title: Dok5 is substrate of TrkB and TrkC receptors and involved in neurotrophin induced MAPK activation.
abstract: Tropomyosin-related kinase (Trk) family receptors are a group of high affinity receptors for neurotrophin growth factors, which have pivotal functions in many physiological processes of nervous system. Trk receptors can dimerize and autophosphorylate upon neurotrophin stimulation, then recruit multiple adaptor proteins to transduct signal. In this report, we identified Dok5, a member of Dok family, as a new substrate of TrkB/C receptors. In yeast two-hybrid assay, Dok5 can interact with intracellular domain of TrkB and TrkC receptor through its PTB domain, but not with that of TrkA receptor. The interaction was then confirmed by GST pull-down assay and Co-IP experiment. Dok5 co-localized with TrkB and TrkC in differentiated PC12 cells, providing another evidence for their interaction. By using mutational analysis, we characterized that Dok5 PTB domain bound to Trk receptor NPQY motif in a kinase-activity-dependent manner. Furthermore, competition experiment indicated that Dok5 competed with N-shc for binding to the receptors at the same site. Finally, we showed that Dok5 was involved in the activation of MAPK pathway induced by neurotrophin stimulation. Taken together, these results suggest that Dok5 acts as substrate of TrkB/C receptors and is involved in neurotrophin induced MAPK signal pathway activation.
authors.affiliation: The National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Chinese National Human Genome Center, Beijing 100005, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Jiping
authors.initials: J
authors.lastname: Yue
authors.forename: Yuangang
authors.initials: Y
authors.lastname: You
authors.forename: Bin
authors.initials: B
authors.lastname: Yin
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Gong
authors.forename: Caimin
authors.initials: C
authors.lastname: Xu
authors.forename: Boqin
authors.initials: B
authors.lastname: Qiang
authors.forename: Jiangang
authors.initials: J
authors.lastname: Yuan
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiaozhong
authors.initials: X
authors.lastname: Peng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000378:metabolism / Q000494:pharmacology*; D016716:PC12 Cells; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D020813:Receptor, trkB / Q000378:metabolism*; D020812:Receptor, trkC / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction; D020798:Two-Hybrid System Techniques
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C432912:DOK5 protein, human; D009414:Nerve Growth Factors; D010750:Phosphoproteins; D020813:Receptor, trkB; D020812:Receptor, trkC; D020928:Mitogen-Activated Protein Kinases