Pathway Map Details
Immune response_Role of DAP12 receptors in NK cells
Object list (links open in MetaCore):
PLC-gamma 2, Actin cytoskeletal, SHP-2, WASP, KLRC3, LAT, MEK2(MAP2K2), PKC-theta, PAK1, KIR3DL1, 22.214.171.124, NKG2A, KIR2DL5, CD94, Arp2/3, KIR2DL1, NKG2C, PLC-gamma 1, KIR2DS2, SOS, ZAP70, IP3, Fyn, KIR2DL4, c-Raf-1, PI3K reg class IA, DAP12, PtdIns(4,5)P2, HLA-E, PtdIns(3,4,5)P3, NKp44, Lck, VAV-3, HLA-G, DAG, Shc, Erk (MAPK1/3), SHP-1, 126.96.36.199, WaspIP, Syk, Rac1, KIR2DS1, GRB2, HLA-C, MEK1(MAP2K1), CrkL, H-Ras, KIR2DL3, VAV-2, KLRA1, PI3K cat class IA, KIR2DL2, HLA-B
Role of DAP12 receptors in NK cells
Natural killer (NK) cells is an important component of large granular lymphocyte population. NK cells mediate cytolytic activity against virally infected cells and malignant cells. .
The map shows signaling pathways from the activated receptors in NK cells via TYRO protein tyrosine kinase binding protein ( DAP12 )  and inhibitory receptors. The receptors include Natural cytotoxicity triggering receptor 2 ( NKp44 ), Killer cell lectin-like receptor subfamily A, member 1 ( KLRA1 ), Killer cell immunoglobulin-like receptor, two domains, short cytoplasmic tail, 1 and 2 ( KIR2DS1, KIR2DS2 ), Killer cell lectin-like receptor subfamily C, member 3 ( KLRC3 ) and Killer cell lectin-like receptor subfamily C, member 2 ( NKG2C ).
No natural ligands are known for KLRA1, KLRC3, KIR2DS1 and KIR2DS2 , . NKG2C, a member of NKG2 receptor family recognizes non-conventional MHC class IB ligands: major histocompatibility complex, class I, E ( HLA-E ) . Upon ligand-receptor recognition, DAP12 is phosphorylated by Lymphocyte-specific protein tyrosine kinase ( Lck ) and FYN oncogene related to SRC, FGR and YES ( Fyn ) . Theses phosphorylation events result in recruitment of SYK family kinases such as Spleen tyrosine kinase ( Syk ) and Zeta-chain associated protein kinase 70kDa ( ZAP70 ) , , .
Signal transduction proceeds from ZAP70 via Linker for activation of T cells ( LAT ) to the reorganization of cytoskeletal proteins. LAT activates Phospholipase C, gamma 1 and 2 ( PLC-gamma 2 and PLC-gamma 1) , , which catalyze Diacylglycerol ( DAG ) synthesis. DAG activates Protein kinase C, theta ( PKC-theta ) , . PKC-theta phosphorylates Wiskott-Aldrich syndrome protein interacting protein ( WaspIP ). Separation of WaspIP from Wiskott-Aldrich syndrome (eczema-thrombocytopenia) ( WASP ) and activation of WASP results in rearrangement of Actin cytoskeletal through Apr2/3 complex. Actin cytoskeletal rearrangement is probably required for cytolysis of target cells . V-crk sarcoma virus CT10 oncogene homolog (avian)-like ( CrkL ) participates in recruitment of WaspIP/ WASP to Actin cytoskeletal , .
DAP12 probably activates SHC (Src homology 2 domain containing) transforming protein 1 ( Shc ) via ZAP70. Shc binds and stimulates Growth factor receptor-bound protein 2 ( GRB2 ). In turn, GRB2 activates another guanine nucleotide exchange factors Son of sevenless homolog ( SOS ), which transmit signal via v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras)/ v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/ MEK s/ ERK s cascade .
Syk interacts with Phosphoinositide 3-kinase ( PI3K )  and Syk/ PI3K cascade activates Vav 2 and 3 guanine nucleotide exchange factors ( VAV2 and VAV3) . VAVs participate in activation of mitogen-activated protein kinases 3 and 1 ( ERK1 and ERK2, accordingly) via Ras-related C3 botulinum toxin substrate 1 ( RAC1 )/ p21/Cdc42/Rac1-activated kinase 1 ( PAK1)/ Mitogen-activated protein kinase kinase 1 ( MEK1(MAP2K1) ) pathway , , . ERK1/2 activation results in mobilization of lytic granules with perforin and granzyme B.
