Ubiquitin ligase Cbl-b acts as a negative regulator in discoidin domain receptor 2 signaling via modulation of its stability.

ABSTRACT

Discoidin domain receptor 2 (DDR2), a collagen receptor tyrosine kinase, initiates signal transduction upon collagen binding, but little is known as to how DDR2 signaling is negatively regulated. Herein we demonstrate that Cbl family member Cbl-b predominantly promotes the ubiquitination of DDR2 upon collagen II stimulation. Cbl-b-mediated ubiquitination accelerates the degradation of activated DDR2. Finally, the production of MMP-13, a downstream target of DDR2, is enhanced in Cbl-b-knocked down MC3T3-E1 cells and Cbl-b-deficient mouse primary synovial fibroblasts. Thus, Cbl-b, by promoting the ubiquitination and degradation of DDR2, functions as a negative regulator in the DDR2 signaling pathway.