You say ITAM and I say ITIM, let's call the whole thing off: the ambiguity of immunoreceptor signalling

Abstract

Paradigms of protein tyrosine kinase (PTK)‐mediated immunoreceptor signalling have developed largely from studies of molecules containing immunoreceptor tyrosine‐based activation motifs (ITAM) and immunoreceptor tyrosine‐based inhibition motifs (ITIM). In some circumstances, ITAM can mediate inhibition and ITIM can propagate activation signals. In addition to classical immune cells, some ITAM‐ and ITIM‐encoding proteins are more widely expressed and are crucial to the development of haemopoietic cells, like osteoclasts and natural killer cells, as well as tissues such as bone and brain. Closer analysis of activating proteins reveals that some potentially encode ITIM within an ITAM. These ‘closet’ ITIM could, under conditions of partial ITAM phosphorylation, mediate inhibitory signalling.

DCIR-mediated enhancement of HIV-1 infection requires the ITIM-associated signal transduction pathway

“…36 In general, receptors possessing an ITAM domain acts as activators, whereas receptors bearing an ITIM region act as inhibitors in signal transduction pathways. 37 For example, PECAM-1, which promotes migration of endothelial cells through a process relying on PTP activity, can reduce B-cell receptor-mediated calcium and tyrosine phosphorylation events because of its ITIM region. 37 Interestingly, it was reported that chimeric molecules consisting of the extracellular domain of Fc␥RIIB and the cytoplasmic portion of murine DCIR display an ITIM-mediated inhibitory role.…”

“…37 For example, PECAM-1, which promotes migration of endothelial cells through a process relying on PTP activity, can reduce B-cell receptor-mediated calcium and tyrosine phosphorylation events because of its ITIM region. 37 Interestingly, it was reported that chimeric molecules consisting of the extracellular domain of Fc␥RIIB and the cytoplasmic portion of murine DCIR display an ITIM-mediated inhibitory role. 38 Nevertheless, in the context of our study, we did not observe any inhibitory signal mediated by DCIR at least with respect to HIV-1 biology.…”

“…This is reminiscent of previous findings where the ITIM domain can sometimes propagate positive signals. 37 Ligation of some CLRs can result in phosphorylation of ITIM domain by Src TKs. 37 However, nothing is known about the identity of the phosphorylated amino acid(s) on this motif and the precise nature of the Src involved in this process.…”

“…37 Ligation of some CLRs can result in phosphorylation of ITIM domain by Src TKs. 37 However, nothing is known about the identity of the phosphorylated amino acid(s) on this motif and the precise nature of the Src involved in this process. Some studies postulated that tyrosine phosphorylation is important for signaling induced by an ITIM domain, 37,39 but for DCIR it remains to be established.…”

“…37 However, nothing is known about the identity of the phosphorylated amino acid(s) on this motif and the precise nature of the Src involved in this process. Some studies postulated that tyrosine phosphorylation is important for signaling induced by an ITIM domain, 37,39 but for DCIR it remains to be established. Site-directed mutagenesis of the tyrosine residue present in the ITIM domain revealed the important function of this amino acid in induction of DCIR signaling.…”