PHOSPHORYLATION OF BETA-CATENIN

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have been studying the oncogenic potential of the regulatory serine-threonine kinase CK2, a tetrameric enzyme that is highly evolutionary conserved and overexpressed in many human cancers. In transgenic models, we have shown that CK2 produces lymphomas when overexpression is directed to lymphoid cells, and mammary tumors when directed to the mammary gland. CK2-induced tumors exhibit activation of signaling pathways including the Wnt and NF-KB pathways, and we have shown that CK2 is an activator of those and other pro-oncogenic pathways. We are using homologous recombination and other techniques to elucidate the role of CK2 in Wnt signaling during development and tumorigenesis. We have developed "knockouts" for the two catalytic subunits of CK2. Recently, we have shown that CK2a-/- embryos die in mid-gestation. We are now focusing upon characterizing the defects in the CK2 -/- embryos and using them and other tools to elucidate the essential functions of CK2. We are determining the developmental role of CK2 and examining the status of targets of CK2 in the knockout embryos and in MEFs derived from them. We are determining the role of CK2 in Wnt signaling in cells. We are crossing creating CK2 compound knockouts with graded levels of catalytic CK2 expression, and we arel engineering mice with a conditional CK2 knockout in the mammary gland. These mice are being bred with Wnt pathway oncogene transgenics and treated with carcinogens to determine whether CK2 expression is required for in vivo tumorigenesis; the role of CK2 in in vitro tumorigenesis models is also being assessed. These experiments shouldl allow us to fully explore the function of CK2 as a regulator of tumorigenesis and development, in in vivo and in vitro models. Kinases have proven to be suitable targets for novel cancer therapeutics. For example, the bcr-abl oncoprotein of chronic myelogenous leukemia is effectively inhibited by Imatinib (Gleevec). Since CK2 is upregulated in all human tumors that have been studied, CK2 may be a suitable target for cancer treatment. Understanding basic CK2 biology and signaling is a necessary prelude to developing novel therapeutics against it. In one phase of these explorations, tandem mass spectrometry is being used to assess the phosphorylation pattern of beta-catenin.