KEGG   PATHWAY: hsa04650Help
Entry
hsa04650                    Pathway                                

Name
Natural killer cell mediated cytotoxicity - Homo sapiens (human)
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
BRITE hierarchy
Pathway map
Natural killer cell mediated cytotoxicity
hsa04650

All organismsOrtholog table
Disease
H00090  
NK cell defects
H00344  
Leprosy
H01018  
Metachondromatosis
Drug
D00745  
Interferon alfa-2a (genetical recombination) (JAN)
D00746  
Interferon beta-1b (genetical recombination) (JAN)
D00747  
Interferon gamma-1b (USAN/INN)
D02597  
Adalimumab (genetical recombination) (JAN)
D02744  
Interferon alfacon-1 (genetical recombination) (JAN)
D02745  
Interferon alfa-2b (genetical recombination) (JAN)
D02747  
Peginterferon alfa-2a (genetical recombination) (JAN)
D02748  
Peginterferon alfa-2b (generical recombination) (JAN)
D02811  
Alicaforsen sodium (USAN)
D03304  
Interferon beta (JAN)
D03305  
Interferon alfa (NAMALWA) (JP17)
D03357  
Interferon gamma-1a (genetical recombination) (JAN)
D03441  
Certolizumab pegol (genetical recombination) (JAN)
D03959  
Efalizumab (USAN/INN)
D04000  
Enlimomab (USAN/INN)
D04552  
Interferon alfa-n1 (USAN)
D04554  
Interferon beta-1a (genetical recombination) (JAN)
D06272  
Sorafenib tosilate (JAN)
D06611  
Lexatumumab (USAN/INN)
D08524  
Sorafenib (USAN/INN)
D08805  
Interferon gamma-n1 (JAN)
D08844  
Albinterferon alfa-2b (USAN)
D10483  
Peginterferon beta-1a (USAN/INN)
D10618  
Defactinib (USAN/INN)
Other DBs
BSID: 
GO: 
Organism
Homo sapiens (human) [GN:hsa]
Gene
3105  
HLA-A; major histocompatibility complex, class I, A [KO:K06751]
3106  
HLA-B; major histocompatibility complex, class I, B [KO:K06751]
3107  
HLA-C; major histocompatibility complex, class I, C [KO:K06751]
3135  
HLA-G; major histocompatibility complex, class I, G [KO:K06751]
3133  
HLA-E; major histocompatibility complex, class I, E [KO:K06751]
3812  
KIR3DL2; killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 2 [KO:K07980]
3811  
KIR3DL1; killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 [KO:K07980]
3803  
KIR2DL2; killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 [KO:K07981]
3802  
KIR2DL1; killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 [KO:K07981]
3804  
KIR2DL3; killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 [KO:K07981]
3805  
KIR2DL4; killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 4 [KO:K07981]
57292  
KIR2DL5A; killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 5A [KO:K07981]
3821  
KLRC1; killer cell lectin like receptor C1 [KO:K06541]
3822  
KLRC2; killer cell lectin like receptor C2 [KO:K06541]
3823  
KLRC3; killer cell lectin like receptor C3 [KO:K06541]
3824  
KLRD1; killer cell lectin like receptor D1 [KO:K06516]
5777  
PTPN6; protein tyrosine phosphatase, non-receptor type 6 [KO:K05697] [EC:3.1.3.48]
5781  
PTPN11; protein tyrosine phosphatase, non-receptor type 11 [KO:K07293] [EC:3.1.3.48]
3383  
ICAM1; intercellular adhesion molecule 1 [KO:K06490]
3384  
ICAM2; intercellular adhesion molecule 2 [KO:K06523]
3683  
ITGAL; integrin subunit alpha L [KO:K05718]
3689  
ITGB2; integrin subunit beta 2 [KO:K06464]
2185  
PTK2B; protein tyrosine kinase 2 beta [KO:K05871] [EC:2.7.10.2]
10451  
VAV3; vav guanine nucleotide exchange factor 3 [KO:K05730]
7409  
VAV1; vav guanine nucleotide exchange factor 1 [KO:K05730]
7410  
VAV2; vav guanine nucleotide exchange factor 2 [KO:K05730]
5879  
RAC1; ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) [KO:K04392]
5880  
RAC2; ras-related C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2) [KO:K07860]
5881  
RAC3; ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) [KO:K07861]
5058  
PAK1; p21 protein (Cdc42/Rac)-activated kinase 1 [KO:K04409] [EC:2.7.11.1]
5604  
MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
5605  
MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
5594  
MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  
MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
7124  
TNF; tumor necrosis factor [KO:K03156]
1437  
CSF2; colony stimulating factor 2 [KO:K05427]
3458  
IFNG; interferon, gamma [KO:K04687]
3806  
