Document Detail

Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells.
MedLine Citation:
PMID:  23154388     Owner:  NLM     Status:  MEDLINE    
Activating and inhibitory receptors control natural killer (NK) cell activity. T-cell immunoglobulin and ITIM (immunoreceptor tyrosine-based inhibition motif) domain (TIGIT) was recently identified as a new inhibitory receptor on T and NK cells that suppressed their effector functions. TIGIT harbors the immunoreceptor tail tyrosine (ITT)-like and ITIM motifs in its cytoplasmic tail. However, how its ITT-like motif functions in TIGIT-mediated negative signaling is still unclear. Here, we show that TIGIT/PVR (poliovirus receptor) engagement disrupts granule polarization leading to loss of killing activity of NK cells. The ITT-like motif of TIGIT has a major role in its negative signaling. After TIGIT/PVR ligation, the ITT-like motif is phosphorylated at Tyr225 and binds to cytosolic adapter Grb2, which can recruit SHIP1 to prematurely terminate phosphatidylinositol 3-kinase (PI3K) and MAPK signaling, leading to downregulation of NK cell function. In support of this, Tyr225 or Asn227 mutation leads to restoration of TIGIT/PVR-mediated cytotoxicity, and SHIP1 silencing can dramatically abolish TIGIT/PVR-mediated killing inhibition.
S Liu; H Zhang; M Li; D Hu; C Li; B Ge; B Jin; Z Fan
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-11-16
Journal Detail:
Title:  Cell death and differentiation     Volume:  20     ISSN:  1476-5403     ISO Abbreviation:  Cell Death Differ.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-11     Completed Date:  2013-08-15     Revised Date:  2014-03-07    
Medline Journal Info:
Nlm Unique ID:  9437445     Medline TA:  Cell Death Differ     Country:  England    
Other Details:
Languages:  eng     Pagination:  456-64     Citation Subset:  IM    
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MeSH Terms
Amino Acid Motifs
Cell Line
GRB2 Adaptor Protein / antagonists & inhibitors,  genetics,  metabolism*
Killer Cells, Natural / immunology*
Mitogen-Activated Protein Kinase Kinases / metabolism
Phosphatidylinositol 3-Kinases / metabolism
Phosphoric Monoester Hydrolases / antagonists & inhibitors,  genetics,  metabolism*
RNA Interference
RNA, Small Interfering / metabolism
Receptors, Immunologic / chemistry,  genetics,  metabolism*
Receptors, Virus / metabolism
Signal Transduction
Reg. No./Substance:
0/GRB2 Adaptor Protein; 0/RNA, Small Interfering; 0/Receptors, Immunologic; 0/Receptors, Virus; 0/TIGIT protein, human; 0/poliovirus receptor; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC Protein Kinase Kinases; EC 3.1.3.-/INPPL1 protein, human; EC 3.1.3.-/Phosphoric Monoester Hydrolases; EC,4,5-trisphosphate 5-phosphatase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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