IQGAP Proteins in Cellular Signaling and Tumorigenesis

IQGAP proteins are a family of multi-domain scaffolds that coordinate signalling cascades by binding to small GTPases, cytoskeletal elements and membrane receptors. Through their conserved calponin homology, IQ motifs and RasGAP-related domains, they organise protein assemblies that translate extracellular cues into directed cellular responses, including migration, adhesion and proliferation. In cancer, dysregulated expression or post-translational modification of IQGAP1, IQGAP2 and IQGAP3 alters key pathways such as MAPK, PI3K and TGF-β, promoting tumourigenesis, invasion and metastasis. IQGAP1 is commonly overexpressed across diverse malignancies and enhances oncogenic signalling by stabilising receptor complexes and facilitating actin dynamics. By contrast, IQGAP2 often exerts a tumour-suppressive role, while IQGAP3 supports proliferation and epithelial–mesenchymal transition in specific contexts. Emerging studies highlight the interplay between IQGAPs and phosphotyrosine-binding proteins, uncovering mechanisms by which receptor tyrosine kinases fine-tune scaffold activity. Collectively, IQGAP proteins serve as nodal integrators of signalling networks whose perturbation contributes to cancer development and offers promising targets for therapeutic intervention.

Research from Nature Portfolio

In acute myeloid leukaemia models, proteomic profiling revealed marked enrichment of IQGAP1, and in silico screening identified a small-molecule inhibitor targeting its GRD domain. The lead compound, UR778Br, selectively induced apoptosis and cell-cycle arrest in leukaemic cells while sparing healthy marrow, demonstrating favourable drug-like properties and highlighting IQGAP1 as a druggable vulnerability. Earlier foundational work in pancreatic ductal adenocarcinoma established that IQGAP1 overexpression drives Wnt/β-catenin signalling via interaction with Dishevelled2, promoting proliferation, invasion and metastasis. Genetic or RNA-interference-mediated reduction of IQGAP1 attenuated tumour growth in vivo, underscoring its potential as a prognostic marker and therapeutic target in solid tumours.

IQGAP Proteins in Cellular Signaling and Tumorigenesis publication trend

The graph below shows the total number of articles in iqgap proteins in cellular signaling and tumorigenesis across all publications each year (not limited to Nature Index journals).

Technical terms

Scaffold protein: A molecule that organises multiple signalling components into functional complexes.

GTPase: An enzyme that hydrolyses GTP to GDP, acting as a molecular switch in signal transduction.

GRD domain: GTPase-related domain of IQGAP that binds and regulates small GTPases.

Phosphotyrosine: A tyrosine residue modified by phosphorylation, creating binding sites for SH2 domains.

Epithelial–mesenchymal transition (EMT): A process by which epithelial cells acquire migratory, invasive properties.

References

1. The IQGAP scaffolds: Critical nodes bridging receptor activation to cellular signaling. Journal of Cell Biology (2023).
2. IQGAP1 Is a Phosphotyrosine-Regulated Scaffold for SH2-Containing Proteins. Cells (2023).
3. The Antithetic Roles of IQGAP2 and IQGAP3 in Cancers. Cancers (2023).
4. In silico predicted compound targeting the IQGAP1-GRD domain selectively inhibits growth of human acute myeloid leukemia. Scientific Reports (2024).
5. IQGAP1 promotes pancreatic cancer progression and epithelial-mesenchymal transition (EMT) through Wnt/β-catenin signaling. Scientific Reports (2019).