Identifying a role for the scaffolding protein IQGAP1 in liver health and disease

Chronic liver diseases contribute to approximately 4% of deaths worldwide. The high mortality associated with liver disease is partially due to 1) difficulty diagnosing liver disease until a later stage and 2) difficulty treating liver disease once diagnosed. Therefore, there is an urgent need to better understand the biological mechanisms underlying liver disease. This dissertation is focused on understanding the role of the scaffolding protein IQ motif-containing GTPase-Activating Protein 1 (IQGAP1), an evolutionarily conserved scaffolding protein that is frequently up-regulated in liver disease, in the liver’s response to nutritional and cholestatic stress as well as in liver tumorigenesis. In chapter 2, I review how IQGAP1’s complex structure relates to its dynamic function in cells. In chapter 3, I show that hepatic IQGAP1 expression is increased after a 24-hour fast and that deletion of IQGAP1 blunts the ketogenic response to fasting and ketogenic diet feeding, which is associated with impaired PPARα activation and hyperactive mTORC1 signaling. Furthermore, in chapter 4 I show that IQGAP1 is upregulated at a transcriptional level by bile acid signaling and its deletion results in increased toxin-induced liver injury and bile acid accumulation. E-cadherin, which is important for maintaining adherens junctions, has reduced expression in the absence of IQGAP1, suggesting that IQGAP1 may protect against liver injury by stabilizing E-cadherin and maintaining bile canaliculi integrity. Lastly, in chapter 5 I show that both overexpression and deletion of IQGAP1 can result in increased tumor burden. In these tumors, overexpression of IQGAP1 was associated with increased β-catenin activation while deletion of IQGAP1 increased cell proliferation and MET activation. Together, these results show that while IQGAP1 normally has low expression in the liver of adult mice, its expression increases in response to physiological stresses to maintain nutrient availability and protect against excess damage. However, in the long-term, both too much and too little IQGAP1 can have negative consequences on tumor burden.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Molecular & Integrative Physi

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2019

Author dc:creator

• Erickson, Hanna Lynne

Contributors dc:contributor

• Anakk, Sayeepriyadarshini
• Katzenellenbogen, Benita
• Nelson, Erik
• Shapiro, David

• Liver disease
• scaffolding protein

Statement dc:rights

• Copyright 2019 Hanna Erickson

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/105795

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/105795