title: BRK targets Dok1 for ubiquitin-mediated proteasomal degradation to promote cell proliferation and migration.
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.
authors: Department of Biochemistry, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors: Sayem
authors: S
authors: Miah
authors: Department of Biochemistry, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors: Raghuveera Kumar
authors: RK
authors: Goel
authors: Department of Biochemistry, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors: Chenlu
authors: C
authors: Dai
authors: Department of Biochemistry, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors: Natasha
authors: N
authors: Kalra
authors: 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.
authors: Erika
authors: E
authors: Beaton-Brown
authors: 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.
authors: Edward T
authors: ET
authors: Bagu
authors: 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.
authors: Keith
authors: K
authors: Bonham
authors: Department of Biochemistry, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors: Kiven E
authors: KE
authors: Lukong
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D049452:Green Fluorescent Proteins / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D015398:Signal Transduction; D018909:src Homology Domains
chemical_list: D004268:DNA-Binding Proteins; C489560:DOK1 protein, human; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D049452:Green Fluorescent Proteins; D011505:Protein-Tyrosine Kinases; C088375:PTK6 protein, human; D046988:Proteasome Endopeptidase Complex