BRK targets Dok1 for ubiquitin-mediated proteasomal degradation to promote cell proliferation and migration

Sayem Miah; Raghuveera Kumar Goel; Chenlu Dai; Natasha Kalra; Erika Beaton-Brown; Edward T Bagu; Keith Bonham; Kiven E Lukong

doi:10.1371/journal.pone.0087684

BRK targets Dok1 for ubiquitin-mediated proteasomal degradation to promote cell proliferation and migration

PLoS One. 2014 Feb 11;9(2):e87684. doi: 10.1371/journal.pone.0087684. eCollection 2014.

Authors

Sayem Miah¹, Raghuveera Kumar Goel¹, Chenlu Dai¹, Natasha Kalra¹, Erika Beaton-Brown², Edward T Bagu², Keith Bonham², Kiven E Lukong¹

Affiliations

¹ Department of Biochemistry, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
² Department of Biochemistry, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada ; Cancer Research Unit, Health Research Division, Saskatchewan Cancer Agency, and Division of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.

Abstract

Breast tumor kinase (BRK), also known as protein tyrosine kinase 6 (PTK6), is a non-receptor tyrosine kinase overexpressed in more that 60% of human breast carcinomas. The overexpression of BRK has been shown to sensitize mammary epithelial cells to mitogenic signaling and to promote cell proliferation and tumor formation. The molecular mechanisms of BRK have been unveiled by the identification and characterization of BRK target proteins. Downstream of tyrosine kinases 1 or Dok1 is a scaffolding protein and a substrate of several tyrosine kinases. Herein we show that BRK interacts with and phosphorylates Dok1 specifically on Y362. We demonstrate that this phosphorylation by BRK significantly downregulates Dok1 in a ubiquitin-proteasome-mediated mechanism. Together, these results suggest a novel mechanism of action of BRK in the promotion of tumor formation, which involves the targeting of tumor suppressor Dok1 for degradation through the ubiquitin proteasomal pathway.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Breast Neoplasms / genetics*
Breast Neoplasms / metabolism*
Cell Line, Tumor
Cell Movement
Cell Proliferation
DNA-Binding Proteins / metabolism*
Female
Gene Expression Regulation, Neoplastic*
Genes, Tumor Suppressor
Green Fluorescent Proteins / chemistry
HEK293 Cells
Humans
Neoplasm Proteins / metabolism*
Phosphoproteins / metabolism*
Phosphorylation
Proteasome Endopeptidase Complex / metabolism*
Protein-Tyrosine Kinases / metabolism*
RNA-Binding Proteins / metabolism*
Signal Transduction
src Homology Domains

Substances

DNA-Binding Proteins
DOK1 protein, human
Neoplasm Proteins
Phosphoproteins
RNA-Binding Proteins
Green Fluorescent Proteins
Protein-Tyrosine Kinases
PTK6 protein, human
Proteasome Endopeptidase Complex

Grants and funding

This work was supported by startup funds awarded to KEL by the Department of Biochemistry at the U of S. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.