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RAS signalling through PI3-Kinase controls cell migration via modulation of Reelin expression

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  • Esther Castellano

    (Oncogene Biology, The Francis Crick Institute
    Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London)

  • Miriam Molina-Arcas

    (Oncogene Biology, The Francis Crick Institute
    Lung Cancer Group, The Institute of Cancer Research)

  • Agata Adelajda Krygowska

    (Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London)

  • Philip East

    (Computational Biology, The Francis Crick Institute)

  • Patricia Warne

    (Oncogene Biology, The Francis Crick Institute)

  • Alastair Nicol

    (Light Microscopy Laboratories, The Francis Crick Institute)

  • Julian Downward

    (Oncogene Biology, The Francis Crick Institute
    Lung Cancer Group, The Institute of Cancer Research)

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.

Suggested Citation

  • Esther Castellano & Miriam Molina-Arcas & Agata Adelajda Krygowska & Philip East & Patricia Warne & Alastair Nicol & Julian Downward, 2016. "RAS signalling through PI3-Kinase controls cell migration via modulation of Reelin expression," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11245
    DOI: 10.1038/ncomms11245
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    Cited by:

    1. Ming Yi & Ruoqing Zhu & Robert M Stephens, 2018. "GradientScanSurv—An exhaustive association test method for gene expression data with censored survival outcome," PLOS ONE, Public Library of Science, vol. 13(12), pages 1-28, December.

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