Alternative titles; symbols
HGNC Approved Gene Symbol: DOK4
Cytogenetic location: 16q21 Genomic coordinates (GRCh38): 16:57,471,922-57,487,322 (from NCBI)
DOK4 and DOK5 (608334) form a subgroup of the DOK family and are involved in neuronal differentiation (Grimm et al., 2001).
Grimm et al. (2001) cloned mouse Dok4, which encodes a 325-amino acid protein containing an N-terminal pleckstrin (PLEK; 173570) homology (PH) domain, a central phosphotyrosine-binding (PTB) domain, and a C-terminal region with tyrosine residues in consensus binding sites for SH2 domains and several PxxP SH3-binding motifs. In situ hybridization analysis of mouse embryos showed that Dok4 was expressed in central and peripheral nervous system and in endothelia. In nervous system, Dok4 was distributed in the ventral portion of the neural tube and the dorsal root and cranial sensory ganglia. Northern blot analysis of adult mouse tissues revealed Dok4 expression in many tissues, including brain, heart, lung, and kidney. Western blot analysis showed that mouse Dok4 had an apparent molecular mass of 41 kD.
By database searching with the PH/PTB domains of insulin receptor substrate/docking (IRS/DOK) family members (see, e.g., 602919), both Cai et al. (2003) and Favre et al. (2003) identified human DOK4 and DOK5. Both research groups found that DOK4 and DOK5 are more similar to each other than they are to other members of the DOK family, and Favre et al. (2003) suggested that they constitute a subfamily of the DOK genes. Cai et al. (2003) determined that DOK4 encodes a deduced 326-amino acid protein with a predicted molecular mass of 37.1 kD. In addition to the PH and PTB domains, DOK4 contains a short C terminus with 5 potential sites for tyrosine phosphorylation. By Northern blot analysis, Cai et al. (2003) detected an approximately 3-kb DOK4 transcript with highest expression in kidney and liver and low expression in essentially all other tissues tested. By RT-PCR analysis, Favre et al. (2003) detected expression of DOK4 and DOK5 in peripheral blood T cells. They noted that DOK5 was expressed in activated but not resting T cells, suggesting that the expression of DOK5 is regulated upon T cell activation.
Favre et al. (2003) determined that both DOK4 and DOK5 contain 8 exons.
Gross (2021) mapped the DOK4 gene to chromosome 16q21 based on an alignment of the DOK4 sequence (GenBank BC003541) with the genomic sequence (GRCh38).
Using a yeast 2-hybrid screen, Grimm et al. (2001) identified mouse Dok4 and Dok5 as interaction partners of Ret receptor tyrosine kinase (164761). Binding to Ret was direct and was mediated by the PTB domain of Dok4 and Dok5, and it required phosphorylation of tyr1062 of Ret. In addition, immunoprecipitation showed that Dok4 associated with endothelial receptor tyrosine kinase Tie2 (TEK; 600221). Both Dok4 and Dok5 mediated Ret-dependent neuronal differentiation of PC12 cells.
Cai et al. (2003) found that both DOK4 and DOK5 are tyrosine-phosphorylated in response to insulin (176730) and insulin-like growth factor-1 (IGF1; 147440) in transfected cells. DOK4 is rapidly and heavily phosphorylated in response to insulin and, once phosphorylated, binds a set of SH2 domain proteins, including RasGAP (139150), CRK (164762), and the nonreceptor tyrosine kinases SRS (190090) and FYN (137025). DOK4 also activates MAPK in cells. In contrast, DOK5 is phosphorylated much more slowly and does not associate with this set of SH2 homology domains or activate MAPK.
Favre et al. (2003) suggested that DOK4 and DOK5 may be involved in the regulation of the immune response induced by T cells.
Gerard et al. (2009) showed that T-cell DOK4 was phosphorylated after T-cell receptor engagement and migrated within the cytoplasm before being recruited to the polarized microtubule-organizing center after formation of the immunologic synapse. RNA interference analysis identified DOK4 as a negative regulator of ERK (see MAPK3; 601795) phosphorylation, IL2 (147680) promoter activity, and T-cell proliferation. DOCK1 overexpression activated RAP1 (RAP1A; 179520), a regulator of ERK. The PH domain of DOK4 was required for its cytoplasmic shuttling and relocalization and for its inhibitory properties on T-cell activation.
Cai, D., Dhe-Paganon, S., Melendez, P. A., Lee, J., Shoelson, S. E. Two new substrates in insulin signaling, IRS5/DOK4 and IRS6/DOK5. J. Biol. Chem. 278: 25323-25330, 2003. [PubMed: 12730241] [Full Text: https://doi.org/10.1074/jbc.M212430200]
Favre, C., Gerard, A., Clauzier, E., Pontarotti, P., Olive, D., Nunes, J. A. DOK4 and DOK5: new dok-related genes expressed in human T cells. Genes Immun. 4: 40-45, 2003. [PubMed: 12595900] [Full Text: https://doi.org/10.1038/sj.gene.6363891]
Gerard, A., Ghiotto, M., Fos, C., Guittard, G., Compagno, D., Galy, A., Lemay, S., Olive, D., Nunes, J. A. Dok-4 is a novel negative regulator of T cell activation. J. Immun. 182: 7681-7689, 2009. [PubMed: 19494292] [Full Text: https://doi.org/10.4049/jimmunol.0802203]
Grimm, J., Sachs, M., Britsch, S., Di Cesare, S., Schwarz-Romond, T., Alitalo, K., Birchmeier, W. Novel p62dok family members, dok-4 and dok-5, are substrates of the c-Ret receptor tyrosine kinase and mediate neuronal differentiation. J. Cell Biol. 154: 345-354, 2001. [PubMed: 11470823] [Full Text: https://doi.org/10.1083/jcb.200102032]
Gross, M. B. Personal Communication. Baltimore, Md. 7/15/2021.