KEGG   PATHWAY: mmu04650
mmu04650                    Pathway                                

Natural killer cell mediated cytotoxicity - Mus musculus (mouse)
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.
Organismal Systems; Immune system
Pathway map
mmu04650  Natural killer cell mediated cytotoxicity

Other DBs
GO: 0042267
Mus musculus (mouse) [GN:mmu]
15040  H2-T23; histocompatibility 2, T region locus 23 [KO:K06751]
14964  H2-D1; histocompatibility 2, D region locus 1 [KO:K06751]
14972  H2-K1; histocompatibility 2, K1, K region [KO:K06751]
245616  Kir3dl1; killer cell immunoglobulin-like receptor, three domains, long cytoplasmic tail, 1 [KO:K07980]
245615  Kir3dl2; killer cell immunoglobulin-like receptor, three domains, long cytoplasmic tail, 2 [KO:K07980]
16641  Klrc1; killer cell lectin-like receptor subfamily C, member 1 [KO:K06541]
16643  Klrd1; killer cell lectin-like receptor, subfamily D, member 1 [KO:K06516]
15170  Ptpn6; protein tyrosine phosphatase, non-receptor type 6 [KO:K05697] [EC:]
19247  Ptpn11; protein tyrosine phosphatase, non-receptor type 11 [KO:K07293] [EC:]
15894  Icam1; intercellular adhesion molecule 1 [KO:K06490]
15896  Icam2; intercellular adhesion molecule 2 [KO:K06523]
16408  Itgal; integrin alpha L [KO:K05718]
16414  Itgb2; integrin beta 2 [KO:K06464]
16415  Itgb2l; integrin beta 2-like [KO:K06464]
19229  Ptk2b; PTK2 protein tyrosine kinase 2 beta [KO:K05871] [EC:]
22324  Vav1; vav 1 oncogene [KO:K05730]
22325  Vav2; vav 2 oncogene [KO:K05730]
57257  Vav3; vav 3 oncogene [KO:K05730]
19353  Rac1; Rac family small GTPase 1 [KO:K04392]
19354  Rac2; Rac family small GTPase 2 [KO:K07860]
170758  Rac3; Rac family small GTPase 3 [KO:K07861]
18479  Pak1; p21 (RAC1) activated kinase 1 [KO:K04409] [EC:]
26395  Map2k1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
26396  Map2k2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:]
26413  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
26417  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
21926  Tnf; tumor necrosis factor [KO:K03156]
12981  Csf2; colony stimulating factor 2 (granulocyte-macrophage) [KO:K05427]
15978  Ifng; interferon gamma [KO:K04687]
22177  Tyrobp; TYRO protein tyrosine kinase binding protein [KO:K07992]
16818  Lck; lymphocyte protein tyrosine kinase [KO:K05856] [EC:]
246256  Fcgr4; Fc receptor, IgG, low affinity IV [KO:K06463]
17086  Ncr1; natural cytotoxicity triggering receptor 1 [KO:K06741]
14127  Fcer1g; Fc receptor, IgE, high affinity I, gamma polypeptide [KO:K07983]
12503  Cd247; CD247 antigen [KO:K06453]
22637  Zap70; zeta-chain (TCR) associated protein kinase [KO:K07360] [EC:]
20963  Syk; spleen tyrosine kinase [KO:K05855] [EC:]
16822  Lcp2; lymphocyte cytosolic protein 2 [KO:K07361]
16797  Lat; linker for activation of T cells [KO:K07362]
18803  Plcg1; phospholipase C, gamma 1 [KO:K01116] [EC:]
234779  Plcg2; phospholipase C, gamma 2 [KO:K05859] [EC:]
24055  Sh3bp2; SH3-domain binding protein 2 [KO:K07984]
18706  Pik3ca; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:]
18707  Pik3cd; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:]
74769  Pik3cb; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:]
18709  Pik3r2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
18708  Pik3r1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
18710  Pik3r3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
14360  Fyn; Fyn proto-oncogene [KO:K05703] [EC:]
20416  Shc1; src homology 2 domain-containing transforming protein C1 [KO:K06279]
216148  Shc2; SHC (Src homology 2 domain containing) transforming protein 2 [KO:K17447]
20418  Shc3; src homology 2 domain-containing transforming protein C3 [KO:K17448]
271849  Shc4; SHC (Src homology 2 domain containing) family, member 4 [KO:K17449]
14784  Grb2; growth factor receptor bound protein 2 [KO:K04364]
20662  Sos1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
20663  Sos2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
15461  Hras; Harvey rat sarcoma virus oncogene [KO:K02833]
16653  Kras; Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
