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J. Biol. Chem., Vol. 279, Issue 40, 42072-42081, October 1, 2004

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Dok-6, a Novel p62 Dok Family Member, Promotes Ret-mediated Neurite Outgrowth^*

Robert J. Crowder, Hideki Enomoto, Mao Yang, Eugene M. Johnson, Jr.¶, and Jeffrey Milbrandt||

From the Departments of Pathology and Immunology and ^¶Neurology and Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri, 63110 and the Laboratory for Neuronal Differentiation and Regeneration, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan

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 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 1 (GFR1)-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.

Received for publication, April 5, 2004 , and in revised form, July 27, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY599248.

^* This work was supported by National Institutes of Health Grant AG13730 (to J. M. and E. M. J.) and T32-DKO7296 (to R. J. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Ave., Campus Box 8118, St. Louis, MO 63110. Tel.: 314-362-4651; Fax: 314-362-8756; E-mail: jeff{at}pathbox.wustl.edu.

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