Pathway maps

Immune response_CD16 signaling in NK cells
Immune response_CD16 signaling in NK cells

Object List (links open in MetaCore):

c-Jun/c-Fos, GRB2, IFN-gamma, Syk, Cytohesin1, IgG3, NKG2A, Calmodulin, c-Raf-1,, GM-CSF, Rac1, Shc, ZAP70, Calcineurin A (catalytic), PI3K cat class IA, VAV-1, CD94, Arp2/3, , PLC-gamma 2, IP3 receptor, Calcineurin B (regulatory), 2.7.1., CD3 zeta, IgG1, PLC-gamma 1, MEK2, DAG, LAT, c-Fos, IL-2, 1-(1,2-diacyl-glycerol 3-phospho)-inositol 4-phosphate, Ca(2+) endoplasmic reticulum, AP-1, CDC42, IL-4, Ca(2+) cytosol, TNF-alpha, c-Cbl, PKC-theta, PI3K reg class IA,, PIP5K1A, Actin cytoskeletal, IP3, NF-AT1(NFATC2), PLD1,, PtdIns(3,4,5)P3, MEK1, IL-3, PtdIns(3,4)P2, SOS, FasL(TNFSF6), WaspIP, SHIP, PtdIns(4,5)P2, Fc gamma RIII alpha (CD16), PLA2, H-Ras, WASP, ERK1/2, HLA-E, ERK2, ARF6, SHP-1, c-Jun, Lck


CD16 signaling in NK cells

Natural killer (NK) cells mediate antibody-depend cellular cytotoxicity through the Fc fragment of IgG, low affinity IIIa and receptor (CD16a) ( Fc gamma RIII alpha (CD16) ) [1], [2]. The preferred ligands for Fc gamma RIII alpha (CD16) on NK cells are Immunoglobulins gamma 1 and 3 ( IgG1 and IgG3 ) [3], [4]. Fc gamma RIII alpha (CD16) covalently associates with the Membrane-bound signaling adaptor CD247 molecule ( CD3 zeta ), which transduces signal to cytoplasm [5], [6]. Upon ligand binding and receptor activation, CD3 zeta is phosphorilated by Lymphocyte-specific protein tyrosine kinase ( Lck ) [7], followed by recruitment of SYK family kinases - Spleen tyrosine kinase ( Syk ) [8] and Zeta-chain associated protein kinase 70kDa ( ZAP70 ) [9], [10].

Ligation of Fc gamma RIII alpha (CD16) stimulates expression of many cytokines via Ca('2+) -depend mechanism [11]. Both ZAP70 and Syk phosphorylate Linker for activation of T cells ( LAT ) [8], [12]. LAT activates Phospholipases C gamma 1 and 2 ( PLC-gamma 1 and 2 ), which control intracellular concentration of Ca('2+) [13], [14]. Ca('2+) activates Calmodulin 2 ( Calmodulin )/ Protein phosphatase 3 ( Calcineurin ) signal. Activated Calcineurin dephosphorylates Nuclear factor of activated T-cells cytoplasmic calcineurin-dependent 2 ( NF-AT1(NFATC2) ). NF-AT1(NFATC2), in turn, migrates to the nucleus and activates transcription of cytokines Tumor necrosis factor ( TNF-alpha ), Colony stimulating factor 2 ( GM-CSF ), Interleukin 2 ( IL-2 ), Interleukin 3 ( IL-3 ), Interleukin 4 ( IL-4 ) [15], Fas ligand ( FasL ) [16] and, possibly, Interferon gamma ( IFN-gamma ) [17].

These cytokines play various roles in immune response. FasL participates in lysis of target cells [18], [19], [20], [21], [22], [23].

The second mechanism leading to cytokines transcription in NK cells is by activation of v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-RAS ) via SHC transforming protein 1 ( Shc )/ Growth factor receptor-bound protein 2 ( Grb2 )/ Son of sevenless homologes ( SOS ) cascade [24], [25]. H-RAS activates v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/ Mitogen-activated protein kinase kinases 1 and 2 ( MEK1(MAP2K1) and MEK2(MAP2K2) )/ Mitogen-activated protein kinases 3 and 1 ( ERK1 and ERK2 ) cascade [26], [25], [27]. ERK1 and ERK2 phosphorylate Jun oncogene ( c-Jun ) and V-fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ), which form homo- and hetero-dimmers complex AP-1 and participate in activation of transcription TNF-alpha [28], IL-2 [15] and GM-CSF [15].

On the other hand, Fc gamma RIII alpha (CD16) ligation induces pathways leading to exocytosis of secretory lysosomes [29]. PLC-gamma 2 probably participates in the first pathway leading to cytoskeleton rearrangement [30]. It catalyzes diacylglycerol ( DAG ) synthesis leading to activation of Protein kinase C theta ( PKC-theta ) [31], [32]. PKC-theta phosphorylates Wiskott-Aldrich syndrome protein interacting protein ( WaspIP ) which leads to separation of WaspIP from Wiskott-Aldrich syndrome ( WASP ), activation of WASP and, eventually, rearrangement of Actin cytoskeletal through Apr2/3 complex. Actin cytoskeletal rearrangement may be also required for cytolysis of target cell [33].

The second pathway leading to exocytosis starts from Syk and ZAP70, which phosphorylates Vav 1 guanine nucleotide exchange factor ( VAV-1 ) directly [34], [35]. Then VAV-1 participates in activation of Ras-related C3 botulinum toxin substrate 1 ( Rac1 ) [36], [35]. This pathway proceeds from Rac1 to formation of granules [36], [37]. In addition, VAV-1 may activate Cell division cycle 42 ( CDC42 ), which participates in activation of WASP [38], [33].

Another pathway which leads to secretion of granules includes Syk/ Cas-Br-M ecotropic retroviral transforming sequence ( c-Cbl )/ Phosphoinositide 3-kinase ( PI3K ) cascade, which activates Pleckstrin homology, Sec7 and coiled-coil domains 1 ( Cytohesin1 ). Grb2 probably helps to activate c-Cbl [39]. Cytohesin1 activates ADP-ribosylation factor 6 Arf6 [40], [41]. From Arf6, signal proceeds to Phosphatidylinositol-4-phosphate 5-kinase type I alpha ( PIP5K1A ) and Phospholipase D1 phosphatidylcholine-specific ( PLD1 ) directly and/or via PIP5K1A. The products of reactions of both PIP5KA1 and PLD1 participate in the vesicle secretion [42].

ERK2 also participates in degranulation via activation of Phospholipase A2 group IIA ( PLA2 ) by phosphorylation [43], [44].

Inhibitory receptor Killer cell lectin-like receptor subfamily C, member 1 ( NKG2A ) and Killer cell lectin-like receptor subfamily D, member 1 ( CD94 ) deactivate stimulation from Fc gamma RIII alpha (CD16) after ligation Classical MHC class I molecules major histocompatibility complex, class I E ( HLA-E ) to NKG2A. It attracts Protein tyrosine phosphatase non-receptor type 6 ( SHP-1 ), which dephosphorylates CD3 zeta, Syk and Shc [25].

Fc gamma RIII alpha (CD16) autoregulates activation of downstream signals trough CD3 zeta/ Shc/ Inositol polyphosphate-5-phosphatase 145kDa ( SHIP ) pathway. The hypothetical mechanism consists of SHIP participation in inhibition of Ca('2+) -depend pathway and signal from PI3K via decreased amount IP3 [45] and PtdIns(3,4,5)P3 [46].


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