Investigation of LIN-1 and its inhibitor MPK-1

Washington University, Saint Louis MO

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Abstract

DESCRIPTION (provided by applicant): The objectives of this proposal are to elucidate how the LIN-1 ETS transcription factor and its inhibitor MAP kinase regulate cell proliferation and cell fate determination. UN-1 and MAPK are two down-stream components of the highly-conserved Ras/MAPK signaling pathway, a pathway that is activated multiple times during development to elicit distinct cell fate decisions in different developmental contexts. The study of this pathway is critical for understanding human disease as 20-30% of the most common cancers contain activating mutations of ras. MAPK function will be investigated by identifying the domains within MAPK that mediate association with LIN-1 and its other substrates, and defining how mutation of these domains affects the ability of MAPK to phosphorylate these substrates. These studies will define how the substrate specificity of MAPK is modulated and will illuminate how specific substrates regulate development and cell proliferation. The Elk subfamily of ETS proteins, which includes C. elegans LIN-1, are conserved targets for MAPK. To gain insight into how LIN-1 regulates proliferation and cell fate decisions, proteins that associate with LIN-1 are being isolated and their contribution to the Ras/MAPK pathway will be investigated in C. elegans. These studies will unveil novel components of the Ras/MAPK pathway that may serve as effective targets for treatment of Ras-associated malignancies.