DAP12 -activating receptors action in NK cells is repressed by inhibitory receptors whch include cell immunoglobulin-like receptor, three domains, long cytoplasmic tail, 2 ( KIR3DL2 ) and 1 ( KIR3DL1 ) correspondingly; Killer cell lectin-like receptor subfamily C, member 1 ( NKG2A ); Killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail 1-5 ( KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR2DL5) , , 
Most inhibitory receptors belong to the killer immunoglobulin (Ig)-like receptor (KIR) superfamily which recognizes classical MHC class I molecules major histocompatibility complex, class I B ( HLA-B ) and C ( HLA-C ), E ( HLA-E ) , G ( HLA-G ). KIR3DL1 is activated by HLA-B; NKG2A - by HLA-E; KIR2DL1, KIR2DL2; KIR2DL3 - by HLA-C; KIR2DL4 - by HLA-G. The ligand for KIR2DL5 is not known , , .
Inhibitory receptors block signals from the activating receptors by attraction of phosphatase and following dephosphorylation of signaling proteins downstream of activating receptors. Tow phosphatases: Tyrosine phosphatase protein tyrosine phosphatase, non-receptor type 6 ( SHP-1 ) and 11 ( SHP-2 ) bind to inhibitory receptors upon ligand recognition, , , . Some receptors recruits only one of two phosphatases, for example, KIR2DL4 requires SHP-2 . The others receptors bind both phosphatases, for example, KIR2DL2 .
Dephosphorylation by SHP-1 blocks association of the adaptor protein LAT 1 with PLC-gamma 1 and PLC-gamma 2 . In addition, SHP-1 may inhibit Syk . Both SHP-1 and SHP-1 inhibit Lck , , .
- Farag SS, Caligiuri MA
Human natural killer cell development and biology. Blood reviews 2006 May;20(3):123-37
- Tomasello E, Vivier E
KARAP/DAP12/TYROBP: three names and a multiplicity of biological functions. European journal of immunology 2005 Jun;35(6):1670-7
- Colucci F, Di Santo JP, Leibson PJ
Natural killer cell activation in mice and men: different triggers for similar weapons? Nature immunology 2002 Sep;3(9):807-13
- Parham P
MHC class I molecules and KIRs in human history, health and survival. Nature reviews. Immunology. 2005 Mar;5(3):201-14
- Mason LH, Willette-Brown J, Taylor LS, McVicar DW
Regulation of Ly49D/DAP12 Signal Transduction by Src-Family Kinases and CD45. Journal of immunology (Baltimore, Md. : 1950) 2006 Jun 1;176(11):6615-6623
- Wu J, Cherwinski H, Spies T, Phillips JH, Lanier LL
DAP10 and DAP12 form distinct, but functionally cooperative, receptor complexes in natural killer cells. The Journal of experimental medicine 2000 Oct 2;192(7):1059-68
- Lanier LL, Bakker AB
The ITAM-bearing transmembrane adaptor DAP12 in lymphoid and myeloid cell function. Immunology today 2000 Dec;21(12):611-4
- Maghazachi AA
Insights into seven and single transmembrane-spanning domain receptors and their signaling pathways in human natural killer cells. Pharmacological reviews 2005 Sep;57(3):339-57
- Upshaw JL, Schoon RA, Dick CJ, Billadeau DD, Leibson PJ
The isoforms of phospholipase C-gamma are differentially used by distinct human NK activating receptors. Journal of immunology (Baltimore, Md. : 1950) 2005 Jul 1;175(1):213-8
- Caraux A, Kim N, Bell SE, Zompi S, Ranson T, Lesjean-Pottier S, Garcia-Ojeda ME, Turner M, Colucci F
Phospholipase C-gamma2 is essential for NK cell cytotoxicity and innate immunity to malignant and virally infected cells. Blood 2006 Feb 1;107(3):994-1002
- Sasahara Y, Rachid R, Byrne MJ, de la Fuente MA, Abraham RT, Ramesh N, Geha RS
Mechanism of recruitment of WASP to the immunological synapse and of its activation following TCR ligation. Molecular cell 2002 Dec;10(6):1269-81
- Villalba M