KIR2DS1; killer cell immunoglobulin like receptor, two Ig domains and short cytoplasmic tail 1 [KO:K07982]
3808  
KIR2DS3; killer cell immunoglobulin like receptor, two Ig domains and short cytoplasmic tail 3 [KO:K07982]
3809  
KIR2DS4; killer cell immunoglobulin like receptor, two Ig domains and short cytoplasmic tail 4 [KO:K07982]
3810  
KIR2DS5; killer cell immunoglobulin like receptor, two Ig domains and short cytoplasmic tail 5 [KO:K07982]
KIR2DS2; killer cell immunoglobulin like receptor, two Ig domains and short cytoplasmic tail 2 [KO:K07982]
9436  
NCR2; natural cytotoxicity triggering receptor 2 [KO:K06742]
7305  
TYROBP; TYRO protein tyrosine kinase binding protein [KO:K07992]
3932  
LCK; LCK proto-oncogene, Src family tyrosine kinase [KO:K05856] [EC:2.7.10.2]
putative V-set and immunoglobulin domain-containing-like protein IGHV4OR15-8; K06856 immunoglobulin heavy chain [KO:K06856]
2214  
FCGR3A; Fc fragment of IgG receptor IIIa [KO:K06463]
2215  
FCGR3B; Fc fragment of IgG receptor IIIb [KO:K06463]
9437  
NCR1; natural cytotoxicity triggering receptor 1 [KO:K06741]
259197  
NCR3; natural cytotoxicity triggering receptor 3 [KO:K06743]
2207  
FCER1G; Fc fragment of IgE receptor Ig [KO:K07983]
919  
CD247; CD247 molecule [KO:K06453]
7535  
ZAP70; zeta chain of T cell receptor associated protein kinase 70kDa [KO:K07360] [EC:2.7.10.2]
6850  
SYK; spleen tyrosine kinase [KO:K05855] [EC:2.7.10.2]
3937  
LCP2; lymphocyte cytosolic protein 2 [KO:K07361]
27040  
LAT; linker for activation of T-cells [KO:K07362]
5335  
PLCG1; phospholipase C gamma 1 [KO:K01116] [EC:3.1.4.11]
5336  
PLCG2; phospholipase C gamma 2 [KO:K05859] [EC:3.1.4.11]
6452  
SH3BP2; SH3-domain binding protein 2 [KO:K07984]
5290  
PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
5293  
PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
5291  
PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
5294  
PIK3CG; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma [KO:K00922] [EC:2.7.1.153]
5295  
PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
23533  
PIK3R5; phosphoinositide-3-kinase regulatory subunit 5 [KO:K02649]
5296  
PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
8503  
PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
2534  
FYN; FYN proto-oncogene, Src family tyrosine kinase [KO:K05703] [EC:2.7.10.2]
6464  
SHC1; SHC (Src homology 2 domain containing) transforming protein 1 [KO:K06279]
25759  
SHC2; SHC (Src homology 2 domain containing) transforming protein 2 [KO:K17447]
53358  
SHC3; SHC (Src homology 2 domain containing) transforming protein 3 [KO:K17448]
399694  
SHC4; SHC (Src homology 2 domain containing) family member 4 [KO:K17449]
2885  
GRB2; growth factor receptor bound protein 2 [KO:K04364]
6654  
SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
6655  
SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
3265  
HRAS; Harvey rat sarcoma viral oncogene homolog [KO:K02833]
3845  
KRAS; Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
4893  
NRAS; neuroblastoma RAS viral (v-ras) oncogene homolog [KO:K07828]
369  
ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
673  
BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]
5894  
RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
4277  
MICB; MHC class I polypeptide-related sequence B [KO:K07985]
MICA; MHC class I polypeptide-related sequence A [KO:K07985]
80329  
ULBP1; UL16 binding protein 1 [KO:K07986]
80328  
ULBP2; UL16 binding protein 2 [KO:K07986]
79465  
ULBP3; UL16 binding protein 3 [KO:K07986]
353091  
RAET1G; retinoic acid early transcript 1G [KO:K07987]
154064  
RAET1L; retinoic acid early transcript 1L [KO:K07987]
135250  
RAET1E; retinoic acid early transcript 1E [KO:K07987]
22914  
KLRK1; killer cell lectin like receptor K1 [KO:K06728]
KLRC4-KLRK1; KLRC4-KLRK1 readthrough [KO:K06728]
10870  
HCST; hematopoietic cell signal transducer [KO:K07988]
962  
CD48; CD48 molecule [KO:K06479]
51744  
CD244; CD244 molecule [KO:K06582]
5530  
PPP3CA; protein phosphatase 3 catalytic subunit alpha [KO:K04348] [EC:3.1.3.16]
5532  
PPP3CB; protein phosphatase 3 catalytic subunit beta [KO:K04348] [EC:3.1.3.16]
5533  
