While the list of the confirmed binding partners of IQGAP2 remains relatively short, its extensively studied homolog IQGAP1 binds ERK1/2 through its WW domain andMEK1/2 and Akt through the IQ motifs. Since IQGAP1 LY3039478 andIQGAP2 IQ motifs share 72% of their amino acids, it is conceivable thatIQGAP2 is capable of binding these kinases as well. Finally, recent studies have implicated the Hippo signaling pathway in self-renewal and repair of the intestinal epithelium. Unchanged or even modestly decreased levels of Iqgap2 RNA transcript observed inhuman colitis specimens can be interpreted as follows. Our IHC results in IBD colonic specimens show that significant changes in IQGAP2 protein expression maybe occurring in infiltrating myeloid cells rather than in epithelium and the microarray studies reviewed here do not distinguish between cell types. Further studies of IQGAP2 protein expression in larger specimen cohorts of human IBD of different types and stages are needed to determine whether IQGAP2 plays a role in initiation or maintenance of colonic inflammation, as well as to address IQGAP2 protein stability and epigenetic mechanisms possibly regulating IQGAP2 expression. In summary, the current study identifies IQGAP2 as a novel regulator of colonic inflammation and also provides evidence that it may play a role in the systemic immune response through control of macrophage maturation and recruitment to the site of injury. Signaling scaffolding proteins such as IQGAP2 represent amenable therapeutic targets due to their domain structure. Synthetic IQGAP2 domain-specific inhibiting peptides make attractive candidates for investigation of potential immune modulatory properties, since their Scriptaid action would constitute a selective blockage of IQGAP2 interactions with specific binding partners rather than ablation of the entire functional spectrum of IQGAP2. Of note, the first successful inhibition of IQGAP1 homolog using WW domain-mimicking synthetic peptides has been recently reported.The peptides effectively blocked IQGAP1 interaction with ERK1/2, resulting in inhibition of tumorigenesis in mouse models for melanoma, breast and pancreatic cancers.