Watch the GAP: Emerging Roles for IQ Motif-Containing GTPase-Activating Proteins IQGAPs in Hepatocellular Carcinoma

Abstract

IQ motif-containing GTPase-activating proteins IQGAP1 and IQGAP2 are highly homologous multidomain scaffolding proteins. Their major function consists of integration of Rho GTPase and Ca(2+)/calmodulin signals with cell adhesive and cytoskeletal reorganizational events. Recent studies showed that they play an important role in carcinogenesis. There is growing evidence that IQGAP2 is a novel tumor suppressor counteracting the effects of IQGAP1, an oncogene, in several cancers, especially in hepatocellular carcinoma (HCC). While HCC is highly prevalent and one of the deadliest cancers worldwide, the signaling pathways involved are not fully understood and treatment of advanced disease still represents an area of high unmet medical need. This paper compiles various findings from studies in mouse models, cell lines, and patient samples that support future development of IQGAPs into new therapeutic targets. It also discusses distinct features of IQGAP2 in an attempt to provide insight into the mechanism of the seemingly paradoxical opposing roles of the two very similar IQGAP proteins in carcinogenesis.

Figure 1

The domain structure of human IQGAP1 and IQGAP2. CH (calponin homology) domain, WW, polyproline binding domain, IQ calmodulin-binding motif, GBD-GTPase binding domain, and RGCT-RasGAP C-terminus domain. Domain percent homology is shown. Adapted from [15, 16]. Also shown binding partners of IQGAP2 identified to date. While it has been confirmed that IQGAP2 co-immunoprecipitates with β-catenin [27], RGCT is marked as a domain responsible for β-catenin binding based on analogy with IQGAP1. A list of IQGAP1 numerous binding partners can be found in [28].

Figure 2

Schema summarizing the proposed hypothesis for IQGAP1 and IQGAP2 involvement in HCC development. In wild-type hepatocytes, IQGAP2 exists in two pools-bound to β-catenin and anchored at the submembrane region along with E-cadherin and IQGAP1, and as a part of the β-catenin destruction complex consisting of GSK3β kinase, Axin and Adenomatous polyposis coli (APC). The β-catenin destruction complex prevents β-catenin activation and translocation to the nucleus. In Iqgap2 ^−/− hepatocytes, E-cadherin disappears from the membrane, while β-catenin escapes the destruction complex, accumulates in the cytoplasm, and enters the nucleus, where it initiates transcription of various target genes. Simultaneously, IQGAP1, released from the submembrane region, is upregulated and perhaps acts in the similar to active β-catenin manner. Overexpressed IQGAP1 may also stimulate activity of destabilized β-catenin.