18176  Nras; neuroblastoma ras oncogene [KO:K07828]
11836  Araf; Araf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:]
109880  Braf; Braf transforming gene [KO:K04365] [EC:]
110157  Raf1; v-raf-leukemia viral oncogene 1 [KO:K04366] [EC:]
77777  Ulbp1; UL16 binding protein 1 [KO:K07986]
27007  Klrk1; killer cell lectin-like receptor subfamily K, member 1 [KO:K06728]
23900  Hcst; hematopoietic cell signal transducer [KO:K07988]
12506  Cd48; CD48 antigen [KO:K06479]
18106  Cd244a; CD244 molecule A [KO:K06582]
19057  Ppp3cc; protein phosphatase 3, catalytic subunit, gamma isoform [KO:K04348] [EC:]
19055  Ppp3ca; protein phosphatase 3, catalytic subunit, alpha isoform [KO:K04348] [EC:]
19056  Ppp3cb; protein phosphatase 3, catalytic subunit, beta isoform [KO:K04348] [EC:]
19058  Ppp3r1; protein phosphatase 3, regulatory subunit B, alpha isoform (calcineurin B, type I) [KO:K06268]
19059  Ppp3r2; protein phosphatase 3, regulatory subunit B, alpha isoform (calcineurin B, type II) [KO:K06268]
18018  Nfatc1; nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 1 [KO:K04446]
18019  Nfatc2; nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 2 [KO:K17332]
18750  Prkca; protein kinase C, alpha [KO:K02677] [EC:]
18751  Prkcb; protein kinase C, beta [KO:K19662] [EC:]
18752  Prkcg; protein kinase C, gamma [KO:K19663] [EC:]
26904  Sh2d1b1; SH2 domain containing 1B1 [KO:K07989]
545378  Sh2d1b2; SH2 domain containing 1B2 [KO:K07989]
20400  Sh2d1a; SH2 domain containing 1A [KO:K07990]
15979  Ifngr1; interferon gamma receptor 1 [KO:K05132]
15980  Ifngr2; interferon gamma receptor 2 [KO:K05133]
15962  Ifna1; interferon alpha 1 [KO:K05414]
15965  Ifna2; interferon alpha 2 [KO:K05414]
15967  Ifna4; interferon alpha 4 [KO:K05414]
15968  Ifna5; interferon alpha 5 [KO:K05414]
15969  Ifna6; interferon alpha 6 [KO:K05414]
15970  Ifna7; interferon alpha 7 [KO:K05414]
15972  Ifna9; interferon alpha 9 [KO:K05414]
15964  Ifna11; interferon alpha 11 [KO:K05414]
242519  Ifna12; interferon alpha 12 [KO:K05414]
230396  Ifna13; interferon alpha 13 [KO:K05414]
404549  Ifna14; interferon alpha 14 [KO:K05414]
15974  Ifnab; interferon alpha B [KO:K05414]
242517  Ifna15; interferon alpha 15 [KO:K05414]
230398  Ifna16; interferon alpha 16 [KO:K05414]
15977  Ifnb1; interferon beta 1, fibroblast [KO:K05415]
15975  Ifnar1; interferon (alpha and beta) receptor 1 [KO:K05130]
15976  Ifnar2; interferon (alpha and beta) receptor 2 [KO:K05131]
22035  Tnfsf10; tumor necrosis factor (ligand) superfamily, member 10 [KO:K04721]
21933  Tnfrsf10b; tumor necrosis factor receptor superfamily, member 10b [KO:K04722]
14103  Fasl; Fas ligand (TNF superfamily, member 6) [KO:K04389]
14102  Fas; Fas (TNF receptor superfamily member 6) [KO:K04390]
14939  Gzmb; granzyme B [KO:K01353] [EC:]
18646  Prf1; perforin 1 (pore forming protein) [KO:K07818]
12367  Casp3; caspase 3 [KO:K02187] [EC:]
12122  Bid; BH3 interacting domain death agonist [KO:K04726]
16627  Klra1; killer cell lectin-like receptor, subfamily A, member 1 [KO:K24207]
16634  Klra3; killer cell lectin-like receptor, subfamily A, member 3 [KO:K24208]
16638  Klra7; killer cell lectin-like receptor, subfamily A, member 7 [KO:K24238]
16640  Klra9; killer cell lectin-like receptor subfamily A, member 9 [KO:K24240]
16635  Klra4; killer cell lectin-like receptor, subfamily A, member 4 [KO:K23459]
16639  Klra8; killer cell lectin-like receptor, subfamily A, member 8 [KO:K24239]
19368  Raet1a; retinoic acid early transcript 1, alpha [KO:K07987]
19369  Raet1b; retinoic acid early transcript beta [KO:K07987]
19370  Raet1c; retinoic acid early transcript gamma [KO:K07987]
56554  Raet1d; retinoic acid early transcript delta [KO:K07987]
379043  Raet1e; retinoic acid early transcript 1E [KO:K07987]
15101  H60a; histocompatibility 60a
16642  Klrc2; killer cell lectin-like receptor subfamily C, member 2
17059  Klrb1c; killer cell lectin-like receptor subfamily B member 1C [KO:K06543]
C00076  Calcium cation
C00165  Diacylglycerol
C01245  D-myo-Inositol 1,4,5-trisphosphate
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Chiesa S, Tomasello E, Vivier E, Vely F.
