Regulation of NKG2D by RKIP: Implications on NK-mediated cytotoxicity and cytokine production

Abstract

RKIP (Raf kinase inhibitory protein) is a metastatic suppressor and a chemo-immuno-sensitizer. The deficiency or loss of RKIP has been linked with different cancer types, resulting in the activation of the MAPK pathway, as a result of Raf protein activation, which eventually leads to cell growth. Studies have suggested that RKIP can be used therapeutically to augment the proapoptotic tendencies in tumor cells, regulate the epithelial-mesenchymal transition (EMT), and decrease metastasis. NKG2D is a C-lectin-type receptor of the NK cell. It binds to a large variety of different surface proteins or ligands that are commonly expressed in virally infected and transformed cells and triggers the cytotoxic activity and production of cytokines. Accordingly, the regulation mechanisms underlying the dysregulated MAPK pathway by RKIP expression and NKG2Dexpression inNKcells are important for theNKcytotoxic anticancer activity. Hypothesizing that there may be a biochemical link between the two, we examined the potential cross talks of signaling pathways between NKG2D and RKIP. To this end, we examined whether the expression and activity of the NKG2D receptor are, in part, regulated by RKIP. Our findings indicate that there is a cross talk between the expression of RKIP and NKG2D inNKcells and an inverse correlation was established. These findings were corroborated by bioinformatic analyses using Oncomine, TCGA, and HPA data. We stipulate that overexpressing NKG2D by targeting RKIP in NK cells could potentiate their antitumor activity.