Mechanism of AXIN1 degradation after MEK inhibition
Funding period: 2021-2025
Project Leaders
Abstract
Small molecule inhibitors of MEK1/2 are clinically used for the treatment of cancers with activating Ras pathway mutations. Recently, MEK inhibitors were found to induce Wnt signaling in colorectal cancer, which is mediated by a rapid loss of AXIN1. AXIN1 is a main regulatory element of the destruction complex and its protein levels determine the activity of the canonical Wnt pathway. In this project, we will investigate if MEK inhibitors induce post-translational modifications of AXIN1, focusing on changes in phosphorylation and ubiquitination. We will determine if rewiring of interaction partners of AXIN1 occurs upon MEK inhibition and identify genetic alterations that modify the kinetics of AXIN1 degradation upon targeting of the Ras pathway.
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