Trends in Immunology
Volume 28, Issue 2, February 2007, Pages 66-73
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Review
The many faces of ITAMs

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Innate and adaptive immune responses are regulated by receptors that signal through immunoreceptor tyrosine-based activation motifs (ITAMs). The molecular basis of ITAM signaling has been extensively characterized and serves as a model for receptor-mediated signal transduction. Src family kinases typically phosphorylate ITAMs on dual tyrosines, which enable recruitment and activation of Syk family kinases through binding to dual SH2 domains on these kinases. Examples of ITAM-based signaling that do not conform precisely to the standard model are becoming increasingly common. ITAMs that suppress signaling under specific conditions and activate under others have been described, as have ITAM-like signaling mechanisms using nonstandard sequence motifs. Elucidating the diversity of ITAM-based signaling mechanisms will clarify how activating signals generated by ITAMs are tightly regulated and will open opportunities for specific therapeutic manipulation of ITAM-based signaling pathways.

Section snippets

ITAM-containing receptors

In the immune system and beyond, signals transduced through cytoplasmic immunoreceptor tyrosine-based activation motifs (ITAMs) control a variety of key cellular responses, including phagocytosis and degranulation, cell migration and adhesion, proliferation and differentiation, and gene induction [1]. ITAMs can be found directly on the cytoplasmic tails of surface receptors, such as the cytoplasmic tail of Fcγ receptor IIA (FcγRIIA); alternatively, receptors can associate with common

Current model of ITAM signaling

An ITAM is defined by two tyrosine residues contained in a consensus sequence: YxxI/Lx(6–12)YxxI/L 1, 3, 4 (Figure 1a). ITAM sequences are often found in multiples. For example, FcɛRI signals through FcRγ, which dimerizes and thus itself contains two ITAMs, as well as the FcɛRI β-chain, which also contains an ITAM. Similarly, the TCR complex has up to ten ITAMs distributed on its CD3γ, δ, ɛ and ζ chains. ITAM clustering is thought to amplify signaling by increasing local concentrations of

Inhibitory ITAMs?

With a clean model of ITAM-based activation and ITIM-based inhibition in hand, investigators have been surprised recently to observe cases where ITAM signaling is clearly acting in an inhibitory role. DAP12 is a signaling adaptor molecule with an aspartic acid in its transmembrane domain that interacts with positively charged residues in the transmembrane domains of a variety of receptors. These receptors transmit intracellular signals through activation of ITAMs on DAP12. For example,

ITAM recruitment of inhibitory proteins

The basic model of ITAM signaling has Src family kinases interacting with and phosphorylating ITAMs, and prompting association with and activation of Syk family kinases. The association of phosphatases, including SHP-1, SHP-2 and SHIP, with ITIM-containing receptors is a well-established mechanism of inhibition of ITAM-mediated activation. However, several studies have reported phosphatase activation when ITAM-containing ‘activating’ receptors are clustered in the absence of ITIM-containing

Variations in ITAM sequences

As discussed earlier, the ITAM sequence is fairly well established but there is significant room in the consensus for variation between ITAMs. Differences in surrounding amino acids probably account for the differing inhibitory and activating natures of ITAMs. However, a few ITAM-like sequences have been demonstrated to activate Src/Syk-based signaling, even though they do not conform to the consensus. Dectin-1 [also known as C-type lectin 7A (CLEC7A)] is a C-type lectin receptor for β-glucan

Concluding remarks

ITAM-based signaling is central to the regulation of innate and adaptive immune responses. The molecular basis of ITAM signaling has been extensively characterized and serves as a model for receptor-mediated signal transduction. Examples of ITAM-based signaling that do not conform precisely to the standard model are becoming increasingly common. Rather than reflecting weaknesses in our understanding of ITAMs, these observations demonstrate the flexibility of this signaling mechanism, in that it

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