Upstream regulatory mechanisms and clinical significance of IQGAP2 deficiency in affecting PI3K activity to drive cell proliferation.

IQGAP2 gene defects can lead to aberrant cell proliferation and are associated with multiple diseases. Previous studies suggest that IQGAP2 knockdown can activate AKT/mTORC1 and thereby promote aberrant cell proliferation. However, the upstream molecular regulatory mechanisms remain unclear. In our study, we found that IQGAP2 knockdown enhances PI3K activity, leading to accumulation of PI(3,4,5)P3, thereby activating downstream AKT and mTORC1 activity. Integrative multi-omics and co-immunoprecipitation analyses revealed that IQGAP2 downregulation promotes PI3K activation within the IQGAP1 complex, while simultaneously activating the Wnt/β-catenin and AREG/EREG-EGFR signaling axes, thereby directly or indirectly enhancing PI3K activity. Furthermore, we found that the IQGAP1/IQGAP2 expression ratio is significantly elevated in tumor tissues and this ratio is associated with poor patient survival prognosis by TCGA pan-cancer analysis. This study provides insights into the signaling mechanisms associated with IQGAP2 downregulation, suggesting that the IQGAP1/IQGAP2 expression ratio may have clinical potential as a pan-cancer prognostic biomarker, and providing a basis for further investigation of targeted interventions for IQGAP2-related diseases.