KEGG   PATHWAY: hsa04650
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
Pathway map
hsa04650  Natural killer cell mediated cytotoxicity
hsa04650

Drug
D00107  Tacrolimus (USP/INN)
D00184  Cyclosporine (USP)
D00745  Interferon alfa-2a (USAN/INN)
D00746  Interferon beta-1b (USAN/INN)
D00747  Interferon gamma-1b (USAN/INN)
D02597  Adalimumab (USAN/INN)
D02744  Interferon alfacon-1 (USAN/INN)
D02745  Interferon alfa-2b (USAN)
D02747  Peginterferon alfa-2a (USAN/INN)
D02748  Peginterferon alfa-2b (USAN/INN)
D02811  Alicaforsen sodium (USAN)
D03304  Interferon beta (JAN)
D03305  Interferon alfa (NAMALWA) (JP19)
D03357  Interferon gamma-1a (genetical recombination) (JAN)
D03441  Certolizumab pegol (USAN/INN)
D03959  Efalizumab (USAN/INN)
D04000  Enlimomab (USAN/INN)
D04045  Erlizumab (USAN/INN)
D04552  Interferon alfa-n1 (USAN)
D04553  Interferon alfa-n3 (USAN)
D04554  Interferon beta-1a (USAN)
D04687  Lenalidomide (JAN/USAN/INN)
D05480  Pimecrolimus (JAN/USAN/INN)
D08556  Tacrolimus (INN)
D08805  Interferon gamma-n1 (JAN)
D08844  Albinterferon alfa-2b (USAN)
D08976  Pomalidomide (JAN/USAN/INN)
D09033  Voclosporin (JAN/USAN/INN)
D09813  Lenalidomide hydrate (JAN)
D10374  Lifitegrast (USAN/INN)
D10392  Lifitegrast sodium (USAN)
D10483  Peginterferon beta-1a (USAN/INN)
D10618  Defactinib (USAN/INN)
D10983  Ruclosporin (USAN/INN)
D10993  Tucidinostat (JAN/USAN/INN)
D11027  Ropeginterferon alfa-2b (INN)
D12179  Tesnatilimab (USAN/INN)
D12458  Ozekibart (USAN)
D12893  Zimistobart
D12913  Ingitamig (USAN)
D12953  Sovleplenib (USAN/INN)
D12954  Sovleplenib acetate (USAN)
D13057  Bexatamig (USAN/INN)
D13238  Monalizumab (USAN/INN)
D13269  Dibotatug (USAN/INN)
D13325  Xelafaslatide (USAN/INN)
Other DBs
GO: 0042267
Organism
Homo sapiens (human) [GN:hsa]
Gene
100132285  KIR2DS2; killer cell immunoglobulin-like receptor 2DS2 isoform a precursor [KO:K07982]
100507436  MICA; MHC class I polypeptide-related sequence A isoform 2 (MICA*00801) precursor [KO:K07985]
100528032  KLRC4-KLRK1; NKG2-D type II integral membrane protein [KO:K06728]
102723407  [KO:K06856]
10451  VAV3; guanine nucleotide exchange factor VAV3 isoform 1 [KO:K05730]
10870  HCST; hematopoietic cell signal transducer isoform 1 precursor [KO:K07988]
110117499  P3R3URF-PIK3R3; LOC110117498-PIK3R3 readthrough [KO:K02649]
117157  SH2D1B; SH2 domain-containing protein 1B [KO:K07989]
135250  RAET1E; retinoic acid early transcript 1E isoform 1 precursor [KO:K07987]
1437  CSF2; granulocyte-macrophage colony-stimulating factor precursor [KO:K05427]
154064  RAET1L; UL16-binding protein 6 precursor [KO:K07987]
2185  PTK2B; protein-tyrosine kinase 2-beta isoform a [KO:K05871] [EC:2.7.10.2]
2207  FCER1G; high affinity immunoglobulin epsilon receptor subunit gamma precursor [KO:K07983]
2214  FCGR3A; low affinity immunoglobulin gamma Fc region receptor III-A isoform c precursor [KO:K06463]
2215  FCGR3B; low affinity immunoglobulin gamma Fc region receptor III-B isoform 2 precursor [KO:K06463]
22914  KLRK1; NKG2-D type II integral membrane protein [KO:K06728]
2534  FYN; tyrosine-protein kinase Fyn isoform a [KO:K05703] [EC:2.7.10.2]
25759  SHC2; SHC-transforming protein 2 isoform 1 [KO:K17447]
259197  NCR3; natural cytotoxicity triggering receptor 3 isoform a precursor [KO:K06743]
27040  LAT; linker for activation of T-cells family member 1 isoform a [KO:K07362]
2885  GRB2; growth factor receptor-bound protein 2 isoform 1 [KO:K04364]
3002  GZMB; granzyme B isoform 1 preproprotein [KO:K01353] [EC:3.4.21.79]
3105  HLA-A; HLA class I histocompatibility antigen, A alpha chain isoform A*03:01:01:01 precursor [KO:K06751]
3106  HLA-B; major histocompatibility complex, class I, B precursor [KO:K06751]
3107  HLA-C; HLA class I histocompatibility antigen, C alpha chain precursor [KO:K06751]
3133  HLA-E; HLA class I histocompatibility antigen, alpha chain E precursor [KO:K06751]
3135  HLA-G; HLA class I histocompatibility antigen, alpha chain G isoform 2 precursor [KO:K06751]
