[5] Its name stems from the fact that its RasGAP-related domain (GRD) has sequence homology to the Sar1 GTPase.

IQGAP is particularly interesting as a therapeutic target since it acts as a node for so many signaling pathways implicated in cancer progression.

[8] Importantly, approximately 10% of genes that show increased expression in metastatic cells are IQGAP1 binding partners.

Since this area of the protein is conserved in amino acid sequence and structure, it can be characterized by function or binding partner.

IQGAP1 does bind Rho GTPases CDC42 and RAC1, however, IQGAP1 is unusual in that it actually has no GAP function, and instead stabilizes the GTP-bound proteins in their active state.

[9] Homologues of IQGAP1 are known in species as divergent as yeast, worms, and humans (as well as other mammals), though the domains are not always highly conserved.

IQGAP2 is found in the liver, stomach, and platelets and is 62% identical to IQGAP1,[9] but appears to have a drastically divergent function in terms of pathology.

For example, IQGAP1 expression is necessary for neuronal process outgrowth on the cell adhesion molecule PTPmu (PTPRM).

[21] Expression of the protein is upregulated by gene amplification in two gastric cancer cell lines[7] and its over-expression and distinct membrane localisation is also observed in a range of tumours.

To simplify, due to its diverse range of binding partners, IQGAP1 may act as a link between logically related but molecularly distinct cellular functions.

The Ras→Raf→MEK→ERK MAPK signaling pathway plays an integral part in the processes of cell proliferation, differentiation, and apoptosis.

Various extracellular signals induce the ERK MAPK pathway including EGF, IGF-1, PDGF, and NGF.

IQGAP directly binds b-RAF,[35] MEK1/2 and ERK1/2, and is in fact necessary for the phosphorylation (activation) of ERK upon stimulation by EGF.

[43] Active RAC1 binds IQGAP1 to crosslink actin filaments and prevents IQGAP1 from interacting with beta-catenin, stabilizing cell-cell contacts.

IQGAP1 binds b-catenin and increases nuclear localization and expression of beta-catenin’s transcriptional targets.

Since cancer is a disease characterized by the perturbation of many of these cellular processes, IQGAP1 is a logical oncogene candidate and therapeutic target.

IQGAP1 knockdown in MCF-7 cancer cells reduced the malignant phenotype (serum-dependent proliferation and anchorage independent growth).

IQGAP1 null mice appear significantly normal, with the only life history abnormality being an increase in gastric hyperplasia.