Dok-1 (for downstream of tyrosine kinase-1) was identified as a tyrosine phosphorylated protein in the cell lysates of lineage negative blasts from Philadelphia chromosome positive chronic myelogenous leukemia (CML) patients and as well as a major substrate of many PTKs (receptor tyrosine kinases). The Dok family has since been expanded to seven members, Dok-1 to Dok-7. Among seven members, Dok-1, Dok-2 and Dok-3 are mainly expressed in hematopoietic lineage cells. Overexpression data suggests that the Dok proteins may be inhibitors of cellular activation. We have shown that Dok-1 is negative regulator of Ras pathway using Dok-1 knock out mouse and that concomitant loss of Dok-1 and Dok-2 results in a myeloproliferative disease, similar to CML in mice. Although Dok has been implicated in playing a role in several cancers, its role in lung cancer has not previously been described. Examination of mice lacking Dok-1, Dok-2 and Dok-3 (TKO) demonstrate a high frequency of spontaneous lung adenocarcinoma of the lung. Prior to the development of lung cancer, mice also develop spontaneous lung inflammation with a predominance of lymphocytes. Examination of bronchioalveolar stem cells (BASCs) from wild type mice demonstrates that they do express Dok-1, Dok-2 and Dok-3. These data lead us to hypothesize that Dok proteins are suppressors of lung cancer. Our grant proposes to determine if this suppression of lung carcinogenesis is due to changes in the BASC population and whether the lung inflammation observed in these mice plays a role. In addition, we will extend these data to humans and attempt to identify human BASCs and determine if they express Dok proteins.
|Berger, Alice H; Niki, Masaru; Morotti, Alessandro et al. (2010) Identification of DOK genes as lung tumor suppressors. Nat Genet 42:216-23|