KEGG   PATHWAY: ko04650
Entry
ko04650                     Pathway                                

Name
Natural killer cell mediated cytotoxicity
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
ko04650  Natural killer cell mediated cytotoxicity
ko04650

Other DBs
GO: 0042267
Orthology
K07980  killer cell immunoglobulin-like receptor 3DL
K07981  killer cell immunoglobulin-like receptor 2DL1/2/3
K24232  killer cell immunoglobulin-like receptor 2DL5
K06541  killer cell lectin-like receptor subfamily C1
K06516  killer cell lectin-like receptor subfamily D member 1
K05697  tyrosine-protein phosphatase non-receptor type 6 [EC:3.1.3.48]
K07293  tyrosine-protein phosphatase non-receptor type 11 [EC:3.1.3.48]
K06490  intercellular adhesion molecule 1
K06523  intercellular adhesion molecule 2
K05718  integrin alpha L
K06464  integrin beta 2
K05871  focal adhesion kinase 2 [EC:2.7.10.2]
K05730  guanine nucleotide exchange factor VAV
K04392  Ras-related C3 botulinum toxin substrate 1
K07860  Ras-related C3 botulinum toxin substrate 2
K07861  Ras-related C3 botulinum toxin substrate 3
K04409  p21-activated kinase 1 [EC:2.7.11.1]
K04368  mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]
K04369  mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]
K04371  mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K03156  tumor necrosis factor superfamily, member 2
K05427  granulocyte-macrophage colony-stimulating factor
K04687  interferon gamma
K07982  killer cell immunoglobulin-like receptor 2DS
K24233  killer cell lectin-like receptor subfamily C2/3
K06742  natural cytotoxicity triggering receptor 2
K07992  TYRO protein tyrosine kinase binding protein
K05856  lymphocyte cell-specific protein tyrosine kinase [EC:2.7.10.2]
K19251  Influenza A virus hemagglutinin
K06856  immunoglobulin heavy chain
K06463  low affinity immunoglobulin gamma Fc receptor III
K06741  natural cytotoxicity triggering receptor 1
K06743  natural cytotoxicity triggering receptor 3
K07983  high affinity immunoglobulin epsilon receptor subunit gamma
K06453  CD3Z antigen, zeta polypeptide
K07360  tyrosine-protein kinase ZAP-70 [EC:2.7.10.2]
K05855  spleen tyrosine kinase [EC:2.7.10.2]
K07361  lymphocyte cytosolic protein 2
K07362  linker for activation of T cells
K01116  phosphatidylinositol phospholipase C, gamma-1 [EC:3.1.4.11]
K05859  phosphatidylinositol phospholipase C, gamma-2 [EC:3.1.4.11]
K07984  SH3-domain binding protein 2
K00922  phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153]
K02649  phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K05703  tyrosine-protein kinase Fyn [EC:2.7.10.2]
K06279  SHC-transforming protein 1
K17447  SHC-transforming protein 2
K17448  SHC-transforming protein 3
K17449  SHC-transforming protein 4
K04364  growth factor receptor-bound protein 2
K03099  son of sevenless
K02833  GTPase HRas
K07827  GTPase KRas
K07828  GTPase NRas
K08845  A-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04365  B-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04366  RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K07985  MHC class I-related protein
K07986  UL16 binding protein
K06728  killer cell lectin-like receptor subfamily K member 1
K07988  hematopoietic cell signal transducer
K06479  CD48 antigen
K06582  natural killer cell receptor 2B4
K04348  serine/threonine-protein phosphatase 2B catalytic subunit [EC:3.1.3.16]
K06268  serine/threonine-protein phosphatase 2B regulatory subunit
K04446  nuclear factor of activated T-cells, cytoplasmic 1
K17332  nuclear factor of activated T-cells, cytoplasmic 2
K02677  classical protein kinase C alpha type [EC:2.7.11.13]
K19662  classical protein kinase C beta type [EC:2.7.11.13]
K19663  classical protein kinase C gamma type [EC:2.7.11.13]
K07989  SH2 domain-containing protein 1B
K07990  SH2 domain-containing protein 1A
K05132  interferon gamma receptor 1
K05133  interferon gamma receptor 2
K05414  interferon alpha
K05415  interferon beta
K05130  interferon receptor 1
K05131  interferon receptor 2
K04721  tumor necrosis factor ligand superfamily member 10
K04722  tumor necrosis factor receptor superfamily member 10A/B
K04389  tumor necrosis factor ligand superfamily member 6
K04390  tumor necrosis factor receptor superfamily member 6
K01353  granzyme B [EC:3.4.21.79]
K07818  perforin 1
K02187  caspase 3 [EC:3.4.22.56]
K04726  BH3 interacting domain death agonist
K24207  killer cell lectin-like receptor subfamily A member 1
K24208  killer cell lectin-like receptor subfamily A member 3
K24238  killer cell lectin-like receptor subfamily A member 7
K24240  killer cell lectin-like receptor subfamily A member 9
K23459  killer cell lectin-like receptor subfamily A member 4
K24239  killer cell lectin-like receptor subfamily A member 8
K07987  retinoic acid early transcript 1
Compound
C00076  Calcium cation
C00165  Diacylglycerol
C01245  D-myo-Inositol 1,4,5-trisphosphate
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Reference
  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
  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
  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
  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
  Authors
Perussia B.
  Title
Signaling for cytotoxicity.
  Journal
Nat Immunol 1:372-4 (2000)
DOI:10.1038/80808
Reference
  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
  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
  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
  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
  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
  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
  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
  Authors
Blott EJ, Griffiths GM.
  Title
Secretory lysosomes.
  Journal
Nat Rev Mol Cell Biol 3:122-31 (2002)
DOI:10.1038/nrm732
Reference
  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
  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
  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
  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
ko04010  MAPK signaling pathway
ko04020  Calcium signaling pathway
ko04060  Cytokine-cytokine receptor interaction
ko04210  Apoptosis
ko04630  JAK-STAT signaling pathway

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