FROM MUTATIONS TO RATE CONSTANTS: MUTATIONS IN MEK DIFFERENTIALLY AFFECT THE BIOCHEMICAL PROCESSES IN THE ERK SIGNALING PATHWAY

Abstract

The ERK signaling pathway is important for cellular regulation. Mutations in one of its components, MEK, have been linked to many human diseases, including developmental abnormalities and cancer.

To better understand the quantitative effect of mutations on the biochemical processes in which MEK is involved, I combined biochemical assays and parameter estimation to determine the effects of MEK disease mutations on MEK’s activation by Raf, its downstream activation of ERK, protein stability, and its ATPase activities. I found that while F53S and Y130C affect activation by Raf, E203K affects ERK phosphorylation by having a more processive phosphorylation. My work demonstrates that despite the proximity of these mutations, they function through different mechanisms. This difference in mechanism can potentially explain their differences in severity of symptoms in patients. My approach can be extended to evaluate other mutations in other systems. Additionally, I was involved in the testing of the TMTc+ method and contributed greatly to the establishment of the reference dataset containing the relative and absolute protein abundances of Drosophila embryos. This dataset is a valuable contribution to the Drosophila embryogenesis field.