HemITAM: A single tyrosine motif that packs a punch

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Sci. Signal.  05 Dec 2017:
Vol. 10, Issue 508, eaan3676
DOI: 10.1126/scisignal.aan3676


  • Fig. 1 Immunoreceptor-associated tyrosine-based signaling motifs.

    The tyrosine-based signaling motifs found in immunoreceptors include the immunoreceptor tyrosine-based activation motif (ITAM), the immunoreceptor tyrosine-based inhibition motif (ITIM), the hemi-immunoreceptor tyrosine-based activation motif (hemITAM), the immunoreceptor tyrosine-switch motif (ITSM), the immunoglobulin tail tyrosine (ITT) motif, and an ITT-like motif. The consensus sequence for each motif is shown below a cartoon depicting a prototypic receptor of each type, with “x” denoting any amino acid. The protein chains containing the signaling motif/motifs are indicated in blue, and the tyrosine core motifs are highlighted in red. These core tyrosine motifs are present as tandem copies in ITAMs and as single copies in the other motifs. Immunoreceptors that couple to ITAM- or ITIM-bearing polypeptides are indicated in gray. CD94/NKG2A and CLEC-2 are C-type lectin-like receptors (CTLRs); all others are members of the immunoglobulin-like superfamily.

  • Fig. 2 Genomic organization of hemITAM-utilizing receptors and alignment of hemITAM sequences.

    (A) Genomic organization of a subregion of the natural killer gene complex (NKC) on human chromosome 12. HemITAM-utilizing receptors are indicated as blue bars with labels below the chromosome and grouped in either the NKRP1/CLEC2 family or the Dectin-1 cluster. Intermingled genes are depicted for completeness with labels above the chromosome, and receptor-ligand pairs are denoted by dashed lines. (B) Amino acid sequence alignment of the cytoplasmic portions of hemITAM-utilizing receptors. The tyrosine core module is indicated in bold, and the triacidic motif is highlighted in gray. Amino acids identical to the upper CLEC-2 amino acid sequence are shown as dashes, and missing amino acids are depicted by dots. The consensus sequence is shown below, with “x” denoting any amino acid.

  • Fig. 3 Models for proximal signaling events initiated by hemITAM receptors.

    (A) Current model of CLEC-2 signaling in which tyrosine phosphorylation and Syk phosphorylation depend on relocalization of CLEC-2 into lipid rafts and actin polymerization. The hemITAM is initially phosphorylated by Src family kinases (SFKs), which also activate phosphatidylinositol 3-kinase (PI3K), leading to the production of phosphatidylinositol 3,4,5-trisphosphate (PIP3) from phosphatidylinositol 4,5-bisphosphate (PIP2). PIP3 creates docking sites for Tec family kinases (TFKs), which in turn become activated and phosphorylate Syk. Syk further phosphorylates and associates with the hemITAM. (B) Alternative model of the hemITAM proximal signaling mechanism as deduced from several studies (9496). Relocalization of Syk to the plasma membrane upon actin polymerization is facilitated by filamin A or ITAM-containing ezrin/radixin/moesin (ERM) proteins, or both, in the absence of a direct association of Syk with the hemITAM-containing immunoreceptor.



  • Table 1 Natural ligands, expression profiles, and functions of hemITAM receptors.

    HemITAM receptors are C-type lectin-like receptors (CTLRs) that are encoded by genes clustered together in the natural killer gene complex (NKC), which includes the Dectin-1 cluster and members of the NKRP1 receptor family. The expression profile for each receptor is indicated for both mice (m) and humans (h). DC, dendritic cell; ROS, reactive oxygen species; TEM cells, effector memory T cells; TLR, Toll-like receptor.

    Dectin-1 cluster
    m: platelets, neutrophils, monocytes,
    macrophages, DC, NK
    Platelet aggregation
    Modulation of TLR signaling
    h: platelets, liver-resident Kupffer cells
    Undefined cellular ligand
    m: DC, monocytes, macrophages,
    neutrophils, γδ T cells
    ROS production
    Cytokine production in synergy with TLR2
    DC adaptation for priming of CD8 T cells
    Leukotriene production
    h: DC, monocytes, macrophages, neutrophils,
    γδ T cells, B cells, eosinophils, mast cells
    DNGR-1F-actinm: CD8α+ DC, plasmacytoid DCCross-presentation of dead cell–associated antigens
    h: BDCA3+ DC
    NKRP1 receptors
    NKp80AICLm: absent in rodentsCytotoxicity
    Cytokine production
    h: NK cells, TEM cells
    NKp65KACLm: absent in rodentsCytotoxicity
    Cytokine production
    h: NK-92