OR25-2 Bridging the gap between diabetes and cancer: Role of the tumor suppressor IQGAP2 in metabolic homeostasis

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR25-Signaling Originating from Membrane Receptors
Basic/Translational
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 11:30 AM
Room 133 (Moscone Center)
Bhavapriya Vaitheesvaran*1, Kirsten Hartil2, Chunxiang Zheng3, Arti Navare3, James Bruce3, Chandan Guha4 and Irwin Kurland5
1Albert Einstein College of Medicine, Bronx, NY, 2Albert Einstein College of Medicine, Bronx, 3University of Washington, Seattle, WA, 4Montefiore Medical Center, Bronx, NY, 5Albert Einstein College Of Medicine, Bronx, NY
IQGAP2, is a multi-domain scaffolding protein, primarily expressed in liver and to some extent in white adipose tissue and pancreas. Originally identified as a tumor suppressor, IQGAP2 is also the binding partner for protein kinase A-anchoring protein220 (AKAP220). Whole body genetic ablation of IQGAP2 in C57Bl6 mice results in glucose intolerance, obesity and an eventual ‘prediabetic phenotype. Using integrative metabolomics and proteomics studies, we found IQGAP2 deficiency leads to profound impairments in metabolic pathways controlled by cAMP-PKA signaling. Plasma metabolome is indicative of increased gluconeogenesis and unsuppressed lipolysis. Hepatic metabolite profiling reveals Iqgap2-/- mice had increased levels of acetyl CoA, pentose cycle metabolites and triose phosphates critical for lipid synthesis. Flux studies demonstrate that hepatic denovo lipogenesis was increased, but cholesterol synthesis and glycogenolysis was decreased in Iqgap2-/- mice. Hepatic proteomic profiling is suggestive that IQGAP2 might have dual tumorigenic and metabolic physiological function because besides proteins in cellular proliferation, several metabolic proteins were also differentially expressed with IQGAP2 deficiency. Our study demonstrates that deletion of a tumor suppressor leads to the development of a ‘pre-diabetic’ phenotype. We also provide evidence to establish the novel role of the tumor suppressor Iqgap2 in regulating substrate utilization. Metabolite and proteomic profiling reveals a possible “Warburg effect” associated with most malignant transformations. Our results indicate that the ultimate ‘pre-diabetic’ Iqgap2-/- phenotype is due to the lack of fidelity and specificity in AKAP-PKA signaling caused by impaired scaffolding. Since IQGAP2 resides at the intersection of two critical cellular signaling pathways Wnt (GSK3β) and cAMP-PKA (AKAPs) relevant to cancer and diabetes, we propose IQGAP2 to be a candidate mediator protein and potential biological link between the two diseases.

Nothing to Disclose: BV, KH, CZ, AN, JB, CG, IK

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: 1U19AI091175 Stem Cell-Based Therapies for Mitigation of  Acute Radiation Syndromes