3265  HRAS; GTPase HRas isoform 1 [KO:K02833]
3383  ICAM1; intercellular adhesion molecule 1 precursor [KO:K06490]
3384  ICAM2; intercellular adhesion molecule 2 precursor [KO:K06523]
3439  IFNA1; interferon alpha-1 precursor [KO:K05414]
3440  IFNA2; interferon alpha-2 precursor [KO:K05414]
3441  IFNA4; interferon alpha-4 precursor [KO:K05414]
3442  IFNA5; interferon alpha-5 precursor [KO:K05414]
3443  IFNA6; interferon alpha-6 precursor [KO:K05414]
3444  IFNA7; interferon alpha-7 precursor [KO:K05414]
3445  IFNA8; interferon alpha-8 precursor [KO:K05414]
3446  IFNA10; interferon alpha-10 precursor [KO:K05414]
3447  IFNA13; interferon alpha-13 precursor [KO:K05414]
3448  IFNA14; interferon alpha-14 precursor [KO:K05414]
3449  IFNA16; interferon alpha-16 precursor [KO:K05414]
3451  IFNA17; interferon alpha-17 precursor [KO:K05414]
3452  IFNA21; interferon alpha-21 precursor [KO:K05414]
3454  IFNAR1; interferon alpha/beta receptor 1 isoform 2 precursor [KO:K05130]
3455  IFNAR2; interferon alpha/beta receptor 2 isoform a precursor [KO:K05131]
3456  IFNB1; interferon beta precursor [KO:K05415]
3458  IFNG; interferon gamma precursor [KO:K04687]
3459  IFNGR1; interferon gamma receptor 1 isoform 1 precursor [KO:K05132]
3460  IFNGR2; interferon gamma receptor 2 isoform 2 precursor [KO:K05133]
353091  RAET1G; UL-16 binding protein 5 preproprotein [KO:K07987]
355  FAS; tumor necrosis factor receptor superfamily member 6 isoform 1 precursor [KO:K04390]
356  FASLG; tumor necrosis factor ligand superfamily member 6 isoform 1 [KO:K04389]
3683  ITGAL; integrin alpha-L isoform a precursor [KO:K05718]
3689  ITGB2; integrin beta-2 isoform 1 precursor [KO:K06464]
369  ARAF; serine/threonine-protein kinase A-Raf isoform 1 [KO:K08845] [EC:2.7.11.1]
3802  KIR2DL1; killer cell immunoglobulin-like receptor 2DL1 precursor [KO:K07981]
3803  KIR2DL2; killer cell immunoglobulin-like receptor 2DL2 precursor [KO:K07981]
3804  KIR2DL3; killer cell immunoglobulin-like receptor 2DL3 precursor [KO:K07981]
3805  KIR2DL4; killer cell immunoglobulin-like receptor 2DL4 isoform c precursor [KO:K24231]
3806  KIR2DS1; killer cell immunoglobulin-like receptor 2DS1 precursor [KO:K07982]
3808  KIR2DS3; killer cell immunoglobulin-like receptor 2DS3 precursor [KO:K07982]
3809  KIR2DS4; killer cell immunoglobulin-like receptor 2DS4 isoform 2 precursor [KO:K07982]
3810  KIR2DS5; killer cell immunoglobulin-like receptor 2DS5 precursor [KO:K07982]
3811  KIR3DL1; killer cell immunoglobulin-like receptor 3DL1 isoform 1 precursor [KO:K07980]
3812  KIR3DL2; killer cell immunoglobulin-like receptor 3DL2 isoform 1 precursor [KO:K07980]
3821  KLRC1; NKG2-A/NKG2-B type II integral membrane protein isoform NKG2-A [KO:K06541]
3822  KLRC2; NKG2-C type II integral membrane protein [KO:K24233]
3823  KLRC3; NKG2-E type II integral membrane protein isoform E [KO:K24233]
3824  KLRD1; natural killer cells antigen CD94 isoform 1 [KO:K06516]
3845  KRAS; GTPase KRas isoform a [KO:K07827]
3932  LCK; tyrosine-protein kinase Lck isoform a [KO:K05856] [EC:2.7.10.2]
3937  LCP2; lymphocyte cytosolic protein 2 [KO:K07361]
399694  SHC4; SHC-transforming protein 4 [KO:K17449]
4068  SH2D1A; SH2 domain-containing protein 1A isoform 1 [KO:K07990]
4277  MICB; MHC class I polypeptide-related sequence B isoform 1 precursor [KO:K07985]
4772  NFATC1; nuclear factor of activated T-cells, cytoplasmic 1 isoform F [KO:K04446]
4773  NFATC2; nuclear factor of activated T-cells, cytoplasmic 2 isoform C [KO:K17332]
4893  NRAS; GTPase NRas [KO:K07828]
5058  PAK1; serine/threonine-protein kinase PAK 1 isoform 2 [KO:K04409] [EC:2.7.11.1]
51744  CD244; natural killer cell receptor 2B4 isoform 2 precursor [KO:K06582]
5290  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
5291  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform 1 [KO:K00922] [EC:2.7.1.153]
5293  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform 1 [KO:K00922] [EC:2.7.1.153]
5295  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform 1 [KO:K02649]
