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Dok-6, a Novel p62 Dok family member, promotes Ret-mediated neurite outgrowth.

Activation of Ret, the receptor-tyrosine kinase for the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs), results in the recruitment and assembly of adaptor protein complexes that function to transduce signals downstream of the receptor. Here we identify Dok-6, a novel member of the Dok-4/5 subclass of the p62 Dok family of intracellular adaptor molecules, and characterize its interaction with Ret. Expression analysis reveals that Dok-6 is highly expressed in the developing central nervous system and is co-expressed with Ret in several locations, including sympathetic, sensory, and parasympathetic ganglia, as well as in the ureteric buds of the developing kidneys. Pull-down assays using the Dok-6 phosphotyrosine binding (PTB) domain and GDNF-activated Ret indicate that Dok-6 binds to the phosphorylated Ret Tyr(1062) residue. Moreover, ligand activation of Ret resulted in phosphorylation of tyrosine residue(s) located within the unique C terminus of Dok-6 predominantly through a Src-dependent mechanism, indicating that Dok-6 is a substrate of the Ret-Src signaling pathway. Interestingly, expression of Dok-6 potentiated GDNF-induced neurite outgrowth in GDNF family receptor alpha1 (GFRalpha1)-expressing Neuro2A cells that was dependent upon the C-terminal residues of Dok-6. Taken together, these data identify Dok-6 as a novel Dok-4/5-related adaptor molecule that may function in vivo to transduce signals that regulate Ret-mediated processes such as axonal projection.

Pubmed ID: 15286081

Authors

  • Crowder RJ
  • Enomoto H
  • Yang M
  • Johnson EM
  • Milbrandt J

Journal

The Journal of biological chemistry

Publication Data

October 1, 2004

Associated Grants

  • Agency: NIA NIH HHS, Id: AG13730
  • Agency: NIDDK NIH HHS, Id: T32-DK07296

Mesh Terms

  • Adaptor Proteins, Vesicular Transport
  • Animals
  • Base Sequence
  • Binding Sites
  • Cell Line, Tumor
  • Embryo, Mammalian
  • Humans
  • Mice
  • Molecular Sequence Data
  • Neurites
  • Oncogene Proteins
  • Protein Binding
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Sequence Alignment
  • Signal Transduction
  • Tissue Distribution
  • Transfection