Development of hepatocellular carcinoma in Iqgap2-deficient mice is IQGAP1-dependent

Department of Medicine, State University of New York, Stony Brook, New York 11794; Program in Genetics, State University of New York at Stony Brook; Department of Pharmacological Sciences, State University of New York, Stony Brook, New York 11794; Department of Pathology, State University of New York, Stony Brook, New York 11794

^* To whom correspondence should be addressed. Email: vaschmidt{at}notes.cc.sunysb.edu.

	Abstract

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 overexpression of IQGAP1, loss of membrane E-cadherin expression, cytoplasmic translocation (and activation) of -catenin, and overexpression of -catenin's nuclear target cyclin D1. In normal hepatocytes, IQGAP2 was found to exist as one component of a multifunctional scaffolding complex comprised of IQGAP1, -catenin and E-cadherin, with no evidence for direct IQGAP1/IQGAP2 interactions. Interbreeding of Iqgap2^-/- mice into the Iqgap1^-/- background resulted in phenotypic correction of the pre-existing hepatopathy, a lower incidence and smaller size of HCC tumors, and normalization of overall survival compared to Iqgap2^-/- mice, suggesting that maximal penetrance of the Iqgap2^-/- HCC phenotype requires coordinate expression of IQGAP1. These results identify Iqgap2 as a novel tumor suppressor gene specifically linked to the development of HCC and activation of the Wnt/-catenin signaling pathway, while also suggesting that IQGAP1 and IQGAP2 retain functionally divergent roles in hepatocellular carcinogenesis.