TY - JOUR
T1 - Dok-6, a novel p62 Dok family member, promotes ret-mediated neurite outgrowth
AU - Crowder, Robert J.
AU - Enomoto, Hideki
AU - Yang, Mao
AU - Johnson, Eugene M.
AU - Milbrandt, Jeffrey
PY - 2004/10/1
Y1 - 2004/10/1
N2 - 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 Tyr1062 residue. Moreover, ligand activation of Ret resulted in phosphorylation of tyrosine residue(s) located within the unique C termines 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 out-growth in GDNF family receptor α1 (GFRα1)-expressing Nenro2A cells that was dependent upon the C-terminal residties 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.
AB - 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 Tyr1062 residue. Moreover, ligand activation of Ret resulted in phosphorylation of tyrosine residue(s) located within the unique C termines 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 out-growth in GDNF family receptor α1 (GFRα1)-expressing Nenro2A cells that was dependent upon the C-terminal residties 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.
UR - http://www.scopus.com/inward/record.url?scp=4944261293&partnerID=8YFLogxK
U2 - 10.1074/jbc.M403726200
DO - 10.1074/jbc.M403726200
M3 - Article
C2 - 15286081
AN - SCOPUS:4944261293
SN - 0021-9258
VL - 279
SP - 42072
EP - 42081
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 40
ER -