Recombinant Human T-cell immunoreceptor with Ig and ITIM domains (TIGIT), partial (Active)

Function

Inhibitory receptor that plays a role in the modulation of immune responses. Suppresses T-cell activation by promoting the generation of mature immunoregulatory dendritic cells (PubMed:19011627). Upon binding to its ligands PVR/CD155 or NECTIN2/CD112, which are expressed on antigen-presenting cells, sends inhibitory signals to the T-cell or NK cell. Mechanistically, interaction with ligand leads to phosphorylation of the cytoplasmic tail by Src family tyrosine kinases such as FYN or LCK, allowing subsequent binding to adapter GRB2 and SHIP1/INPP5D. In turn, inhibits PI3K and MAPK signaling cascades (PubMed:23154388). In addition, associates with beta-arrestin-2/ARRB2 to recruit SHIP1/INPP5D that suppresses autoubiquitination of TRAF6 and subsequently inhibits NF-kappa-B signaling pathway (PubMed:24817116). Also acts as a receptor for NECTIN4 to inhibit NK cell cytotoxicity (PubMed:32503945)

Subcellular Location

Cell membrane (Single-pass type I membrane protein)

Tissue Specificity

Expressed at low levels on peripheral memory and regulatory CD4+ T-cells and NK cells and is up-regulated following activation of these cells (at protein level)

Subunit

Homodimer in cis; binds with high affinity to PVR, forming a heterotetrameric assembly of two TIGIT and two PVR molecules. Binds with lower affinity to NECTIN2 and NECTIN3. Interacts with GRB2 (PubMed:23154388). Interacts with NECTIN4 (PubMed:32503945)

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• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Yu X. et al. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. — Nat. Immunol. (2009)
• Liu S. et al. Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells. — Cell Death Differ. (2013)
• Li M. et al. T-cell immunoglobulin and ITIM domain (TIGIT) receptor/poliovirus receptor (PVR) ligand engagement suppresses interferon-gamma production of natural killer cells via beta-arrestin 2-mediated negative signaling. — J. Biol. Chem. (2014)
• Reches A. et al. Nectin4 is a novel TIGIT ligand which combines checkpoint inhibition and tumor specificity. — J. Immunother. Cancer (2020)
• Stengel K.F. et al. Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell-cell adhesion and signaling mechanism that requires cis-trans receptor clustering. — Proc. Natl. Acad. Sci. U.S.A. (2012)