KEGG   PATHWAY: rno04650
Entry
rno04650                    Pathway                                
Name
Natural killer cell mediated cytotoxicity - Rattus norvegicus (rat)
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
rno04650  Natural killer cell mediated cytotoxicity
rno04650

Other DBs
GO: 0042267
Organism
Rattus norvegicus (rat) [GN:rno]
Gene
353253  Kir3dl1; killer cell immunoglobulin-like receptor 3DL1 precursor [KO:K07980]
29683  Klrc1; killer cell lectin-like receptor subfamily C, member 1 [KO:K06541]
25110  Klrd1; natural killer cells antigen CD94 [KO:K06516]
116689  Ptpn6; tyrosine-protein phosphatase non-receptor type 6 [KO:K05697] [EC:3.1.3.48]
25622  Ptpn11; tyrosine-protein phosphatase non-receptor type 11 isoform 2 [KO:K07293] [EC:3.1.3.48]
25464  Icam1; intercellular adhesion molecule 1 precursor [KO:K06490]
360647  Icam2; intercellular adhesion molecule 2 precursor [KO:K06523]
308995  Itgal; integrin alpha-L precursor [KO:K05718]
309684  Itgb2; integrin beta-2 precursor [KO:K06464]
50646  Ptk2b; protein-tyrosine kinase 2-beta [KO:K05871] [EC:2.7.10.2]
25156  Vav1; proto-oncogene vav [KO:K05730]
295378  Vav3; guanine nucleotide exchange factor VAV3 [KO:K05730]
296603  Vav2; guanine nucleotide exchange factor VAV2 [KO:K05730]
363875  Rac1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
366957  Rac2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
688319  Rac3; ras-related C3 botulinum toxin substrate 3 [KO:K07861]
29431  Pak1; serine/threonine-protein kinase PAK 1 [KO:K04409] [EC:2.7.11.1]
170851  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
58960  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
116590  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
50689  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
24835  Tnf; tumor necrosis factor [KO:K03156]
116630  Csf2; granulocyte-macrophage colony-stimulating factor precursor [KO:K05427]
25712  Ifng; interferon gamma precursor [KO:K04687]
361537  Tyrobp; TYRO protein tyrosine kinase-binding protein precursor [KO:K07992]
313050  Lck; proto-oncogene tyrosine-protein kinase LCK [KO:K05856] [EC:2.7.10.2]
116591  Fcgr2a; low affinity immunoglobulin gamma Fc region receptor III isoform 1 [KO:K06463]
304966  Fcgr3a; low affinity immunoglobulin gamma Fc region receptor III-A precursor [KO:K06463]
117547  Ncr1; natural cytotoxicity triggering receptor 1 precursor [KO:K06741]
294251  Ncr3; natural cytotoxicity triggering receptor 3 precursor [KO:K06743]
25441  Fcer1g; high affinity immunoglobulin epsilon receptor subunit gamma precursor [KO:K07983]
25300  Cd247; T-cell surface glycoprotein CD3 zeta chain isoform 2 precursor [KO:K06453]
301348  Zap70; tyrosine-protein kinase ZAP-70 [KO:K07360] [EC:2.7.10.2]
25155  Syk; tyrosine-protein kinase SYK [KO:K05855] [EC:2.7.10.2]
155918  Lcp2; lymphocyte cytosolic protein 2 [KO:K07361]
81511  Lat; linker for activation of T-cells family member 1 [KO:K07362]
317676  Lat2; linker for activation of T-cells family member 2 precursor [KO:K26356]
25738  Plcg1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 [KO:K01116] [EC:3.1.4.11]
29337  Plcg2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
305450  Sh3bp2; SH3 domain-binding protein 2 isoform 1 [KO:K07984]
85243  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
170911  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
366508  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
134484121  LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform-like [KO:K00922] [EC:2.7.1.153]
25513  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
60664  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
29741  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
25150  Fyn; tyrosine-protein kinase Fyn [KO:K05703] [EC:2.7.10.2]
85385  Shc1; SHC-transforming protein 1 isoform b [KO:K06279]
314612  Shc2; SHC-transforming protein 2 [KO:K17447]
114858  Shc3; SHC-transforming protein 3 [KO:K17448]
679845  Shc4; SHC-transforming protein 4 [KO:K17449]
81504  Grb2; growth factor receptor-bound protein 2 [KO:K04364]
85384  Sos2; son of sevenless homolog 2 [KO:K03099]
313845  Sos1; son of sevenless homolog 1 [KO:K03099]
293621  Hras; GTPase HRas [KO:K02833]
367858  Hrasl1; HRas proto-oncogene, GTPase like 1 [KO:K02833]
24525  Kras; GTPase KRas [KO:K07827]
24605  Nras; GTPase NRas [KO:K07828]
64363  Araf; serine/threonine-protein kinase A-Raf isoform 1 [KO:K08845] [EC:2.7.11.1]
114486  Braf; serine/threonine-protein kinase B-raf isoform X2 [KO:K04365] [EC:2.7.11.1]
24703  Raf1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
24934  Klrk1; NKG2-D type II integral membrane protein [KO:K06728]
474146  Hcst; hematopoietic cell signal transducer precursor [KO:K07988]
245962  Cd48; CD48 antigen precursor [KO:K06479]
64025  Cd244l1; natural killer cell receptor 2B4 precursor [KO:K06582]
24674  Ppp3ca; protein phosphatase 3 catalytic subunit alpha [KO:K04348] [EC:3.1.3.16]
24675  Ppp3cb; serine/threonine-protein phosphatase 2B catalytic subunit beta isoform [KO:K04348] [EC:3.1.3.16]
171378  Ppp3cc; serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform [KO:K04348] [EC:3.1.3.16]
29748  Ppp3r1; calcineurin subunit B type 1 [KO:K06268]
29749  Ppp3r2; calcineurin subunit B type 2 [KO:K06268]
100361818  Nfatc1; nuclear factor of activated T-cells, cytoplasmic 1 isoform 1 [KO:K04446]
311658  Nfatc2; nuclear factor of activated T-cells, cytoplasmic 2 [KO:K17332]
24680  Prkca; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
25023  Prkcb; protein kinase C beta type isoform 2 [KO:K19662] [EC:2.7.11.13]
24681  Prkcg; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
501869  Sh2d1b; SH2 domain-containing protein 1B [KO:K07989]
102556681  Sh2d1b2; SH2 domain containing 1B2 [KO:K07989]
501502  Sh2d1a; SH2 domain-containing protein 1A [KO:K07990]
116465  Ifngr1; interferon gamma receptor 1 precursor [KO:K05132]
360697  Ifngr2; interferon gamma receptor 2 precursor [KO:K05133]
298205  Ifna4; interferon, alpha 4 precursor [KO:K05414]
298213  Ifna2; interferon alpha family, gene 2 precursor [KO:K05414]
298210  Ifna5; interferon alpha-1 precursor [KO:K05414]
690894  Ifna1; interferon alpha family, gene 5 precursor [KO:K05414]
100912314  interferon alpha-1-like [KO:K05414]
502961  Ifna4l2; similar to Interferon alpha-1 precursor [KO:K05414]
500491  Ifna16l1; interferon, alpha 16-like 1 precursor [KO:K05414]
134487075  interferon alpha-1-like [KO:K05414]
134487077  interferon alpha-1-like [KO:K05414]
100911527  Ifna4l1; interferon alpha-11-like [KO:K05414]
100912356  interferon alpha-1-like precursor [KO:K05414]
502959  Ifna1l1; similar to put. precursor MuIFN-alpha 5 precursor [KO:K05414]
24481  Ifnb1; interferon beta precursor [KO:K05415]
288264  Ifnar1; interferon alpha/beta receptor 1 isoform 1 precursor [KO:K05130]
686326  Ifnar2; interferon alpha and beta receptor subunit 2 isoform 1 precursor [KO:K05131]
246775  Tnfsf10; tumor necrosis factor ligand superfamily member 10 [KO:K04721]
25385  Faslg; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
246097  Fas; tumor necrosis factor receptor superfamily member 6 precursor [KO:K04390]
171528  Gzmb; granzyme B precursor [KO:K01353] [EC:3.4.21.79]
50669  Prf1; perforin-1 precursor [KO:K07818]
25402  Casp3; caspase-3 [KO:K02187] [EC:3.4.22.56]
64625  Bid; BH3-interacting domain death agonist [KO:K04726]
292461  Raet1l; retinoic acid early transcript 1L precursor [KO:K07987]
292450  Raet1e; retinoic acid early-inducible protein 1-beta [KO:K07987]
292458  Raet1c; retinoic acid early-inducible protein 1-gamma [KO:K07987]
502217  Raet1d; retinoic acid early-inducible protein 1-gamma-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
rno04010  MAPK signaling pathway
rno04020  Calcium signaling pathway
rno04060  Cytokine-cytokine receptor interaction
rno04210  Apoptosis
rno04630  JAK-STAT signaling pathway
KO pathway
ko04650   
LinkDB

DBGET integrated database retrieval system