KEGG   PATHWAY: sara04650
Entry
sara04650                   Pathway                                
Name
Natural killer cell mediated cytotoxicity - Sorex araneus (European shrew)
Description
Natural killer (NK) cells are lymphocytes of the innate immune system that are involved in early defenses against both allogeneic (nonself) cells and autologous cells undergoing various forms of stress, such as infection with viruses, bacteria, or parasites or malignant transformation. Although NK cells do not express classical antigen receptors of the immunoglobulin gene family, such as the antibodies produced by B cells or the T cell receptor expressed by T cells, they are equipped with various receptors whose engagement allows them to discriminate between target and nontarget cells. Activating receptors bind ligands on the target cell surface and trigger NK cell activation and target cell lysis. However Inhibitory receptors recognize MHC class I molecules (HLA) and inhibit killing by NK cells by overruling the actions of the activating receptors. This inhibitory signal is lost when the target cells do not express MHC class I and perhaps also in cells infected with virus, which might inhibit MHC class I exprssion or alter its conformation. The mechanism of NK cell killing is the same as that used by the cytotoxic T cells generated in an adaptive immune response; cytotoxic granules are released onto the surface of the bound target cell, and the effector proteins they contain penetrate the cell membrane and induce programmed cell death.
Class
Organismal Systems; Immune system
Pathway map
sara04650  Natural killer cell mediated cytotoxicity
sara04650

Other DBs
GO: 0042267
Organism
Sorex araneus (European shrew) [GN:sara]
Gene
101552758  putative killer cell immunoglobulin-like receptor-like protein KIR3DX1 [KO:K07980]
101556807  NKG2-C type II integral membrane protein-like [KO:K06541]
105943105  NKG2-A/NKG2-B type II integral membrane protein-like [KO:K06541]
101557070  NKG2-C type II integral membrane protein-like [KO:K06541]
101558164  NKG2-D type II integral membrane protein-like [KO:K06516]
101558703  natural killer cells antigen CD94-like [KO:K06516]
101546555  PTPN6; tyrosine-protein phosphatase non-receptor type 6 [KO:K05697] [EC:3.1.3.48]
101556236  tyrosine-protein phosphatase non-receptor type 11-like [KO:K07293] [EC:3.1.3.48]
101552022  PTPN11; tyrosine-protein phosphatase non-receptor type 11 [KO:K07293] [EC:3.1.3.48]
101549044  ICAM1; LOW QUALITY PROTEIN: intercellular adhesion molecule 1 [KO:K06490]
101546407  ICAM2; intercellular adhesion molecule 2 [KO:K06523]
101541898  ITGAL; integrin alpha-L [KO:K05718]
101539217  ITGB2; integrin beta-2 [KO:K06464]
101544808  PTK2B; protein-tyrosine kinase 2-beta [KO:K05871] [EC:2.7.10.2]
101549936  VAV1; LOW QUALITY PROTEIN: proto-oncogene vav [KO:K05730]
101550254  VAV2; guanine nucleotide exchange factor VAV2 [KO:K05730]
101557373  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
101555118  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
101553997  RAC3; ras-related C3 botulinum toxin substrate 3 [KO:K07861]
101546136  PAK1; serine/threonine-protein kinase PAK 1 [KO:K04409] [EC:2.7.11.1]
101550720  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
101555057  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
101559341  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
101541587  mitogen-activated protein kinase 1-like [KO:K04371] [EC:2.7.11.24]
101545848  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
101558664  TNF; tumor necrosis factor [KO:K03156]
101537997  CSF2; granulocyte-macrophage colony-stimulating factor [KO:K05427]
101540972  IFNG; interferon gamma [KO:K04687]
105943106  NKG2-C type II integral membrane protein-like [KO:K24233]
101541483  TYROBP; TYRO protein tyrosine kinase-binding protein isoform X2 [KO:K07992]
101555087  LCK; tyrosine-protein kinase Lck [KO:K05856] [EC:2.7.10.2]
101553484  LOW QUALITY PROTEIN: uncharacterized protein LOC101553484 [KO:K06856]
101557492  uncharacterized protein LOC101557492 [KO:K06856]
101546778  LOW QUALITY PROTEIN: putative V-set and immunoglobulin domain-containing-like protein IGHV4OR15-8 [KO:K06856]
101553968  low affinity immunoglobulin gamma Fc region receptor III-like [KO:K06463]
101547742  NCR3; LOW QUALITY PROTEIN: natural cytotoxicity triggering receptor 3 [KO:K06743]
101555828  FCER1G; high affinity immunoglobulin epsilon receptor subunit gamma [KO:K07983]
101559420  CD247; T-cell surface glycoprotein CD3 zeta chain [KO:K06453]
101542134  ZAP70; tyrosine-protein kinase ZAP-70 [KO:K07360] [EC:2.7.10.2]
101551795  SYK; tyrosine-protein kinase SYK isoform X1 [KO:K05855] [EC:2.7.10.2]
101551045  LCP2; lymphocyte cytosolic protein 2 [KO:K07361]
