The multi-tRNA synthetase complex (MSC), a macromolecular protein complex, is composed of minoacyl-transfer RNA synthetase-interacting multifunctional protein 2 (AIMP2). When AIMP2 separates from the MSC, it affects the p53, TGF-β, TNF-α, and WNT signaling pathways, which each function to prevent tumorigenesis. AIMP2-DX2, an alternative splicing variant of AIMP2 that eliminates exon 2, has a positive correlation with the aggressiveness of cancer. AIMP2-DX2 interacts competitively with p53, FBP, and TRAF2 to reduce the tumor-suppressive activity of native AIMP2. AIMP2-DX2 is a tumorigenic factor that is frequently upregulated in a variety of cancers. AIMP2-DX2 is highly expressed in colon, lung, and pancreatic cancer tissues, implying that AIMP2-DX2 is a potential target for cancer control.