Coordination of activating and inhibitory signals in natural killer cells.
Mol Immunol 42:477-84 (2005)
Maghazachi AA.
Insights into seven and single transmembrane-spanning domain receptors and their signaling pathways in human natural killer cells.
Pharmacol Rev 57:339-57 (2005)
Vivier E, Nunes JA, Vely F.
Natural killer cell signaling pathways.
Science 306:1517-9 (2004)
Colucci F, Di Santo JP, Leibson PJ.
Natural killer cell activation in mice and men: different triggers for similar weapons?
Nat Immunol 3:807-13 (2002)
Perussia B.
Signaling for cytotoxicity.
Nat Immunol 1:372-4 (2000)
Smyth MJ, Cretney E, Kelly JM, Westwood JA, Street SE, Yagita H, Takeda K, van Dommelen SL, Degli-Esposti MA, Hayakawa Y.
Activation of NK cell cytotoxicity.
Mol Immunol 42:501-10 (2005)
Djeu JY, Jiang K, Wei S.
A view to a kill: signals triggering cytotoxicity.
Clin Cancer Res 8:636-40 (2002)
Smyth MJ, Takeda K, Hayakawa Y, Peschon JJ, van den Brink MR, Yagita H.
Nature's TRAIL--on a path to cancer immunotherapy.
Immunity 18:1-6 (2003)
Colonna M.
Fine-tuning NK cell responses: it's a family affair.
Nat Immunol 6:961-2 (2005)
Bonnema JD, Leibson PJ.
Signal transduction during NK cell activation.
Chem Immunol 64:28-43 (1996)
Tassi I, Presti R, Kim S, Yokoyama WM, Gilfillan S, Colonna M.
Phospholipase C-gamma 2 is a critical signaling mediator for murine NK cell activating receptors.
J Immunol 175:749-54 (2005)
Rao A, Luo C, Hogan PG.
Transcription factors of the NFAT family: regulation and function.
Annu Rev Immunol 15:707-47 (1997)
Wu J, Lanier LL.
Natural killer cells and cancer.
Adv Cancer Res 90:127-56 (2003)
Cerwenka A, Lanier LL.
Natural killer cells, viruses and cancer.
Nat Rev Immunol 1:41-9 (2001)
Blott EJ, Griffiths GM.
Secretory lysosomes.
Nat Rev Mol Cell Biol 3:122-31 (2002)
Lieberman J.
The ABCs of granule-mediated cytotoxicity: new weapons in the arsenal.
Nat Rev Immunol 3:361-70 (2003)
Lord SJ, Rajotte RV, Korbutt GS, Bleackley RC.
Granzyme B: a natural born killer.
Immunol Rev 193:31-8 (2003)
Liu D, Xu L, Yang F, Li D, Gong F, Xu T.
Rapid biogenesis and sensitization of secretory lysosomes in NK cells mediated by target-cell recognition.
Proc Natl Acad Sci U S A 102:123-7 (2005)
Trotta R, Puorro KA, Paroli M, Azzoni L, Abebe B, Eisenlohr LC, Perussia B.
Dependence of both spontaneous and antibody-dependent, granule exocytosis-mediated NK cell cytotoxicity on extracellular signal-regulated kinases.
J Immunol 161:6648-56 (1998)
Jevremovic D, Billadeau DD, Schoon RA, Dick CJ, Leibson PJ.
Regulation of NK cell-mediated cytotoxicity by the adaptor protein 3BP2.
J Immunol 166:7219-28 (2001)
mmu04010  MAPK signaling pathway
mmu04020  Calcium signaling pathway
mmu04060  Cytokine-cytokine receptor interaction
mmu04210  Apoptosis
mmu04630  JAK-STAT signaling pathway
KO pathway

DBGET integrated database retrieval system