Functional connection between two oncogenic proteins, K-Ras and AIMP2-DX2

Abstract

K-Ras is the most famous oncogene that is frequently mutated in human cancers, and it influences on poor prognosis with low survival rate of cancer patients. Although K-Ras is a strong target of cancer therapeutics, the mechanism underlying pathological increase of K-Ras is unclear. Here we report that AIMP2-DX2, oncogenic splicing variant of AIMP2-F, is critical determinant of K-Ras stabilization. Through transcriptome analysis in AIMP2-DX2 high- and low-expressing lung cancer cells, we identified AIMP2-DX2 is positively correlated with Ras signaling. In AIMP2-DX2-inducible in vitro and in vivo model, we monitored the stabilization of K-Ras by induction of AIMP2-DX2. AIMP2-DX2 GST-N domain binds to the positively charged hypervariable region of K-Ras and inhibits the β-TrCP-, E3 ligase of K-Ras, mediated ubiquitination. Therefore, this work unveiled that the stabilization of K-Ras can be determined by interaction with AIMP2-DX2 and suggested that the interaction of two oncogenic proteins leads to pathologically synergic cancer-promoting property.