5296  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
5335  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform b [KO:K01116] [EC:3.1.4.11]
53358  SHC3; SHC-transforming protein 3 [KO:K17448]
5336  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
5530  PPP3CA; protein phosphatase 3 catalytic subunit alpha isoform 1 [KO:K04348] [EC:3.1.3.16]
5532  PPP3CB; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform isoform b [KO:K04348] [EC:3.1.3.16]
5533  PPP3CC; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform isoform 2 [KO:K04348] [EC:3.1.3.16]
5534  PPP3R1; calcineurin subunit B type 1 [KO:K06268]
5535  PPP3R2; calcineurin subunit B type 2 [KO:K06268]
5551  PRF1; perforin-1 precursor [KO:K07818]
5578  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
5579  PRKCB; protein kinase C beta type isoform 1 [KO:K19662] [EC:2.7.11.13]
5582  PRKCG; protein kinase C gamma type isoform 2 [KO:K19663] [EC:2.7.11.13]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  MAPK3; mitogen-activated protein kinase 3 isoform 1 [KO:K04371] [EC:2.7.11.24]
5604  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform 1 [KO:K04368] [EC:2.7.12.2]
5605  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform 1 [KO:K04369] [EC:2.7.12.2]
57292  KIR2DL5A; killer cell immunoglobulin-like receptor 2DL5A precursor [KO:K24232]
5777  PTPN6; tyrosine-protein phosphatase non-receptor type 6 isoform 1 [KO:K05697] [EC:3.1.3.48]
5781  PTPN11; tyrosine-protein phosphatase non-receptor type 11 isoform 1 [KO:K07293] [EC:3.1.3.48]
5879  RAC1; ras-related C3 botulinum toxin substrate 1 isoform Rac1 [KO:K04392]
5880  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
5881  RAC3; ras-related C3 botulinum toxin substrate 3 isoform 1 [KO:K07861]
5894  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform b [KO:K04366] [EC:2.7.11.1]
637  BID; BH3-interacting domain death agonist isoform 2 [KO:K04726]
6452  SH3BP2; SH3 domain-binding protein 2 isoform a [KO:K07984]
6464  SHC1; SHC-transforming protein 1 isoform 1 [KO:K06279]
6654  SOS1; son of sevenless homolog 1 isoform 1 [KO:K03099]
6655  SOS2; son of sevenless homolog 2 isoform 1 [KO:K03099]
673  BRAF; serine/threonine-protein kinase B-raf isoform 1 [KO:K04365] [EC:2.7.11.1]
6850  SYK; tyrosine-protein kinase SYK isoform Syk(L) [KO:K05855] [EC:2.7.10.2]
7124  TNF; tumor necrosis factor [KO:K03156]
7305  TYROBP; TYRO protein tyrosine kinase-binding protein isoform 1 precursor [KO:K07992]
7409  VAV1; proto-oncogene vav isoform 1 [KO:K05730]
7410  VAV2; guanine nucleotide exchange factor VAV2 isoform 1 [KO:K05730]
7462  LAT2; linker for activation of T-cells family member 2 [KO:K26356]
7535  ZAP70; tyrosine-protein kinase ZAP-70 isoform 1 [KO:K07360] [EC:2.7.10.2]
79465  ULBP3; UL16-binding protein 3 precursor [KO:K07986]
80328  ULBP2; UL16-binding protein 2 preproprotein [KO:K07986]
80329  ULBP1; UL16-binding protein 1 isoform 1 precursor [KO:K07986]
836  CASP3; caspase-3 isoform a preproprotein [KO:K02187] [EC:3.4.22.56]
8503  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform 1 [KO:K02649]
8743  TNFSF10; tumor necrosis factor ligand superfamily member 10 isoform 1 [KO:K04721]
8795  TNFRSF10B; tumor necrosis factor receptor superfamily member 10B isoform 1 precursor [KO:K04722]
8797  TNFRSF10A; tumor necrosis factor receptor superfamily member 10A [KO:K04722]
919  CD247; T-cell surface glycoprotein CD3 zeta chain isoform 1 precursor [KO:K06453]
9436  NCR2; natural cytotoxicity triggering receptor 2 isoform 1 precursor [KO:K06742]
9437  NCR1; natural cytotoxicity triggering receptor 1 isoform a precursor [KO:K06741]
962  CD48; CD48 antigen isoform 1 precursor [KO:K06479]
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
hsa04010  MAPK signaling pathway
hsa04020  Calcium signaling pathway
hsa04060  Cytokine-cytokine receptor interaction
hsa04210  Apoptosis
hsa04630  JAK-STAT signaling pathway
KO pathway
ko04650   

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