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Immune response Role of DAP12 receptors in NK cells


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Immune response Role of DAP12 receptors in NK cells

Role of DAP12 receptors in NK cells

Natural killer (NK) cells is an important component of large granular lymphocytepopulation. NK cells mediate cytolytic activity against virally infected cells andmalignant cells. [1].

The map shows signaling pathways from the activated receptors in NK cells via TYROprotein tyrosine kinase binding protein ( DAP12 ) [2] and inhibitoryreceptors. The receptors include Natural cytotoxicity triggering receptor 2 (NKp44 ), Killer cell lectin-like receptor subfamily A, member 1 ( KLRA1 ),Killer cell immunoglobulin-like receptor, two domains, short cytoplasmic tail, 1 and 2 (KIR2DS1, KIR2DS2 ), Killer cell lectin-like receptor subfamily C, member 3 (KLRC3 ) and Killer cell lectin-like receptor subfamily C, member 2 ( NKG2C).

No natural ligands are known for KLRA1, KLRC3, KIR2DS1 andKIR2DS2 [3], [4]. NKG2C, a member of NKG2receptor family recognizes non-conventional MHC class IB ligands: majorhistocompatibility complex, class I, E ( HLA-E ) [3]. Uponligand-receptor recognition, DAP12 is phosphorylated by Lymphocyte-specificprotein tyrosine kinase ( Lck ) and FYN oncogene related to SRC, FGR and YES (Fyn ) [5]. Theses phosphorylation events result in recruitment of SYKfamily kinases such as Spleen tyrosine kinase ( Syk ) and Zeta-chain associatedprotein kinase 70kDa ( ZAP70 ) [6], [7], [8].

Signal transduction proceeds from ZAP70 via Linker for activation of T cells (LAT ) to the reorganization of cytoskeletal proteins. LAT activatesPhospholipase C, gamma 1 and 2 ( PLC-gamma 2 and PLC-gamma 1) [9], [10], which catalyze Diacylglycerol ( DAG ) synthesis.DAG activates Protein kinase C, theta ( PKC-theta ) [11],[12]. PKC-theta phosphorylates Wiskott-Aldrich syndrome proteininteracting protein ( WaspIP ). Separation of WaspIP from Wiskott-Aldrichsyndrome (eczema-thrombocytopenia) ( WASP ) and activation of WASP resultsin rearrangement of Actin cytoskeletal through Apr2/3 complex. Actincytoskeletal rearrangement is probably required for cytolysis of target cells[13]. V-crk sarcoma virus CT10 oncogene homolog (avian)-like ( CrkL )participates in recruitment of WaspIP/ WASP to Actin cytoskeletal[11], [14].

DAP12 probably activates SHC (Src homology 2 domain containing) transformingprotein 1 ( Shc ) via ZAP70. Shc binds and stimulates Growth factorreceptor-bound protein 2 ( GRB2 ). In turn, GRB2 activates another guaninenucleotide exchange factors Son of sevenless homolog ( SOS ), which transmitsignal via v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras)/ v-raf-1murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/ MEK s/ ERK scascade [8].

Syk interacts with Phosphoinositide 3-kinase ( PI3K ) [15], [16], [8]. ERK1/2 activation results in mobilization of lytic granules withperforin and granzyme B.

DAP12 -activating receptors action in NK cells is repressed by inhibitoryreceptors whch include cell immunoglobulin-like receptor, three domains, long cytoplasmictail, 2 ( KIR3DL2 ) and 1 ( KIR3DL1 ) correspondingly; Killer celllectin-like receptor subfamily C, member 1 ( NKG2A ); Killer cellimmunoglobulin-like receptor, two domains, long cytoplasmic tail 1-5 ( KIR2DL1,KIR2DL2, KIR2DL3, KIR2DL4, KIR2DL5) [17], [18],[1]

Most inhibitory receptors belong to the killer immunoglobulin (Ig)-like receptor (KIR)superfamily which recognizes classical MHC class I molecules major histocompatibilitycomplex, class I B ( HLA-B ) and C ( HLA-C ), E ( HLA-E ) , G( HLA-G ). KIR3DL1 is activated by HLA-B; NKG2A - byHLA-E; KIR2DL1, KIR2DL2; KIR2DL3 - by HLA-C;KIR2DL4 - by HLA-G. The ligand for KIR2DL5 is not known [17], [3], [1].

Inhibitory receptors block signals from the activating receptors by attraction ofphosphatase and following dephosphorylation of signaling proteins downstream ofactivating receptors. Tow phosphatases: Tyrosine phosphatase protein tyrosinephosphatase, non-receptor type 6 ( SHP-1 ) and 11 ( SHP-2 ) bind toinhibitory receptors upon ligand recognition, [17], [19], [20]. Some receptors recruits only one of two phosphatases, for example,KIR2DL4 requires SHP-2 [17]. The others receptors bind bothphosphatases, for example, KIR2DL2 [21].

Dephosphorylation by SHP-1 blocks association of the adaptor protein LAT1 with PLC-gamma 1 and PLC-gamma 2 [22]. In addition, SHP-1 may inhibit Syk [23]. BothSHP-1 and SHP-1 inhibit Lck [24], [25],[26].