Date of Award

12-31-2021

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology/Molecular, Cellular, and Organismal Biology

First Advisor

Alexey Veraksa

Second Advisor

Linda Huang

Third Advisor

Kellee Siegfried

Abstract

The extracellular signal regulated kinase (ERK) pathway is an essential component of developmental signaling in metazoans. As a final element of the Raf-MEK-ERK kinase cascade, ERK phosphorylates multiple substrates, including transcription factors such as Capicua (Cic), which is a transcriptional repressor that acts downstream of ERK. Cic functions as a regulatory switch in ERK signaling, and controls diverse cellular responses like growth, proliferation, and differentiation. Dysregulation of this signaling pathway gives rise to developmental abnormalities, and mutations in the human ortholog of Capicua, CIC, play a causative role in cancer. In this study I have used Drosophila as a model organism to understand the mechanism of Cic dependent ERK signal propagation. I found that the interaction of ERK with Cic is controlled at the level of ERK phosphorylation, whereby activated, dually phosphorylated ERK binds to Cic with a much higher affinity, compared to unphosphorylated ERK. This preferential binding contributes to efficient ERK signal propagation and prevents unproductive competition of Cic with the unphosphorylated form of ERK. Even though Cic phosphorylation is a critical regulatory step in ERK signaling, the identities and functional importance of Cic phospho-sites are not known. I have systematically mapped ERK dependent phospho-sites in Cic and identified a group of sites that together constitute a phosphodegron signal which is required for Cic degradation downstream of ERK. This research has uncovered previously unknown molecular mechanisms by which ERK controls Cic repressor activity. Components of the RTK/RAS/ERK pathway are actively investigated for therapeutic applications. Understanding the mechanism of functional regulation of Capicua and ERK in flies can be translated to develop therapeutic strategies to treat human diseases that are caused by aberrant functioning of the pathway.

Comments

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