HGNC Approved Gene Symbol: DOK6
Cytogenetic location: 18q22.2 Genomic coordinates (GRCh38) : 18:69,400,888-69,849,087 (from NCBI)
DOK6 is a member of the DOK (see DOK1; 602919) family of intracellular adaptors that play a role in the RET (164761) signaling cascade (Crowder et al., 2004).
By database analysis using mouse Dok4 (608333) and Dok5 (608334) as query, Crowder et al. (2004) identified EST sequences corresponding to human DOK6. The deduced 331-amino acid protein has a calculated molecular mass of 38.3 kD and contains an N-terminal pleckstrin homology (PH) domain, a central phosphotyrosine-binding (PTB) domain, and a unique C-terminal region, similar to DOK family members. DOK6 shares 75% and 78% identity with Dok4 and Dok5, respectively, over the PH and PTB domains and also shares a C-terminal region motif that may distinguish this subclass of DOK proteins. RT-PCR analysis of human tissues detected highest expression in the CNS, especially in fetal brain, and high expression in kidney and testis, as well as several Ret-positive neuroblastoma cell lines. In situ hybridization of mouse embryos detected Dok6 expression in the developing neocortex, diencephalon, and spinal cord, as well as in uteric buds of the developing kidney, and in the cranial parasympathetic, sensory, and sympathetic ganglia and the facial motor nucleus. The distribution of Dok6 developmental expression overlapped with Ret expression.
Using GST pull-down assays and Western analysis with DOK6 constructs and Ret alternative splicing isoforms, Crowder et al. (2004) showed that the DOK6 PTB domain displayed phosphorylation-dependent interaction with Ret tyr1062 and that this interaction occurred in both Ret alternative splicing isoforms examined. In mouse neuroblastoma cells expressing DOK6 mutants, GDNF (600837) stimulation of Ret caused phosphorylation of DOK6 tyrosine residues within the C-terminal region that was reduced in the presence of Src (190090) inhibitors, suggesting that Ret tyrosine phosphorylation of DOK6 occurs through an Src- or Src-family kinase-dependent mechanism. Using lentiviral infection of mouse neuroblastoma cells with DOK6, DOK5, or DOK6 mutants, Crowder et al. (2004) showed that DOK6 expression significantly increased GDNF-induced neurite outgrowth and that the C-terminal region of DOK6 was required for this function.
Crowder et al. (2004) determined that the DOK6 gene contains 8 exons spanning 440 kb.
By genomic sequence analysis, Crowder et al. (2004) mapped the DOK6 gene to chromosome 18q22.2.
Crowder, R. J., Enomoto, H., Yang, M., Johnson, E. M., Jr., Milbrandt, J. Dok-6, a novel p62 Dok family member, promotes Ret-mediated neurite outgrowth. J. Biol. Chem. 279: 42072-42081, 2004. [PubMed: 15286081] [Full Text: https://doi.org/10.1074/jbc.M403726200]