PTK6 promotes degradation of c-Cbl through PTK6-mediated phosphorylation.
PTK6 (also known as Brk) is an intracellular tyrosine kinase which induces proliferation, anti-apoptosis, migration, and anchorage-independent growth. Herein we report that PTK6 phosphorylates and down-regulates E3 ubiquitin ligase c-Cbl. Tyr(700), Tyr(731), and Tyr(774) residues in the C-terminal domain of c-Cbl are major phosphorylation sites targeted by PTK6. The phosphorylated c-Cbl is subjected to auto-ubiquitination and degraded through the ubiquitin-proteasome pathway. These results provide evidence for a novel mechanism demonstrating the oncogenic potential of PTK6 through degradation of c-Cbl, which is an E3 ligase important in down-regulation of oncoproteins.
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
Shin-Ae
SA
Kang
Seung-Taek
ST
Lee
D002384:Catalysis; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
D009363:Neoplasm Proteins; D014443:Tyrosine; D050721:Proto-Oncogene Proteins c-cbl; D011505:Protein-Tyrosine Kinases; C088375:PTK6 protein, human; D046988:Proteasome Endopeptidase Complex