What came first: PKCtheta or the immune synapse? Archivum immunologiae et therapiae experimentalis 2004 Jan-Feb;52(1):6-12
- Krzewski K, Chen X, Orange JS, Strominger JL
Formation of a WIP-, WASp-, actin-, and myosin IIA-containing multiprotein complex in activated NK cells and its alteration by KIR inhibitory signaling. The Journal of cell biology 2006 Apr 10;173(1):121-32
- Anton IM, Jones GE
WIP: a multifunctional protein involved in actin cytoskeleton regulation. European journal of cell biology 2006 Apr;85(3-4):295-304
- Moon KD, Post CB, Durden DL, Zhou Q, De P, Harrison ML, Geahlen RL
Molecular basis for a direct interaction between the Syk protein-tyrosine kinase and phosphoinositide 3-kinase. The Journal of biological chemistry 2005 Jan 14;280(2):1543-51
- Jiang K, Zhong B, Gilvary DL, Corliss BC, Hong-Geller E, Wei S, Djeu JY
Pivotal role of phosphoinositide-3 kinase in regulation of cytotoxicity in natural killer cells. Nature immunology 2000 Nov;1(5):419-25
- Jiang K, Zhong B, Gilvary DL, Corliss BC, Vivier E, Hong-Geller E, Wei S, Djeu JY
Syk regulation of phosphoinositide 3-kinase-dependent NK cell function. Journal of immunology (Baltimore, Md. : 1950) 2002 Apr 1;168(7):3155-64
- Yusa S, Catina TL, Campbell KS
SHP-1- and phosphotyrosine-independent inhibitory signaling by a killer cell Ig-like receptor cytoplasmic domain in human NK cells. Journal of immunology (Baltimore, Md. : 1950) 2002 May 15;168(10):5047-57
- Yusa S, Catina TL, Campbell KS
KIR2DL5 can inhibit human NK cell activation via recruitment of Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2). Journal of immunology (Baltimore, Md. : 1950) 2004 Jun 15;172(12):7385-92
- Yusa S, Campbell KS
Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2) can play a direct role in the inhibitory function of killer cell Ig-like receptors in human NK cells. Journal of immunology (Baltimore, Md. : 1950) 2003 May 1;170(9):4539-47
- Moretta L, Bottino C, Pende D, Vitale M, Mingari MC, Moretta A
Different checkpoints in human NK-cell activation. Trends in immunology 2004 Dec;25(12):670-6
- Tarazona R, Borrego F, Galiani MD, Aguado E, Pena J, Coligan JE, Solana R
Inhibition of CD28-mediated natural cytotoxicity by KIR2DL2 does not require p56(lck) in the NK cell line YT-Indy. Molecular immunology 2002 Jan;38(7):495-503
- Kosugi A, Sakakura J, Yasuda K, Ogata M, Hamaoka T
Involvement of SHP-1 tyrosine phosphatase in TCR-mediated signaling pathways in lipid rafts. Immunity 2001 Jun;14(6):669-80
- Palmieri G, Tullio V, Zingoni A, Piccoli M, Frati L, Lopez-Botet M, Santoni A
CD94/NKG2-A inhibitory complex blocks CD16-triggered Syk and extracellular regulated kinase activation, leading to cytotoxic function of human NK cells. Journal of immunology (Baltimore, Md. : 1950) 1999 Jun 15;162(12):7181-8
- Marti F, Xu CW, Selvakumar A, Brent R, Dupont B, King PD
LCK-phosphorylated human killer cell-inhibitory receptors recruit and activate phosphatidylinositol 3-kinase. Proceedings of the National Academy of Sciences of the United States of America 1998 Sep 29;95(20):11810-5
- Verbrugge A, Ruiter Td T, Clevers H, Meyaard L
Differential contribution of the immunoreceptor tyrosine-based inhibitory motifs of human leukocyte-associated Ig-like receptor-1 to inhibitory function and phosphatase recruitment. International immunology 2003 Nov;15(11):1349-58
- Vyas YM, Maniar H, Dupont B
Cutting edge: differential segregation of the SRC homology 2-containing protein tyrosine phosphatase-1 within the early NK cell immune synapse distinguishes noncytolytic from cytolytic interactions. Journal of immunology (Baltimore, Md. : 1950) 2002 Apr 1;168(7):3150-4