101558989  LAT; linker for activation of T-cells family member 1 [KO:K07362]
101547551  LAT2; linker for activation of T-cells family member 2 [KO:K26356]
101545860  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X2 [KO:K01116] [EC:3.1.4.11]
101554088  PLCG2; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
101559438  SH3BP2; SH3 domain-binding protein 2 [KO:K07984]
101542917  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101556597  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
101548304  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
101547106  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
101541868  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
101540938  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
101538710  FYN; tyrosine-protein kinase Fyn isoform X1 [KO:K05703] [EC:2.7.10.2]
101553821  SHC1; SHC-transforming protein 1 isoform X2 [KO:K06279]
101550526  SHC2; SHC-transforming protein 2 [KO:K17447]
101550468  SHC3; SHC-transforming protein 3 [KO:K17448]
101537303  SHC4; LOW QUALITY PROTEIN: SHC-transforming protein 4 [KO:K17449]
101544020  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
101550972  SOS1; LOW QUALITY PROTEIN: son of sevenless homolog 1 [KO:K03099]
101555769  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
101546777  HRAS; GTPase HRas [KO:K02833]
101557531  KRAS; GTPase KRas isoform X1 [KO:K07827]
101559343  NRAS; GTPase NRas [KO:K07828]
101554406  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
101550676  BRAF; serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
101545329  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
101537725  ULBP3; NKG2D ligand 3 [KO:K07986]
101550913  NKG2D ligand 1-like [KO:K07986]
101557888  NKG2-D type II integral membrane protein [KO:K06728]
101541746  HCST; hematopoietic cell signal transducer [KO:K07988]
101538821  CD48; CD48 antigen [KO:K06479]
101557366  PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform isoform X1 [KO:K04348] [EC:3.1.3.16]
101558512  PPP3CC; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform [KO:K04348] [EC:3.1.3.16]
101555223  PPP3CA; serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform [KO:K04348] [EC:3.1.3.16]
101556800  PPP3R1; calcineurin subunit B type 1 [KO:K06268]
101541742  PPP3R2; calcineurin subunit B type 2 [KO:K06268]
101554287  NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 [KO:K04446]
101555053  NFATC2; nuclear factor of activated T-cells, cytoplasmic 2 [KO:K17332]
101551961  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
101547658  PRKCB; protein kinase C beta type isoform X2 [KO:K19662] [EC:2.7.11.13]
101539279  PRKCG; protein kinase C gamma type isoform X1 [KO:K19663] [EC:2.7.11.13]
101557359  SH2D1B; SH2 domain-containing protein 1B [KO:K07989]
101550066  SH2D1A; SH2 domain-containing protein 1A [KO:K07990]
101546718  IFNGR1; interferon gamma receptor 1 [KO:K05132]
101558386  IFNGR2; interferon gamma receptor 2 [KO:K05133]
101549593  LOW QUALITY PROTEIN: interferon alpha-14 [KO:K05414]
101548268  IFNB1; interferon beta [KO:K05415]
101558656  IFNAR1; interferon alpha/beta receptor 1 [KO:K05130]
101559190  IFNAR2; interferon alpha/beta receptor 2 [KO:K05131]
101536897  TNFSF10; tumor necrosis factor ligand superfamily member 10 [KO:K04721]
101537204  TNFRSF10B; tumor necrosis factor receptor superfamily member 10B [KO:K04722]
101537026  granzyme B-like [KO:K01353] [EC:3.4.21.79]
101537294  granzyme B-like [KO:K01353] [EC:3.4.21.79]
101537553  granzyme B [KO:K01353] [EC:3.4.21.79]
101537826  granzyme B(G,H)-like [KO:K01353] [EC:3.4.21.79]
101551388  granzyme B-like [KO:K01353] [EC:3.4.21.79]
101551660  granzyme B(G,H)-like [KO:K01353] [EC:3.4.21.79]
101555084  granzyme-like protein 1 [KO:K01353] [EC:3.4.21.79]
101555357  granzyme B(G,H)-like [KO:K01353] [EC:3.4.21.79]
101541109  PRF1; perforin-1 [KO:K07818]
101539340  CASP3; caspase-3 [KO:K02187] [EC:3.4.22.56]
101546492  BID; BH3-interacting domain death agonist [KO:K04726]
101538987  NKG2D ligand 4-like [KO:K07987]
Compound
C00076  Calcium cation
C00165  Diacylglycerol
C01245  D-myo-Inositol 1,4,5-trisphosphate
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Reference
PMID:15607802
  Authors
Chiesa S, Tomasello E, Vivier E, Vely F.
  Title
Coordination of activating and inhibitory signals in natural killer cells.
  Journal
Mol Immunol 42:477-84 (2005)
DOI:10.1016/j.molimm.2004.07.030
Reference
PMID:16109839
  Authors
Maghazachi AA.
  Title
Insights into seven and single transmembrane-spanning domain receptors and their signaling pathways in human natural killer cells.
  Journal
Pharmacol Rev 57:339-57 (2005)
DOI:10.1124/pr.57.3.5
Reference
PMID:15567854
  Authors
Vivier E, Nunes JA, Vely F.
  Title
Natural killer cell signaling pathways.
