Alternative titles; symbols
HGNC Approved Gene Symbol: DOK3
Cytogenetic location: 5q35.3 Genomic coordinates (GRCh38) : 5:177,501,904-177,511,100 (from NCBI)
By yeast 2-hybrid analysis using Abl (ABL1; 189980) as bait, followed by 5-prime RACE of a mouse liver cDNA library, Cong et al. (1999) cloned mouse Dok3, which they called Dokl. The deduced 444-amino acid mouse protein contains an N-terminal PH domain, a central PTB domain, and a proline-rich C-terminal domain. Dokl is relatively serine/threonine-rich overall and contains several potential phosphorylation sites for ser/thr protein kinases. Dokl shares 60% and 57% sequence similarity with p62dok (DOK1; 602919) over the PH and PTB domains, respectively, with lower similarity over the C-terminal regions. Northern blot analysis of mouse tissues detected several species with high expression in spleen and lung and low levels in other tissues. RNAse protection studies detected very high Dokl expression in bone marrow and spleen, low expression in thymus, and no expression in NIH3T3 cells. Immunofluorescence studies localized Dokl to the cytoplasm in NIH3T3 cells.
By yeast 2-hybrid analysis using Csk (124095) as bait, followed by 5-prime RACE of a mouse fetal thymus cDNA library, Lemay et al. (2000) independently cloned mouse Dok3. RNAse protection assay of mouse tissues detected high expression in spleen and bone marrow but not in thymus, with little or no expression in nonlymphoid organs.
Berger et al. (2010) stated that the DOK3 gene maps to chromosome 5q35.3.
Using yeast 2-hybrid and immunoprecipitation analysis of Dokl and Abl mutants, Cong et al. (1999) showed that the Dokl PTB domain bound phosphotyrosines on Abl in a kinase-dependent manner. In addition, the Dokl PTB domain bound weakly to insulin receptor (INSR; 147670). Immunoprecipitation and phosphorylation studies showed that Dokl served as a substrate for phosphorylation by v-Abl, c-Abl, and Bcr-Abl (see BCR; 151410). Overexpression of Dokl inhibited v-Abl-dependent activation of MAPK1 (176948) and v-Abl transforming activity.
Lemay et al. (2000) showed that, in response to immunoreceptor stimulation, Dok3 was tyrosine phosphorylated by Src (190090) family members Lck (153390), Fyn (137025), and Lyn (165120). Immunoprecipitation studies showed that Dok3 bound inhibitors SHIP (INPP5D; 601582) and Csk (124095) but did not bind RasGAP (RASA1; 139150). Dok3 binding to SHIP occurred via the SH2 domain. Dok3 also bound Csk via the Csk SH2 domain with possible involvement of the Csk SH3 domain as well. Overexpression of Dok3 in a murine B-cell line inhibited immunoreceptor-mediated NFAT (see 600490) activation. Lemay et al. (2000) concluded that Dok3 acts as an adaptor in the recruitment of inhibitory molecules and may play a role in negative regulation of immunoreceptor signaling in hematopoietic cells.
Using a constitutively active form of Src, Honma et al. (2006) identified Grb2 (108355) as a protein that bound Dok3 downstream of its tyrosine phosphorylation. Dok3 sequestered Grb2 from Shc (600560), resulting in negative regulation of the Ras-Erk pathway.
Berger et al. (2010) found that mice with knockout of Dok1 (602919), Dok2 (604997), or Dok3 each developed lung adenocarcinoma (211980). Mice with double-knockouts of different combinations of these 3 genes developed lung adenocarcinoma at an earlier age and with high penetrance, suggesting that the proteins have partially redundant or overlapping functions. Compared to wildtype lung tissue, Dok-mutant tumors showed moderate staining for phosphorylated Akt (164730) and strong staining for phosphorylated Erk (176872). Immunohistochemical studies on isolated cells showed that the tumor cells arose from a population of bronchioalveolar stem cells with inactivation of the Dok proteins. These findings were consistent with a model of tumorigenesis in which inactivation of the Dok1, Dok2, and Dok3 genes leads to hyperactivation of Akt and Erk, and an expansion of the stem cells that differentiate into alveolar type II cells.
Berger, A. H., Niki, M., Morotti, A., Taylor, B. S., Socci, N. D., Viale, A., Brennan, C., Szoke, J., Motoi, N., Rothman, P. B., Teruya-Feldstein, J., Gerald, W. L., Ladanyi, M., Pandolfi, P. P. Identification of DOK genes as lung tumor suppressors. Nature Genet. 42: 216-223, 2010. [PubMed: 20139980] [Full Text: https://doi.org/10.1038/ng.527]
Cong, F., Yuan, B., Goff, S. P. Characterization of a novel member of the DOK family that binds and modulates Abl signaling. Molec. Cell. Biol. 19: 8314-8325, 1999. [PubMed: 10567556] [Full Text: https://doi.org/10.1128/MCB.19.12.8314]
Honma, M., Higuchi, O., Shirakata, M., Yasuda, T., Shibuya, H., Iemura, S., Natsume, T., Yamanashi, Y. Dok-3 sequesters Grb2 and inhibits the Ras-Erk pathway downstream of protein-tyrosine kinases. Genes Cells 11: 143-151, 2006. [PubMed: 16436051] [Full Text: https://doi.org/10.1111/j.1365-2443.2006.00926.x]
Lemay, S., Davidson, D., Latour, S., Veillette, A. Dok-3, a novel adapter molecule involved in the negative regulation of immunoreceptor signaling. Molec. Cell. Biol. 20: 2743-2754, 2000. [PubMed: 10733577] [Full Text: https://doi.org/10.1128/MCB.20.8.2743-2754.2000]