title: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, The State Key Laboratory of Cancer Biology, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jiangtian
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Biochemistry and Molecular Biology, The State Key Laboratory of Cancer Biology, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry and Molecular Biology, The State Key Laboratory of Cancer Biology, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
authors.forename: Yun-Cai
authors.initials: YC
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, The State Key Laboratory of Cancer Biology, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Libo
authors.initials: L
authors.lastname: Yao
authors.affiliation: Department of Biochemistry and Molecular Biology, The State Key Laboratory of Cancer Biology, The Fourth Military Medical University, Xi'an 710032, China. Electronic address: lixia@fmmu.edu.cn.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, The State Key Laboratory of Cancer Biology, The Fourth Military Medical University, Xi'an 710032, China. Electronic address: sujin923@fmmu.edu.cn.
authors.forename: Jin
authors.initials: J
authors.lastname: Su
mesh_terms: D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D000070818:Discoidin Domain Receptors; D004795:Enzyme Stability; D005347:Fibroblasts / Q000201:enzymology; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000201:enzymology; D050721:Proto-Oncogene Proteins c-cbl / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000378:metabolism*; D015398:Signal Transduction; D013582:Synovial Fluid / Q000166:cytology; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C118387:Cblb protein, mouse; D011975:Receptors, Mitogen; D050721:Proto-Oncogene Proteins c-cbl; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse
keywords: Cbl-b; Collagen receptor; DDR2; Degradation; Ubiquitination