title: Expression, signaling proficiency, and stimulatory function of the NKG2D lymphocyte receptor in human cancer cells.
abstract: The stimulatory natural killer group 2 member D (NKG2D) lymphocyte receptor and its tumor-associated ligands are important mediators in the immune surveillance of cancer. With advanced human tumors, however, persistent NKG2D ligand expression may favor tumor progression. We have found that cancer cells themselves express NKG2D in complex with the DNAX-activating protein 10 (DAP10) signaling adaptor. Triggering of NKG2D on ex vivo cancer cells or on tumor lines which express only few receptor complexes activates the oncogenic PI3K-protein kinase B (PKB/AKT)-mammalian target of rapamycin (mTOR) signaling axis and downstream effectors, the ribosomal protein S6 kinase 1 (S6K1) and the translation initiation factor 4E-binding protein 1 (4E-BP1). In addition, as in lymphocytes, NKG2D ligand engagement stimulates phosphorylation of JNK and ERK in MAP kinase cascades. Consistent with these signaling activities, above-threshold expression of NKG2D-DAP10 in a ligand-bearing tumor line increases its bioenergetic metabolism and proliferation, thus suggesting functional similarity between this immunoreceptor and tumor growth factor receptors. This relationship is supported by significant correlations between percentages of cancer cells that are positive for surface NKG2D and criteria of tumor progression. Hence, in a conceptual twist, these results suggest that tumor co-option of NKG2D immunoreceptor expression may complement the presence of its ligands for stimulation of tumor growth.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Andrea Caballero
authors.initials: AC
authors.lastname: Benitez
authors.forename: Zhenpeng
authors.initials: Z
authors.lastname: Dai
authors.forename: Henning H
authors.initials: HH
authors.lastname: Mann
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Reeves
authors.forename: Daciana H
authors.initials: DH
authors.lastname: Margineantu
authors.forename: Ted A
authors.initials: TA
authors.lastname: Gooley
authors.forename: Veronika
authors.initials: V
authors.lastname: Groh
authors.forename: Thomas
authors.initials: T
authors.lastname: Spies
mesh_terms: D045744:Cell Line, Tumor; D018450:Disease Progression; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D008297:Male; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D051057:Proto-Oncogene Proteins c-akt