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 lymphocyte population. NK cells mediate cytolytic activity against virally infected cells and malignant cells. [1].

The map shows signaling pathways from the activated receptors in NK cells via TYRO protein tyrosine kinase binding protein (DAP12) [2] and inhibitory receptors. 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 and KIR2DS2 [3], [4]. NKG2C, a member of NKG2 receptor family recognizes non-conventional MHC class IB ligands: major histocompatibility complex, class I, E (HLA-E) [3]. Upon ligand-receptor recognition, DAP12 is phosphorylated by Lymphocyte-specific protein tyrosine kinase (Lck) and FYN oncogene related to SRC, FGR and YES (Fyn) [5]. These phosphorylation events result in recruitment of SYK family kinases such as Spleen tyrosine kinase (Syk) and Zeta-chain associated protein 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 activates Phospholipase 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 protein interacting protein (WaspIP). Separation of WaspIP from Wiskott-Aldrich syndrome (eczema-thrombocytopenia) (WASP) and activation of WASP results in rearrangement of Actin cytoskeletal through Apr2/3 complex. Actin cytoskeletal 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) transforming protein 1 (Shc) via ZAP70. Shc binds and stimulates Growth factor receptor-bound protein 2 (GRB2). In turn, GRB2 activates another guanine nucleotide exchange factors Son of sevenless homolog (SOS), which transmit signal via v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras) / v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/ MEKs/ ERKs cascade {PMID: 16109839}.

Syk interacts with Phosphoinositide 3-kinase (PI3K) [15] and Syk/ PI3K cascade activates Vav 2 and 3 guanine nucleotide exchange factors (VAV2 and VAV3) [15]. VAVs participate in activation of mitogen-activated protein kinases 3 and 1 (ERK1 and ERK2, accordingly) via Ras-related C3 botulinum toxin substrate 1 (RAC1)/ p21/Cdc42/Rac1-activated kinase 1 (PAK1)/ Mitogen-activated protein kinase kinase 1 (MEK1(MAP2K1)) pathway [8], [16], [17]. ERK1/2 activation results in mobilization of lytic granules with perforin and granzyme B.

DAP12-activating receptors action in NK cells is repressed by inhibitory receptors whch include cell immunoglobulin-like receptor, three domains, long cytoplasmic tail, 2 (KIR3DL2) and 1 (KIR3DL1) correspondingly; Killer cell lectin-like receptor subfamily C, member 1 (NKG2A); Killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail 1-5 (KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR2DL5) [1], [18], [19]

Most inhibitory receptors belong to the killer immunoglobulin (Ig)-like receptor (KIR) superfamily which recognizes classical MHC class I molecules major histocompatibility complex, class I B (HLA-B) and C (HLA-C), E (HLA-E), G (HLA-G). KIR3DL1 is activated by HLA-B; NKG2A - by HLA-E; KIR2DL1, KIR2DL2; KIR2DL3 - by HLA-C; KIR2DL4 - by HLA-G. The ligand for KIR2DL5 is not known [1], [3], [18].

Inhibitory receptors block signals from the activating receptors by attraction of phosphatase and following dephosphorylation of signaling proteins downstream of activating receptors. Tow phosphatases: Tyrosine phosphatase protein tyrosine phosphatase, non-receptor type 6 (SHP-1) and 11 (SHP-2) bind to inhibitory receptors upon ligand recognition, [18], [20], [21]. Some receptors recruits only one of two phosphatases, for example, KIR2DL4 requires SHP-2 [18]. The others receptors bind both phosphatases, for example, KIR2DL2 [22].

Dephosphorylation by SHP-1 blocks association of the adaptor protein LAT 1 with PLC-gamma 1 and PLC-gamma 2 {PMID: 8976179}, [23]. In addition, SHP-1 may inhibit Syk [24]. Both SHP-1 and SHP-1 inhibit Lck [25], [26], [27].

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