Chronic myelogenous leukemia (CML; 608232) is characterized by the presence of the Philadelphia chromosome translocation t(9;22) and the resulting p210-bcr/abl chimeric protein-tyrosine kinase (see 151410). Di Cristofano et al. (1998) described the purification, cloning, and characterization of a tyrosine-phosphorylated protein, p56dok (DOK2), from a megakaryoblastic cell line expressing p210-bcr/abl (Mo/p210). The DOK2 cDNA clone encodes a 412-amino acid protein with a molecular mass of 53 to 56 kD. The DOK2 protein has a potential pleckstrin homology (PH) domain at the N terminus, 13 potential tyrosine phosphorylation sites, 6 PXXP motifs, and 2 YXXPXD motifs (predicted Ras-GAP (139150) SH2 domain binding sites). It shares 34.8% overall amino acid identity with another tyrosine-phosphorylated protein, p62dok (DOK1; 602919), which also contains a predicted PH domain at its N terminus. Di Cristofano et al. (1998) defined a DOK homology sequence motif within 50 amino acids of the central core region of the proteins. Northern blot analysis revealed that both DOK1 and DOK2 are highly expressed in cells and tissues of hematopoietic origin as well as in lung.

Berger et al. (2010) stated that the DOK2 gene maps to chromosome 8p21.3.

Immunoprecipitation experiments by Di Cristofano et al. (1998) showed that expression of bcr/abl induces additional tyrosine phosphorylation of the DOK1 and DOK2 proteins and their association with Ras-GAP. The authors speculated that DOK association regulates GAP activity toward Ras and that the DOK proteins serve as mediators of bcr-abl signaling.

Yasuda et al. (2004) generated mice lacking Dok1 and/or Dok2 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. Among 199 primary human lung adenocarcinoma samples, 37% showed a deletion of 1 copy of DOK2, and the loss correlated with loss of protein expression. In Dok-mutant mice, haploinsufficiency of Dok2 was sufficient for tumor formation, as the wildtype allele was retained in most tumor samples. Berger et al. (2010) concluded that the findings were consistent for a tumor-suppressor role for DOK2 in human lung cancer.