:Ezrin; C495390:PDCD10 protein, human; C107507:PPP1R14A protein, human; C000597217:STRIP1 protein, human; C000597218:STRIP2 protein, human; C405682:STRN3 protein, human; C071058:moesin; C071776:radixin; C109163:STK24 protein, human; D000099317:Hippo Kinases; C430908:STK26 protein, human; C515851:ROCK1 protein, human; C515852:ROCK2 protein, human; C517188:PPP1CB protein, human