Family NK Receptor Ligands Ras Activation Induces Expression of Raet1

NK cells play a crucial role in innate immunity against tumors. In many human tumors, Ras is chronically active, and tumor cells frequently express ligands for the activating NK cell receptor NKG2D. In this study, we report that Ras activation upregulates the expression of Raet1 protein family members Rae1a and Rae1b in mouse and ULBP1–3 in human cells. In addition, Ras also induced MHC class I chain-related protein expression in some human cell lines. Overexpression of the constitutively active H-RasV12 mutant was sufficient to induce NKG2D ligand expression. H-RasV12–induced NKG2D ligand upregulation depended on Raf, MAPK/MEK, and PI3K, but not ATM or ATR, two PI3K-like kinases previously shown to induce NKG2D ligand expression. Analysis of the 59 untranslated regions of Raet1 family members suggested the presence of features known to impair translation initiation. Overexpression of the rate-limiting translation initiation factor eIF4E induced Rae1 and ULBP1 expression in a Ras-and PI3K-dependent manner. Upregulation of NKG2D ligands by H-RasV12 increased sensitivity of cells to NK cell-mediated cytotoxicity. In summary, our data suggest that chronic Ras activation is linked to innate immune responses, which may contribute to immune surveillance of H-Ras transformed cells. N atural killer cells are lymphocytes of the innate immune system that play a critical role in the elimination of tumor cells (1). They discriminate tumor cells from other healthy " self " cells by a variety of activating and inhibitory receptors. One of the best-characterized NK cell-activating receptors in the context of cancer is NKG2D (reviewed in Ref. 2). NK cells constitutively express NKG2D, and engagement of NKG2D leads to cytokine secretion and cytotoxicity (3). NKG2D recognizes retinoic acid early transcript 1 (RAET1) gene family members and MHC class I chain-related (MIC) A and B proteins in humans. Humans and mice share the RAET1 family. The human RAET1 gene family, also called ULBPs, consists of 10 genes. To date, no MIC homologs have been found in the mouse genome. The mouse genes encoding NKG2D ligands can be grouped into Rae1, H60, and Mult1 subfamilies, which share little homology but are structurally similar (3–5). The Rae1 subfamily consists of the five highly related isoforms Rae1a, b, g, d, and ε encoded by different genes. NKG2D ligand expression has been observed on tumor cells of many origins, in particular in solid tumors, lymphomas, and my-eloid leukemia (6–8). NKG2D was shown to be critical for im-munosurveillance of carcinoma and epithelial and lymphoid …