IQGAP3, the overlooked oncogenic twin of IQGAP1: mapping its interactome and functional roles across cellular signaling and cancer

IQGAP3, the most recently identified member of the IQGAP family of scaffolding proteins, is increasingly recognized as a key regulator of oncogenic signaling networks that govern tumor initiation and progression. IQGAP3 integrates multiple signaling pathways including RAS/MAPK, PI3K/AKT, Wnt/β-catenin, Hedgehog, ATM/Chk2-ATR/Chk1, and TGF-β, thereby modulating cellular processes such as proliferation, DNA repair, genomic stability, epithelial to mesenchymal transition, metastasis, stemness, and resistance to therapy.This review offers a comprehensive overview of IQGAP3, beginning with its genomic organization and structural domains that underlie its distinct regulatory functions. We examine the physiological roles of IQGAP3 in cell cycle control, cytoskeletal organization, and early embryonic development, as well as its extensive network of interacting partners that link signaling pathways to specific cellular outcomes. We then highlight accumulating evidence implicating IQGAP3 dysregulation in oncogenesis, where it promotes tumor initiation, progression, and metastasis. Its contribution to therapy resistance further emphasizes its impact on clinical outcomes.In conclusion, by integrating current insights into the IQGAP3 interactome and associated signaling networks, we position IQGAP3 as a central signaling hub at the intersection of normal cellular physiology and malignant transformation.