title: RAS signalling through PI3-Kinase controls cell migration via modulation of Reelin expression.
abstract: RAS signalling through phosphoinositide 3-kinase (PI3-Kinase) has been shown to have an essential role in tumour initiation and maintenance. RAS also regulates cell motility and tumour invasiveness, but the role of direct RAS binding to PI3-Kinase in this remains uncertain. Here, we provide evidence that disruption of RAS interaction with PI3-Kinase p110α decreases cell motility and prevents activation of Rac GTPase. Analysis of gene expression in cells lacking RAS interaction with p110α reveals increased levels of the extracellular matrix glycoprotein Reelin and activation of its downstream pathway resulting in upregulation of E-cadherin expression. Induction of the Reelin/E-cadherin axis is also observed in Kras mutant lung tumours that are regressing due to blockade of RAS interaction with PI3-Kinase. Furthermore, loss of Reelin correlates with decreased survival of lung and breast cancer patients. Reelin thus plays a role in restraining RAS and PI3-kinase promotion of cell motility and potentially tumour metastasis.
authors.affiliation: Oncogene Biology, The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.|Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Esther
authors.initials: E
authors.lastname: Castellano
authors.affiliation: Oncogene Biology, The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.|Lung Cancer Group, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Miriam
authors.initials: M
authors.lastname: Molina-Arcas
authors.affiliation: Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Agata Adelajda
authors.initials: AA
authors.lastname: Krygowska
authors.affiliation: Computational Biology, The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: East
authors.affiliation: Oncogene Biology, The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Patricia
authors.initials: P
authors.lastname: Warne
authors.affiliation: Light Microscopy Laboratories, The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Alastair
authors.initials: A
authors.lastname: Nicol
authors.affiliation: Oncogene Biology, The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.|Lung Cancer Group, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Downward
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D002465:Cell Movement; D016764:Cell Polarity; D004789:Enzyme Activation; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011485:Protein Binding; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D015820:Cadherins; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D000091042:Reelin Protein; D012697:Serine Endopeptidases; D020830:rac1 GTP-Binding Protein; D018631:ras Proteins; C000717128:Reln protein, mouse