The expanding roles of ITAM adapters FcRγ and DAP12 in myeloid cells

Abstract

Summary The adapter proteins DAP12 and FcRγ associate with a wide spectrum of receptors in a variety of innate immune cells to mediate intracellular signaling pathways when their cognate receptor is engaged. These adapter proteins are coupled to their receptors through charged residues within the transmembrane regions of the adapter and receptor. DAP12 and FcRγ contain specific protein domains (referred to as ITAM domains) that serve as the substrates and docking sites for kinases allowing amplification of intracellular signaling reactions. Recent research has broadened the repertoire of receptors that utilize these adapters for signaling to include not only novel Ig-superfamily members but also cytokine receptors, integrins and other adhesion molecules. Even more amazing, there is abundant evidence that these multifunctional signaling adapters also mediate inhibitory activity, downmodulating signaling from TLRs and other heterologous receptors. In this review, we discuss the newly described receptors that utilize DAP12 and/or FcRγ adapters to modulate innate immune responses.

Control of Pathogenic CD4 T Cells and Lethal Immunopathology by Signaling Immunoadaptor DAP12 during Influenza Infection

“…DNAX-activating protein of 12 kDa (DAP12) is a newly identified, evolutionarily highly conserved two ITAM-containing signaling adaptor molecule expressed only in innate immune cells such as dendritic cells, macrophages, as well as NK cells (24)(25)(26)(27). A number of innate immune receptors including the triggering receptor expressed on myeloid cells, MDL-1 and NKG2D, are associated with and signal though DAP12 (24)(25)(26)(27)(28)(29).…”

Cloning and Characterization of CD300d, a Novel Member of the Human CD300 Family of Immune Receptors

“…These receptors, which usually belong to multigenic families, include molecules with extracellular C-type lectin-like or immunoglobulin-like folds (1)(2)(3). Inhibitory immunoreceptors display long cytoplasmic tails containing immunoreceptor tyrosine-based inhibitory motifs.…”

“…Alternatively, they present a positively charged amino acid residue within their transmembrane domain that enables the interaction with immunoreceptor tyrosine-based activating motif (ITAM) 5 -bearing adaptor proteins (Fc⑀R␥, CD3, and DAP12 (DNAX-activating protein of 12 kDa)), which contain a complementary negative charge in the same domain. Ligand-induced phosphorylation of ITAMs leads to the recruitment of tandem Src homology 2 domaincontaining tyrosine kinases, such as Syk and ZAP-70, to transduce activating signals (1).…”

IMPDHII Protein Inhibits Toll-like Receptor 2-mediated Activation of NF-κB

“…Several receptor and non-receptor molecules such as CEACAM1 (44) and TLR-signaling proteins, including IRAK1, contain ITIM motifs (23). Moreover, some receptors, such as ␤-integrins, coupled with ITAM-containing adaptors interfere with the signaling of TLRs (46,47). Interestingly, molecules such as ␤-integrin also interact with PKC (48), the kinase that phosphorylates SHP1 on serine residues (31).…”

“…Other candidates could include proteins containing immunoreceptor tyrosine-based activation or inhibition motifs (ITAM or ITIM). Indeed, SHP1 activation requires its interaction with phosphorylated tyrosines on these motifs (30,46). Several receptor and non-receptor molecules such as CEACAM1 (44) and TLR-signaling proteins, including IRAK1, contain ITIM motifs (23).…”