Critical role for DOK1 in PDGF-BB stimulated glioma cell invasion via p130Cas and Rap1 signalling | Zendy

Angela N. Barrett | Zendy; Ian Evans | Zendy; Antonina Frolov | Zendy; Gary Britton | Zendy; Caroline PelletMany | Zendy; Maiko Yamaji | Zendy; Vedanta Mehta | Zendy; Rina Bandophadyay | Zendy; Ningning Li | Zendy; Sebastian Brandner | Zendy; Ian Zachary | Zendy; Paul Frankel | Zendy

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Critical role for DOK1 in PDGF-BB stimulated glioma cell invasion via p130Cas and Rap1 signalling

Author(s) -

Angela N. Barrett,

Ian Evans,

Antonina Frolov,

Gary Britton,

Caroline PelletMany,

Maiko Yamaji,

Vedanta Mehta,

Rina Bandophadyay,

Ningning Li,

Sebastian Brandner,

Ian Zachary,

Paul Frankel

Publication year - 2014

Publication title -

journal of cell science

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.384

H-Index - 278

eISSN - 1477-9137

pISSN - 0021-9533

DOI - 10.1242/jcs.135988

Subject(s) - biology , rap1 , signalling , platelet derived growth factor receptor , microbiology and biotechnology , cancer research , signal transduction , genetics , growth factor , receptor

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. 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. [Corrected]

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