CD94/NKG2
From Wikipedia, the free encyclopedia
CD94/NKG2 is a family of C-type lectin receptors which are expressed predominantly on the surface of NK cells and a subset of CD8+ T-lymphocyte.[1][2] These receptors stimulate or inhibit cytotoxic activity of NK cells, therefore they are divided into activating and inhibitory receptors according to their function.[3] CD94/NKG2 recognize nonclassical MHC glycoproteins class I (HLA-E in human and Qa-1 molecules in the mouse).[4]
CD94/NKG2 family includes seven members: NKG2A, B, C, D, E, F and H.[5] Genes encoding these receptors are clustered in the natural killer complex (NKC) on human chromosome 12 and mouse chromosome 6 together with Clr (C-lectin related) genes.[6]
Structure
NKG2 receptors are transmembrane proteins type II which dimerize with CD94 molecule. CD94 contains a short cytoplasmic domain and it is responsible for signal transduction. Therefore NKG2 receptors form disulfide bonded heterodimers. NKG2D represent an exception, it is a homodimer.[7]
Signaling
- NKG2A and NKG2B receptors transmit inhibitory signal. They contain two immunoreceptor tyrosine-based inhibitory motifs (ITIM) in their cytoplasmic tail[8] that are defined by the sequence (I/L/V/S)xYxx(L/V), where “x” means any amino acid at a given position. If ITIM-bearing receptors engage their ligand, probably Src family kinase phosphorylates tyrosine residue, and this allows recruitment of the tyrosine phosphatase SHP-1, SHP-2 or SHIP. It leads to dephosphorylation of tyrosine kinase’s substrates, which are involved in the activating cascades. As a result, NK cell activation is suppressed.[9]
- NKG2C (encoded by the KLRC2 gene), NKG2E and NKG2H are activating receptors. Ligand binding enables interaction between receptor and ITAM-bearing adaptor protein DAP12 (ITAM, Immunoreceptor tyrosine-based activation motif, defined by the sequence (D/E)xxYxx(L/I)x6-8Yxx(L/I)). Src family kinases phosphorylate tyrosine in ITAM sequence. It results in recruitment of tyrosine kinases Syk and ZAP-70 by the adaptor molecules. Finally, actin cytoskeleton is being reorganized and the cell can release cytotolytic granules containing perforin and granzyme. This signaling pathway also induces transcription of many cytokine and chemokine genes. The process is similar to T and B cell signaling through their specific receptors TCR or BCR.[10][11]
- NKG2D is activating receptor as well but it couples with adaptor protein DAP10 which carries signaling motif YINM. Src or Jak kinases phosphorylate DAP10, which can then associate with p85 subunit of PI(3)K or adaptor molecule Grb2. This signaling triggers actin reorganization (cell polarization) and degranulation.[12]
- Function of NKG2F receptor has not been clarified yet.[13] It may not associate with CD94, it has not a C-type lectin domain and contains ITIM-like motif in the cytoplasmic tail. However, ITIM-like motif seems to be non-functional, thus NKG2F was considered as an activating receptor.[14]