Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells

Cell Death Differ. 2013 Mar;20(3):456-64. doi: 10.1038/cdd.2012.141. Epub 2012 Nov 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Cell Line
  • GRB2 Adaptor Protein / antagonists & inhibitors
  • GRB2 Adaptor Protein / genetics
  • GRB2 Adaptor Protein / metabolism*
  • Humans
  • Inositol Polyphosphate 5-Phosphatases
  • Killer Cells, Natural / immunology*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mutation
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
  • Phosphoric Monoester Hydrolases / antagonists & inhibitors
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / metabolism*
  • Phosphorylation
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Receptors, Immunologic / chemistry
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Receptors, Virus / metabolism
  • Signal Transduction


  • GRB2 Adaptor Protein
  • RNA, Small Interfering
  • Receptors, Immunologic
  • Receptors, Virus
  • TIGIT protein, human
  • poliovirus receptor
  • Phosphatidylinositol 3-Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • Phosphoric Monoester Hydrolases
  • Inositol Polyphosphate 5-Phosphatases
  • INPP5D protein, human
  • INPPL1 protein, human
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases