Alternative titles; symbols
HGNC Approved Gene Symbol: DOK1
Cytogenetic location: 2p13.1 Genomic coordinates (GRCh38): 2:74,549,105-74,557,551 (from NCBI)
Chronic myelogenous leukemia (CML; 608232) is caused by a t(9;22) translocation, and is associated with the presence of a chimeric p210(bcr/abl) protein that has elevated protein-tyrosine kinase activity. Wisniewski et al. (1994) found that a 62-kD protein, which they symbolized pp62, was constitutively tyrosine phosphorylated in hematopoietic progenitors isolated from CML patients in the chronic phase. They suggested that pp62 may be a critical p210(bcr/abl) substrate. Carpino et al. (1997) purified the 62-kD protein and designated it p62dok for 'p62 protein downstream of tyrosine kinases.' By carrying out PCR with degenerate oligonucleotide primers based on p62dok peptide sequences, they isolated a partial p62dok cDNA and used it to identify additional cDNAs from a teratocarcinoma library. The predicted 481-amino acid protein contains a putative pleckstrin homology domain at the N terminus and 10 PXXP SH3 recognition motifs. Northern blot analysis revealed that p62dok was expressed as an approximately 2-kb mRNA in various tissues.
By radiation hybrid analysis, Nelms et al. (1998) mapped the human DOK1 gene to 2p13. They mapped the mouse Dok1 gene to chromosome 6 by use of the BSS backcross panel.
Carpino et al. (1997) found that p62dok is associated with p120 Ras-GAP (139150), and this association is correlated with its tyrosine phosphorylation. Carpino et al. (1997) demonstrated that p62dok is rapidly tyrosine phosphorylated upon activation of the c-kit receptor tyrosine kinase (164920), implicating it as a component of a signal transduction pathway downstream of receptor tyrosine kinases. The authors stated that the widespread correlation observed by others between constitutive tyrosine phosphorylation of p62dok and the transformed phenotype suggests that it plays an important role in mitogenic signaling and that aberrant p62dok phosphorylation may contribute to the progression of different human diseases.
Yasuda et al. (2004) generated mice lacking Dok1 and/or Dok2 (604997) and found that double-knockout mice succumbed to myeloproliferative disease resembling human CML and chronic myelomonocytic leukemia. The double-knockout mice had medullary and extramedullary hyperplasia of granulocyte/macrophage progenitors with leukemic potential, and their myeloid cells showed hyperproliferation and hypoapoptosis upon treatment with and deprivation of cytokines, respectively. Cytokine stimulation enhanced Erk (see 176872) and Akt (see 164730) activation in mutant myeloid cells. Yasuda et al. (2004) concluded that DOK1 and DOK2 are key negative regulators of cytokine responses and are essential for myeloid homeostasis and leukemia suppression.
Independently, Niki et al. (2004) observed aberrant hemopoiesis and CML-like lymphoproliferative disease in Dok1 and Dok2 double-knockout mice. Single-knockout mice displayed normal steady-state hemopoiesis.
Shinohara et al. (2005) found that macrophages from mice lacking Dok1 or Dok2 displayed elevated activation of Erk (MAPK3; 601795), but not other MAPKs or Nfkb (see 164011), upon stimulation with lipopolysaccharide (LPS), but not other Toll-like receptor (TLR) ligands, resulting in hyperproduction of Tnf (190160) and nitric oxide. LPS also induced high Tnf production in vivo in mice lacking Dok1 or Dok2. Forced expression of Dok1 or Dok2 in macrophages inhibited LPS-induced Erk activation and Tnf production, but not if Dok1 had a tyr336-to-phe or tyr340-to-phe mutation. Shinohara et al. (2005) concluded that DOK1 and DOK2 are essential negative regulators downstream of TLR4 (603030).
Berger et al. (2010) found that mice with knockout of Dok1, Dok2, or Dok3 (611435) 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 and strong staining for phosphorylated Erk. 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]
Carpino, N., Wisniewski, D., Strife, A., Marshak, D., Kobayashi, R., Stillman, B., Clarkson, B. p62(dok): a constitutively tyrosine-phosphorylated, GAP-associated protein in chronic myelogenous leukemia progenitor cells. Cell 88: 197-204, 1997. [PubMed: 9008160] [Full Text: https://doi.org/10.1016/s0092-8674(00)81840-1]
Nelms, K., Snow, A. J., Noben-Trauth, K. Dok1 encoding p62(dok) maps to mouse chromosome 6 and human chromosome 2 in a region of translocation in chronic lymphocytic leukemia. Genomics 53: 243-245, 1998. [PubMed: 9790776] [Full Text: https://doi.org/10.1006/geno.1998.5514]
Niki, M., Di Cristofano, A., Zhao, M., Honda, H., Hirai, H., Van Aelst, L., Cordon-Cardo, C., Pandolfi, P. P. Role of Dok-1 and Dok-2 in leukemia suppression. J. Exp. Med. 200: 1689-1695, 2004. [PubMed: 15611295] [Full Text: https://doi.org/10.1084/jem.20041306]
Shinohara, H., Inoue, A., Toyama-Sorimachi, N., Nagai, Y., Yasuda, T., Suzuki, H., Horai, R., Iwakura, Y., Yamamoto, T., Karasuyama, H., Miyake, K., Yamanashi, Y. Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling. J. Exp. Med. 201: 333-339, 2005. [PubMed: 15699069] [Full Text: https://doi.org/10.1084/jem.20041817]
Wisniewski, D., Strife, A., Wojchiechowicz, D., Lambek, C., Clarkson, B. A 62-kilodalton tyrosine phosphoprotein constitutively present in primary chronic phase chronic myelogenous leukemia enriched lineage negative blast populations. Leukemia 8: 688-693, 1994. [PubMed: 8152267]
Yasuda, T., Shirakata, M., Iwama, A., Ishii, A., Ebihara, Y., Osawa, M., Honda, K., Shinohara, H., Sudo, K., Tsuji, K., Nakauchi, H., Iwakura, Y., Hirai, H., Oda, H., Yamamoto, T., Yamanashi, Y. Role of Dok-1 and Dok-2 in myeloid homeostasis and suppression of leukemia. J. Exp. Med. 200: 1681-1687, 2004. [PubMed: 15611294] [Full Text: https://doi.org/10.1084/jem.20041247]