TNFAIP8 is a novel phosphoinositide-binding inhibitory regulator of Rho GTPases that promotes cancer cell migration

Abstract

SUMMARYMore than half of human tumors exhibit aberrantly dysregulated phosphoinositide signaling, yet how this is controlled remains not fully understood. While somatic mutations of PI3K, PTEN and Ras account for many cases of the hyperactivated lipid signals, other mechanisms for these dysfunctions in cancer are also being discovered. We report here that TNFAIP8 interacts with PtdIns(4,5)P2and PtdIns(3,4,5)P3and is likely to be hijacked by cancer cells to facilitate directional migration during malignant transformation. TNFAIP8 maintains the quiescent cellular state by sequestering inactive Rho GTPases in the cytosolic pool, which can be set free upon chemoattractant activation at the leading edge. Consequently, loss of TNFAIP8 results in severe defects of chemotaxis and adhesion. Thus, TNFAIP8, whose expression can be induced by inflammatory cytokines such as TNFαfrom tumor microenvironment, represents a molecular bridge from inflammation to cancer by linking NF-κB pathway to phosphoinositide signaling. Our study on the conserved hydrophobic cavity structure will also advisein silicodrug screening and development of new TNFAIP8-based strategies to combat malignant human diseases.