Metastasis-associated kinase in Wnt signaling

Icahn School Of Medicine At Mount Sinai, New York NY

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Abstract

[unreadable] DESCRIPTION (provided by applicant): This proposal focuses on the role of the metastasis-associated kinase (MAK) in Wnt signaling during Xenopus embryogenesis. Wnt signaling is critical for morphogenesis, cell proliferation and cell differentiation during early development and is frequently activated in human cancers. This pathway regulates the polarity of actin cytoskeleton and activates gene transcription by stabilizing beta-catenin. In preliminary studies MAK has been shown to associate with and phosphorylate Dishevelled, a central component of the Wnt pathway. To test a hypothesis that MAK is a critical regulator of different branches of Wnt signal transduction, the subcellular localization and the enzymatic activity of MAK in embryonic tissues will be determined during normal development and in cells responding to a Wnt signal. Upstream regulators and downstream molecular targets of MAK will be identified biochemically and by molecular techniques. A function of MAK in axis specification and in the control of convergent extension movements will be assessed with loss- and gain-of-function approaches. These studies will utilize Xenopus embryos, which allow a combination of cell biological and biochemical experiments with rapid functional analysis in vivo. These studies should have important implications for the understanding of basic signaling mechanisms. Since Wnt signaling is inappropriately regulated in colon carcinomas, melanomas, liver and skin tumors, the proposed experiments should reveal control mechanisms, which operate during embryonic development and misregulated in cancer. The knowledge of the molecular pathways that involve MAK should allow the design of small molecules, which can modulate its enzymatic activity, and may lead to the development of new anti-cancer therapies. [unreadable] [unreadable] [unreadable]