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Updated: May 3, 2026
Impedance-based Real-time Measurement of Cancer Cell Migration and Invasion
Published on: April 2, 2020
BRK targets Dok1 for ubiquitin-mediated proteasomal degradation to promote cell proliferation and migration
Sayem Miah1, Raghuveera Kumar Goel1, Chenlu Dai1
1Department of Biochemistry, 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.
Insights
Breast tumor kinase (BRK) promotes breast cancer by phosphorylating and degrading the tumor suppressor Dok1. This novel mechanism targets Dok1 for destruction via the ubiquitin-proteasome pathway, driving tumor formation.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Breast tumor kinase (BRK), or protein tyrosine kinase 6 (PTK6), is overexpressed in over 60% of human breast carcinomas.
- BRK overexpression sensitizes mammary epithelial cells to mitogenic signals, promoting proliferation and tumor formation.
Purpose of the Study:
- To elucidate the molecular mechanisms by which BRK promotes tumor formation.
- To identify and characterize BRK target proteins involved in its oncogenic function.
Main Methods:
- Investigated the interaction between BRK and Downstream of tyrosine kinases 1 (Dok1).
- Determined the specific phosphorylation site of Dok1 by BRK (Y362).
- Analyzed the effect of BRK-mediated phosphorylation on Dok1 stability and degradation pathways.
Main Results:
- BRK directly interacts with and phosphorylates Dok1 at tyrosine residue 362 (Y362).
- Phosphorylation of Dok1 by BRK leads to its significant downregulation.
- This downregulation occurs through a ubiquitin-proteasome-mediated degradation mechanism.
Conclusions:
- BRK promotes tumor formation by targeting the tumor suppressor Dok1 for degradation.
- BRK utilizes the ubiquitin-proteasomal pathway to destabilize Dok1, contributing to breast cancer progression.
- This study reveals a novel mechanism of BRK action in oncogenesis involving targeted protein degradation.
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