  Journal
Science 306:1517-9 (2004)
DOI:10.1126/science.1103478
Reference
PMID:12205470
  Authors
Colucci F, Di Santo JP, Leibson PJ.
  Title
Natural killer cell activation in mice and men: different triggers for similar weapons?
  Journal
Nat Immunol 3:807-13 (2002)
DOI:10.1038/ni0902-807
Reference
PMID:11062493
  Authors
Perussia B.
  Title
Signaling for cytotoxicity.
  Journal
Nat Immunol 1:372-4 (2000)
DOI:10.1038/80808
Reference
PMID:15607806
  Authors
Smyth MJ, Cretney E, Kelly JM, Westwood JA, Street SE, Yagita H, Takeda K, van Dommelen SL, Degli-Esposti MA, Hayakawa Y.
  Title
Activation of NK cell cytotoxicity.
  Journal
Mol Immunol 42:501-10 (2005)
DOI:10.1016/j.molimm.2004.07.034
Reference
PMID:11895890
  Authors
Djeu JY, Jiang K, Wei S.
  Title
A view to a kill: signals triggering cytotoxicity.
  Journal
Clin Cancer Res 8:636-40 (2002)
Reference
PMID:12530970
  Authors
Smyth MJ, Takeda K, Hayakawa Y, Peschon JJ, van den Brink MR, Yagita H.
  Title
Nature's TRAIL--on a path to cancer immunotherapy.
  Journal
Immunity 18:1-6 (2003)
DOI:10.1016/S1074-7613(02)00502-2
Reference
PMID:16177799
  Authors
Colonna M.
  Title
Fine-tuning NK cell responses: it's a family affair.
  Journal
Nat Immunol 6:961-2 (2005)
DOI:10.1038/ni1005-961
Reference
PMID:8942070
  Authors
Bonnema JD, Leibson PJ.
  Title
Signal transduction during NK cell activation.
  Journal
Chem Immunol 64:28-43 (1996)
Reference
PMID:16002670
  Authors
Tassi I, Presti R, Kim S, Yokoyama WM, Gilfillan S, Colonna M.
  Title
Phospholipase C-gamma 2 is a critical signaling mediator for murine NK cell activating receptors.
  Journal
J Immunol 175:749-54 (2005)
DOI:10.4049/jimmunol.175.2.749
Reference
PMID:9143705
  Authors
Rao A, Luo C, Hogan PG.
  Title
Transcription factors of the NFAT family: regulation and function.
  Journal
Annu Rev Immunol 15:707-47 (1997)
DOI:10.1146/annurev.immunol.15.1.707
Reference
PMID:14710949
  Authors
Wu J, Lanier LL.
  Title
Natural killer cells and cancer.
  Journal
Adv Cancer Res 90:127-56 (2003)
DOI:10.1016/S0065-230X(03)90004-2
Reference
PMID:11905813
  Authors
Cerwenka A, Lanier LL.
  Title
Natural killer cells, viruses and cancer.
  Journal
Nat Rev Immunol 1:41-9 (2001)
DOI:10.1038/35095564
Reference
PMID:11836514
  Authors
Blott EJ, Griffiths GM.
  Title
Secretory lysosomes.
  Journal
Nat Rev Mol Cell Biol 3:122-31 (2002)
DOI:10.1038/nrm732
Reference
PMID:12766758
  Authors
Lieberman J.
  Title
The ABCs of granule-mediated cytotoxicity: new weapons in the arsenal.
  Journal
Nat Rev Immunol 3:361-70 (2003)
DOI:10.1038/nri1083
Reference
PMID:12752668
  Authors
Lord SJ, Rajotte RV, Korbutt GS, Bleackley RC.
  Title
Granzyme B: a natural born killer.
  Journal
Immunol Rev 193:31-8 (2003)
DOI:10.1034/j.1600-065X.2003.00044.x
Reference
PMID:15618404
  Authors
Liu D, Xu L, Yang F, Li D, Gong F, Xu T.
  Title
Rapid biogenesis and sensitization of secretory lysosomes in NK cells mediated by target-cell recognition.
  Journal
Proc Natl Acad Sci U S A 102:123-7 (2005)
DOI:10.1073/pnas.0405737102
Reference
PMID:9862693
  Authors
Trotta R, Puorro KA, Paroli M, Azzoni L, Abebe B, Eisenlohr LC, Perussia B.
  Title
Dependence of both spontaneous and antibody-dependent, granule exocytosis-mediated NK cell cytotoxicity on extracellular signal-regulated kinases.
  Journal
J Immunol 161:6648-56 (1998)
Reference
PMID:11390470
  Authors
Jevremovic D, Billadeau DD, Schoon RA, Dick CJ, Leibson PJ.
  Title
Regulation of NK cell-mediated cytotoxicity by the adaptor protein 3BP2.
  Journal
J Immunol 166:7219-28 (2001)
DOI:10.4049/jimmunol.166.12.7219
Related
pathway
sara04010  MAPK signaling pathway
sara04020  Calcium signaling pathway
sara04060  Cytokine-cytokine receptor interaction
sara04210  Apoptosis
sara04630  JAK-STAT signaling pathway
KO pathway
ko04650   
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