The Antithetic Roles of IQGAP2 and IQGAP3 in Cancers

SIMPLE SUMMARY: The IQ motif-containing GTPase-activating protein family is comprised of three signal scaffolding proteins that regulate a variety of biological functions by aiding signal transduction in cells. IQGAPs induce numerous cancer-related processes, including proliferation, apoptosis, migration, invasion, and angiogenesis. In comparison to IQGAP1, IQGAP2 and IQGAP3 were less researched. In this review, we comprehensively reviewed the significant roles of IQGAP2 and IQGAP3 in cancer-associated pathways as well as the role in carcinogenesis and progression of different cancer entities. ABSTRACT: The scaffold protein family of IQ motif-containing GTPase-activating proteins (IQGAP1, 2, and 3) share a high degree of homology and comprise six functional domains. IQGAPs bind and regulate the cytoskeleton, interact with MAP kinases and calmodulin, and have GTPase-related activity, as well as a RasGAP domain. Thus, IQGAPs regulate multiple cellular processes and pathways, affecting cell division, growth, cell–cell interactions, migration, and invasion. In the past decade, significant evidence on the function of IQGAPs in signal transduction during carcinogenesis has emerged. Compared with IQGAP1, IQGAP2 and IQGAP3 were less analyzed. In this review, we summarize the different signaling pathways affected by IQGAP2 and IQGAP3, and the antithetic roles of IQGAP2 and IQGAP3 in different types of cancer. IQGAP2 expression is reduced and plays a tumor suppressor role in most solid cancer types, while IQGAP3 is overexpressed and acts as an oncogene. In lymphoma, for example, IQGAPs have partially opposite functions. There is considerable evidence that IQGAPs regulate a multitude of pathways to modulate cancer processes and chemoresistance, but some questions, such as how they trigger this signaling, through which domains, and why they play opposite roles on the same pathways, are still unanswered.