HemITAM: A single tyrosine motif that packs a punch

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


Many mammalian immunoreceptors signal through cytoplasmic tyrosine-based sequence motifs. One of the most well characterized motifs is the immunoreceptor tyrosine-based activation motif (ITAM), which contains two tyrosine core modules in tandem orientation. Some activating C-type lectin-like receptors of innate immune cells utilize an unusual single-copy tyrosine-based activation motif called hemITAM. In this Review, which contains three figures, one table, and 96 references, we discuss the current state of knowledge on signaling mechanisms and cellular activation by such hemITAM-bearing immunoreceptors in the context of their diverse functions in innate immunity.


Innate immune cells sense danger through a plethora of germline-encoded receptors that recognize pathogen-associated molecular patterns (PAMPs) or cellular molecules that are exposed only by stressed, infected, malignant, or dead cells. Many of these danger-sensing receptors belong to the C-type lectin-like superfamily (CLSF) and therefore are called C-type lectin-like receptors (CTLRs). Certain activating CTLRs, namely, CLEC-2, Dectin-1, DNGR-1, NKp80, and NKp65, which are encoded by genes that are clustered together in a subregion of the mammalian natural killer gene complex (NKC), use a single copy tyrosine signaling module termed the hemi-immunoreceptor tyrosine-based activation motif (hemITAM). These hemITAM-bearing CTLRs are present on myeloid cells and innate lymphocytes and stimulate various functions, such as phagocytosis, cytokine production, and cytotoxicity. Proximal signaling mechanisms involve the tyrosine phosphorylation of the hemITAM and the subsequent activation of the kinase Syk. Signaling and Syk recruitment by the hemITAM appear to be tuned by variable amino acids within or near the hemITAM, which give rise to differences in downstream signaling events and diverging functional outcomes among hemITAM-bearing receptors.

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