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Hematopoietic cell signal transducer

Definition:

Transmembrane adapter protein which associates with KLRK1 to form an activation receptor KLRK1-HCST in lymphoid and myeloid cells; this receptor plays a major role in triggering cytotoxicity against target cells expressing cell surface ligands such as MHC class I chain-related MICA and MICB, and UL16-binding proteins (ULBPs); these ligands are up-regulated by stress conditions and pathological state such as viral infection and tumor transformation. Functions as docking site for PI3-kinase PIK3R1 and GRB2. Interaction of ULBPs with KLRK1-HCST triggers calcium mobilization and activation of the PIK3R1, MAP2K/ERK, and JAK2/STAT5 signaling pathways. Both PIK3R1 and GRB2 are required for full KLRK1-HCST-mediated activation and ultimate killing of target cells. In NK cells, KLRK1-HCST signaling directly induces cytotoxicity and enhances cytokine production initiated via DAP12/TYROBP-associated receptors. In T-cells, it provides primarily costimulation for TCR-induced signals. KLRK1-HCST receptor plays a role in immune surveillance against tumors and is required for cytolysis of tumors cells; indeed, melanoma cells that do not express KLRK1 ligands escape from immune surveillance mediated by NK cells.

References:

[1]. J Wu, et al. An activating immunoreceptor complex formed by NKG2D and DAP10. Science. 1999 Jul 30;285(5428):730-2. [Content Brief]

[2]. Katrin Wiemann, et al. Systemic NKG2D down-regulation impairs NK and CD8 T cell responses in vivo. J Immunol. 2005 Jul 15;175(2):720-9. [Content Brief]

[3]. Simona Zompi, et al. NKG2D triggers cytotoxicity in mouse NK cells lacking DAP12 or Syk family kinases. Nat Immunol. 2003 Jun;4(6):565-72. [Content Brief]

[4]. Alina I Marusina, et al. Regulation of human DAP10 gene expression in NK and T cells by Ap-1 transcription factors. J Immunol. 2008 Jan 1;180(1):409-17. [Content Brief]

[5]. Daniel D Billadeau, et al. NKG2D-DAP10 triggers human NK cell-mediated killing via a Syk-independent regulatory pathway. Nat Immunol. 2003 Jun;4(6):557-64. [Content Brief]

[6]. J Wu, et al. DAP10 and DAP12 form distinct, but functionally cooperative, receptor complexes in natural killer cells. J Exp Med. 2000 Oct 2;192(7):1059-68. [Content Brief]

[7]. Mobin Karimi, et al. Silencing human NKG2D, DAP10, and DAP12 reduces cytotoxicity of activated CD8+ T cells and NK cells. J Immunol. 2005 Dec 15;175(12):7819-28. [Content Brief]

[8]. C Chang, et al. Cutting edge: KAP10, a novel transmembrane adapter protein genetically linked to DAP12 but with unique signaling properties. J Immunol. 1999 Nov 1;163(9):4651-4. [Content Brief]

[9]. Jadee L Upshaw, et al. NKG2D-mediated signaling requires a DAP10-bound Grb2-Vav1 intermediate and phosphatidylinositol-3-kinase in human natural killer cells. Nat Immunol. 2006 May;7(5):524-32. [Content Brief]

[10]. Claire L Sutherland, et al. UL16-binding proteins, novel MHC class I-related proteins, bind to NKG2D and activate multiple signaling pathways in primary NK cells. J Immunol. 2002 Jan 15;168(2):671-9. [Content Brief]

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