Anakk Lab: The consequences of losing a scaffold

Dr. Sayeepriyadarshini Anakk (left) and graduate student Hanna Erickson (right).

The Anakk lab has investigated the metabolic repercussions of deleting the scaffolding protein IQGAP1. These findings were published in a paper entitled "Identification of IQ motif-containing GTPase Activating Protein 1 as a regulator of long-term ketosis" in JCI Insight.

Written by Ananya Sen, Graduate Student in Microbiology (Imlay Lab)

IQ motif-containing GTPase Activating Protein 1 (IQGAP1) functions as one of the central controllers in cellular processes. By providing a scaffolding surface it helps different proteins, including those involved in cell proliferation and cell structure maintenance, interact with each other. Several studies have shown that IQGAP1 expression is increased in cancer cells and it can coordinate cancer cell proliferation and invasion.

"Although the literature suggests that IQGAP1 can behave like a signaling hub and manage different metabolic processes, there is little evidence that directly supports this hypothesis. Other labs had seen that deleting IQGAP1 had no effect in one-year-old mice," explained Dr. Anakk, Assistant Professor in the Department of Molecular and Integrative Physiology and senior author of the paper. "Our studies show that when we use the right stimuli, in this case prolonged fasting, we were able to identify a role for IQGAP1 in 3-4 month old mice."

When normal mice undergo fasting they first use up the glucose stores and then switch to using fatty acids as a source of energy. The breakdown of fatty acids releases ketone bodies, a process known as ketogenesis. Mice that do not contain IQGAP1 cannot produce ketone bodies to the usual extent.

The cellular responses to fasting, including ketogenesis, are mediated by the signaling molecule PPARα. Mice lacking IQGAP1 show a reduction in the number of PPARα targets that are activated during ketogenesis, indicating that in these mice the PPARα signaling may be compromised. "This result is exciting because it is the first time a relationship between IQGAP1 and PPARα has been demonstrated," said Hanna Erickson, a graduate student in the Anakk lab and first author of the paper.

IQGAP1 also interacts with the nutrient sensor mTOR, which suppresses ketone body formation. Furthermore, other labs have observed some levels of cross-talk between PPARα and mTOR. "We had initially hypothesized that the reduction in ketogenesis in IQGAP1 deficient cells is due to increased mTOR activity. However, inhibiting mTOR in these mice did not restore the defect in ketogenesis in IQGAP1 defective mice," explained Erickson.

Although it remains unknown if there is any cross-talk between IQGAP1, PPARα, and mTOR, the results of the study has interesting implications since there is a growing interest in using IQGAP1 as a target for cancer treatment. At the same time, ketogenic diets have become increasingly popular and are now being examined as anti-cancer therapies. This study shows that targeting IQGAP1 can have adverse consequences on cellular ketone body synthesis and expands the role for IQGAP1 in controlling whole body physiology.

Read the full article here.

December 12, 2018 All News