PPP3CC; protein phosphatase 3 catalytic subunit gamma [KO:K04348] [EC:3.1.3.16]
5534  
PPP3R1; protein phosphatase 3 regulatory subunit B, alpha [KO:K06268]
5535  
PPP3R2; protein phosphatase 3 regulatory subunit B, beta [KO:K06268]
4772  
NFATC1; nuclear factor of activated T-cells 1 [KO:K04446]
4773  
NFATC2; nuclear factor of activated T-cells 2 [KO:K17332]
5578  
PRKCA; protein kinase C alpha [KO:K02677] [EC:2.7.11.13]
5579  
PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
5582  
PRKCG; protein kinase C gamma [KO:K19663] [EC:2.7.11.13]
117157  
SH2D1B; SH2 domain containing 1B [KO:K07989]
4068  
SH2D1A; SH2 domain containing 1A [KO:K07990]
3459  
IFNGR1; interferon gamma receptor 1 [KO:K05132]
3460  
IFNGR2; interferon gamma receptor 2 (interferon gamma transducer 1) [KO:K05133]
3439  
IFNA1; interferon, alpha 1 [KO:K05414]
3440  
IFNA2; interferon, alpha 2 [KO:K05414]
3441  
IFNA4; interferon, alpha 4 [KO:K05414]
3442  
IFNA5; interferon alpha 5 [KO:K05414]
3443  
IFNA6; interferon alpha 6 [KO:K05414]
3444  
IFNA7; interferon, alpha 7 [KO:K05414]
3445  
IFNA8; interferon alpha 8 [KO:K05414]
3446  
IFNA10; interferon, alpha 10 [KO:K05414]
3447  
IFNA13; interferon, alpha 13 [KO:K05414]
3448  
IFNA14; interferon alpha 14 [KO:K05414]
3449  
IFNA16; interferon, alpha 16 [KO:K05414]
3451  
IFNA17; interferon, alpha 17 [KO:K05414]
3452  
IFNA21; interferon, alpha 21 [KO:K05414]
3456  
IFNB1; interferon beta 1 [KO:K05415]
3454  
IFNAR1; interferon alpha and beta receptor subunit 1 [KO:K05130]
3455  
IFNAR2; interferon alpha and beta receptor subunit 2 [KO:K05131]
8743  
TNFSF10; tumor necrosis factor superfamily member 10 [KO:K04721]
8797  
TNFRSF10A; tumor necrosis factor receptor superfamily member 10a [KO:K04722]
8795  
TNFRSF10B; tumor necrosis factor receptor superfamily member 10b [KO:K04722]
8794  
TNFRSF10C; tumor necrosis factor receptor superfamily member 10c [KO:K04722]
8793  
TNFRSF10D; tumor necrosis factor receptor superfamily member 10d [KO:K04722]
356  
FASLG; Fas ligand [KO:K04389]
355  
FAS; Fas cell surface death receptor [KO:K04390]
3002  
GZMB; granzyme B [KO:K01353] [EC:3.4.21.79]
5551  
PRF1; perforin 1 [KO:K07818]
836  
CASP3; caspase 3 [KO:K02187] [EC:3.4.22.56]
637  
BID; BH3 interacting domain death agonist [KO:K04726]
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)
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)
Reference
  Authors
Vivier E, Nunes JA, Vely F.
  Title
Natural killer cell signaling pathways.
  Journal
Science 306:1517-9 (2004)
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)
Reference
  Authors
Perussia B.
  Title
Signaling for cytotoxicity.
  Journal
Nat Immunol 1:372-4 (2000)
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)
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)
Reference
  Authors
Colonna M.
  Title
Fine-tuning NK cell responses: it's a family affair.
  Journal
Nat Immunol 6:961-2 (2005)
Reference
PMID:8942070
  Authors
Bonnema JD, Leibson PJ.
  Title
Signal transduction during NK cell activation.
  Journal
Chem Immunol 64:28-43 (1996)
Reference
(Japanese)
  Authors
Satoh T, Arase H.
  Title
[Recognition of virus infected cells by NK cell receptor.] (In Japanese)
  Journal
Experimental Medicine 23(17):2685-2691 (2005)
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)
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)
Reference
  Authors
Wu J, Lanier LL.
  Title
Natural killer cells and cancer.
  Journal
Adv Cancer Res 90:127-56 (2003)
Reference
  Authors
Cerwenka A, Lanier LL.
  Title
Natural killer cells, viruses and cancer.
  Journal
Nat Rev Immunol 1:41-9 (2001)
Reference
  Authors
Blott EJ, Griffiths GM.
  Title
Secretory lysosomes.
  Journal
Nat Rev Mol Cell Biol 3:122-31 (2002)
Reference
  Authors
Lieberman J.
  Title
The ABCs of granule-mediated cytotoxicity: new weapons in the arsenal.
  Journal
Nat Rev Immunol 3:361-70 (2003)
Reference
  Authors
Lord SJ, Rajotte RV, Korbutt GS, Bleackley RC.
  Title
Granzyme B: a natural born killer.
  Journal
Immunol Rev 193:31-8 (2003)
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)
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)
KO pathway
 

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