RAS signalling through PI3-Kinase controls cell migration via modulation of Reelin expression.
Loading...
Embargo End Date
ICR Authors
Authors
Castellano, E
Molina-Arcas, M
Krygowska, AA
East, P
Warne, P
Nicol, A
Downward, J
Molina-Arcas, M
Krygowska, AA
East, P
Warne, P
Nicol, A
Downward, J
Document Type
Journal Article
Date
2016-04-13
Date Accepted
2016-03-03
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.
Citation
Nature communications, 2016, 7 pp. 11245 - ?
Source Title
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
Collections
Research Team
Lung Cancer Group