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

被引：56

作者：

Castellano, Esther ^{[1
,2
]}

Molina-Arcas, Miriam ^{[1
,3
]}

Krygowska, Agata Adelajda ^{[2
]}

East, Philip ^{[4
]}

Warne, Patricia ^{[1
]}

Nicol, Alastair ^{[5
]}

Downward, Julian ^{[1
,3
]}

机构：

[1] Francis Crick Inst, Oncogene Biol, 44 Lincolns Inn Fields, London WC2A 3LY, England

[2] Queen Mary Univ London, Barts Canc Inst, Ctr Canc & Inflammat, London EC1M 6BQ, England

[3] Inst Canc Res, Lung Canc Grp, 237 Fulham Rd, London SW3 6JB, England

[4] Francis Crick Inst, Computat Biol, 44 Lincolns Inn Fields, London WC2A 3LY, England

[5] Francis Crick Inst, Light Microscopy Labs, 44 Lincolns Inn Fields, London WC2A 3LY, England

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

英国惠康基金;

关键词：

COLON-CANCER CELLS; GENE-EXPRESSION; MESSENGER-RNA; RHO-GTPASES; LUNG-CANCER; K-RAS; CYTOSKELETAL ORGANIZATION; NEURONAL MIGRATION; REGULATORY SUBUNIT; SMALL-INTESTINE;

D O I：

10.1038/ncomms11245

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 p110 alpha decreases cell motility and prevents activation of Rac GTPase. Analysis of gene expression in cells lacking RAS interaction with p110 alpha 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.

引用

页数：13

共 67 条

[1] Activation of a Dab1/CrkL/C3G/Rap1 pathway in reelin-stimulated neurons [J].