IQGAPs are multidomain scaffolding proteins that integrate Rho GTPase and Ca2؉ /calmodulin signals with cell adhesive and cytoskeletal reorganizational events. Targeted disruption of the murine Iqgap2 gene resulted in the age-dependent development of apoptosis and hepatocellular carcinoma (HCC), characterized by the overexpression of IQGAP1, the loss of membrane E-cadherin expression, the cytoplasmic translocation (and activation) of ␤-catenin, and the overexpression of a nuclear target of ␤-catenin, cyclin D1. In normal hepatocytes, IQGAP2 was found to exist as one component of a multifunctional scaffolding complex comprising IQGAP1, ␤-catenin, and E-cadherin, with no evidence for direct IQGAP1-IQGAP2 interactions. Interbreeding of Iqgap2 ؊/؊ mice into the Iqgap1 ؊/؊ background resulted in the phenotypic correction of the preexisting hepatopathy, decreases in the incidence and sizes of HCC tumors, and the normalization of overall survival rates compared to those of Iqgap2 ؊/؊ mice, suggesting that maximal penetrance of the Iqgap2 ؊/؊ HCC phenotype requires the coordinate expression of IQGAP1. These results identify Iqgap2 as a novel tumor suppressor gene specifically linked to the development of HCC and the activation of the Wnt/␤-catenin signaling pathway, while also suggesting that IQGAP1 and IQGAP2 retain functionally divergent roles in hepatocellular carcinogenesis.

Long-chain fatty acids (LCFA) serve as structural components for membrane biogenesis and as primary energy sources during mitochondrial-oxidation reactions. Hepatic LCFA uptake is complex, with characteristics suggestive of a dual-kinetic model manifested by rapid (carrier-assisted/facilitated) and delayed (passive diffusional) phases. Our previous work using mice deficient of the Iqgap2 gene established a highly novel link between IQGAP2, a putative GTPase-activating protein, and hepatocarcinogenesis. Now we report that Iqgap2 deficiency also results in selective loss of the facilitated phase of hepatocyte LCFA uptake with preservation of the diffusional component. This molecular defect was seen in Iqgap2-/- hepatocytes of all ages studied (1-, 4-, 8-months). The loss of facilitated LCFA uptake protected against development of hepatic triglyceride accumulation in Iqgap2-deficient mice fed high-fat diet, consistent with a fundamental role in physiological fat partitioning. These phenotypic changes could not be explained by genetic loss of fatty acid processing proteins known to regulate lipid uptake or metabolic processing pathways. Iqgap2-deficient livers also displayed enhanced insulin sensitivity. Conclusion These observations identify a novel property of the putative GTPase-activating protein IQGAP2 in LCFA uptake in vitro and in vivo, and implicate IQGAP2 in an intracellular signaling pathway necessary for functional fatty acid uptake, lipid processing, and, possibly, glucose homeostasis.