p62^dok, a negative regulator of Ras and mitogen-activated protein kinase (MAPK) activity, opposes leukemogenesis by p210^bcr-abl

p62^dok has been identified as a substrate of many oncogenic tyrosine kinases such as the chronic myelogenous leukemia (CML) chimeric p210^bcr-abl oncoprotein. It is also phosphorylated upon activation of many receptors and cytoplamic tyrosine kinases. However, the biological functions of p62^dok in normal cell signaling as well as in p210^bcr-abl leukemogenesis are as yet not fully understood. Here we show, in hemopoietic and nonhemopoietic cells derived from p62^dok-/- mice, that the loss of p62^dok results in increased cell proliferation upon growth factor treatment. Moreover, Ras and mitogen-activated protein kinase (MAPK) activation is markedly sustained in p62^dok-/- cells after the removal of growth factor. However, p62^dok inactivation does not affect DNA damage and growth factor deprivation-induced apoptosis. Furthermore, p62^dok inactivation causes a significant shortening in the latency of the fatal myeloproliferative disease induced by retroviral-mediated transduction of p210^bcr-abl in bone marrow cells. These data indicate that p62^dok acts as a negative regulator of growth factor-induced cell proliferation, at least in part through downregulating Ras/MAPK signaling pathway, and that p62^dok can oppose leukemogenesis by p210^bcr-abl.