A crucial role for DOK1 in PDGF-BB-stimulated glioma cell invasion through p130Cas and Rap1 signalling

被引：15
作者：
Barrett, Angela [1 ]
Evans, Ian M. [1 ]
Frolov, Antonina [1 ]
Britton, Gary [1 ]
Pellet-Many, Caroline [1 ]
Yamaji, Maiko [1 ]
Mehta, Vedanta [1 ]
Bandopadhyay, Rina [2 ]
Li, Ningning [3 ,4 ]
Brandner, Sebastian [3 ,4 ]
Zachary, Ian C. [1 ]
Frankel, Paul [1 ]
机构：
[1] UCL, Ctr Cardiovasc Biol & Med, Div Med, London WC1E 6JJ, England
[2] UCL, Reta Lila Weston Inst Neurol Studies, Inst Neurol, London WC1E 6JJ, England
[3] UCL, Div Neuropathol, Inst Neurol, London WC1E 6JJ, England
[4] UCL, Dept Neurodegenerat Dis, Inst Neurol, London WC1E 6JJ, England
来源：
JOURNAL OF CELL SCIENCE | 2014年 / 127卷 / 12期
基金：
英国生物技术与生命科学研究理事会;
关键词：
Cell motility; PDGF signalling; DOK1; p130Cas; GTPase; MEMBRANE RECRUITMENT; PHOSPHORYLATES DOK1; GROWTH; PROTEIN; IDENTIFICATION; P62(DOK); CANCER; EXPRESSION; INTEGRIN; ADHESION;
D O I：
10.1242/jcs.135988
中图分类号：
Q2 [细胞生物学];
学科分类号：
071009 ; 090102 ;
摘要：
DOK1 regulates platelet-derived growth factor (PDGF)-BB-stimulated glioma cell motility. Mechanisms regulating tumour cell motility are essential for invasion and metastasis. We report here that PDGF-BB-mediated glioma cell invasion and migration are dependent on the adaptor protein downstream of kinase 1 (DOK1). DOK1 is expressed in several glioma cell lines and in tumour biopsies from high-grade gliomas. DOK1 becomes tyrosine phosphorylated upon PDGF-BB stimulation of human glioma cells. Knockdown of DOK1 or expression of a DOK1 mutant (DOK1FF) containing Phe in place of Tyr at residues 362 and 398, resulted in inhibition of both the PDGF-BB-induced tyrosine phosphorylation of p130Cas (also known as BCAR1) and the activation of Rap1 (also known as TERF2IP). DOK1 colocalises with tyrosine phosphorylated p130Cas at the cell membrane of PDGF-BB-treated cells. Expression of a non-tyrosine-phosphorylatable substrate domain mutant of p130Cas (p130Cas15F) inhibited PDGF-BB-mediated Rap1 activation. Knockdown of DOK1 and Rap1 inhibited PDGF-BB-induced chemotactic cell migration, and knockdown of DOK1 and Rap1 and expression of DOK1FF inhibited PDGF-mediated three-dimensional (3D) spheroid invasion. These data show a crucial role for DOK1 in the regulation of PDGF-BB-mediated tumour cell motility through a p130Cas-Rap1 signalling pathway.
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收藏
页码：2647 / 2658
页数：12
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