Role of the tumor suppressor IQGAP2 in metabolic homeostasis: possible link between diabetes and cancer

Abstract

Deficiency of IQGAP2, a scaffolding protein expressed primarily in liver leads to rearrangements of hepatic protein compartmentalization and altered regulation of enzyme functions predisposing development of hepatocellular carcinoma and diabetes. Employing a systems approach with proteomics, metabolomics and fluxes characterizations, we examined the effects of IQGAP2 deficient proteomic changes on cellular metabolism and the overall metabolic phenotype. Iqgap2−/− mice demonstrated metabolic inflexibility, fasting hyperglycemia and obesity. Such phenotypic characteristics were associated with aberrant hepatic regulations of glycolysis/gluconeogenesis, glycogenolysis, lipid homeostasis and futile cycling corroborated with corresponding proteomic changes in cytosolic and mitochondrial compartments. IQGAP2 deficiency also led to truncated TCA-cycle, increased anaplerosis, increased supply of acetyl-CoA for de novo lipogenesis, and increased mitochondrial methyl-donor metabolism necessary for nucleotides synthesis. Our results suggest that changes in metabolic networks in IQGAP2 deficiency create a hepatic environment of a ‘pre-diabetic’ phenotype and a predisposition to non-alcoholic fatty liver disease (NAFLD) which has been linked to the development of hepatocellular carcinoma.

Altered methylation of specific DNA loci in the liver of Bhmt‐null mice results in repression of Iqgap2 and F2rl2 and is associated with development of preneoplastic foci

“…Iqgap2 belongs to a family of scaffolding proteins, which mediate Rho GTPase and Ca 2+ /calmodulin signaling in regulating multiple cellular processes, such as cell adhesion, motility, and exocytosis (42). Iqgap2 silencing has metabolic effects, such as increasing mitochondrial methyl‐donor metabolism by elevating Gnmt (Glycine N ‐methyltransferase) expression, the enzyme responsible for converting AdoMet to AdoHcy (43). Iqgap2 is important in multiple reactions in the liver, regulating activation and translocation of β‐catenin and expression of E‐cadherin, as well as reacting to key regulators of liver neoplastic transformation, such as c‐Myc (v‐Myc avian myelocytomatosis viral oncogene homolog; Fig.…”

Haploid embryonic stem cells can be enriched and maintained by simple filtration

“…We first attempted induction of large-deletion in a gene of interest, Iqgap2 (27,28). We transfected constructs expressing Cas9 and two sgRNAs targeting exon 17 and exon 30, respectively, which may cause a 35-kb deletion (Fig.…”

IQGAP scaffold proteins are the multifunctional regulators of cellular signaling and malignant transformation

“…У мышей, дефицит-ных по гену Iqgap2, наблюдается повышение уровня инсулина в плазме крови, а также гиперактивация глюконеогенеза и гликолиза в печени, что способст-вует развитию гипергликемии и увеличению синтеза липидов. Быстрое накопление липидов совместно с повышением уровня инсулина приводит к ожирению [22]. В толстом кишечнике IQGAP2 необходим для раз-вития воспалительной реакции; мыши с инактивиро-ванным IQGAP2 проявляют повышенную устойчи-вость к действию химических агентов, индуцирующих острый колит [23].…”