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. Tyr700, Tyr731, and Tyr774 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.

► PTK6 directly phosphorylates tyrosine residues located on the C-terminal domain of c-Cbl.
► Phosphorylation of c-Cbl by PTK6 promotes degradation of c-Cbl.
► PTK6-induced down-regulation of c-Cbl is mediated by the ubiquitin–proteasome pathway.
► Downstream effects of PTK6-mediated c-Cbl degradation include multiple pro-oncogenic conduits.