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Cross-regulation of signaling by ITAM-associated receptors

Nature Immunology volume 10, pages 340–347 (2009)Cite this article

Abstract

An important function of receptors that signal through immunoreceptor tyrosine-based activation motifs (ITAMs) is to regulate signaling by heterologous receptors. This review describes mechanisms by which ITAM-associated receptors modulate signaling by Toll-like receptors (TLRs), tumor necrosis factor receptor family members and cytokine receptors that use the Jak–STAT signaling pathway, and the biological importance of this signal transduction cross-talk. ITAM-mediated cross-regulation can either augment or dampen signaling by other receptors. Conversely, TLRs and cytokines modulate ITAM-mediated signaling, by means including activation of β2 integrins that are coupled to the ITAM-containing adaptors DAP12 and FcRγ. Integration of ITAM signaling into signaling networks through cross-talk with other signal transduction pathways results in tight regulation and fine tuning of cellular responses to various extracellular stimuli and contributes to induction of specific activation and differentiation pathways.

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Figure 1: Integration of RANK and ITAM signaling to activate NFATc1.
Figure 2: Integrated signaling by ITAM-associated receptors and TLRs leads to enhanced activation of NF-κB and MAPKs.
Figure 3: Integration of ITAM and cytokine Jak–STAT signaling.
Figure 4: Indirect activation of calcium signaling by TLRs and TNFR through integrins.

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Acknowledgements

I thank M. Nakamura for discussions and X. Hu and K.-H. Park-Min for critical review of the manuscript. Supported by the US National Institutes of Health.

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  1. Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA

    Lionel B Ivashkiv

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Ivashkiv, L. Cross-regulation of signaling by ITAM-associated receptors. Nat Immunol 10, 340–347 (2009). https://doi.org/10.1038/ni.1706

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