Cross-regulation of signaling by ITAM-associated receptors

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 beta2 integrins that are coupled to the ITAM-containing adaptors DAP12 and FcRgamma. 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.

Figure 1

Integration of RANK and ITAM signaling to activate NFATc1. RANK signaling induces NFATc1 gene expression by way of TRAF6 and transcription factors NF-κB and AP-1 and contributes to induction of calcium signaling by activating Btk and Tec tyrosine kinases and transactivating ITAM-associated receptors. ITAM-associated receptors TREM-2 and SIRPβ are activated by ligands constitutively expressed on osteoclast precursors; OSCAR and PIR-A, by ligands expressed on stromal and osteoblast lineage cells; β₃ integrins, by extracellular matrix; and c-Fms by M-CSF and IL-34, which are secreted by various cell types; some of these receptors can also be superactivated after stimulation of RANK by its ligand RANKL. ITAM-associated receptors cooperate with RANK to induce calcium signaling, which activates calcineurin (Cn), which in turn dephosphorylates (de-P) and induces nuclear translocation of NFATc1. NFATc1 is a master regulator of osteoclast differentiation that autoamplifies expression of its own promoter, activates expression of osteoclast-related genes and drives osteoclastogenesis. Specific integration points in RANK and ITAM signaling discussed in the text are labeled 1, 2 and 3. InsP₃, inositol-1,4,5-trisphosphate; IKK, IκB kinase.

Figure 2

Integrated signaling by ITAM-associated receptors and TLRs leads to enhanced activation of NF-κB and MAPKs. ITAM-associated receptors and TLRs activate distinct signaling pathways that converge on common signaling effectors such as NF-κB and MAPKs. Signaling pathways can also converge on upstream signaling molecules, such as CARD9. Integrated and additive activation of signaling molecules by different signaling pathways leads to enhanced signaling and amplified cellular responses. Cn, calcineurin; IRAK1/4, interleukin 1 receptor–associated kinases 1 and 4; MyD88, myeloid differentiation factor adaptor molecule.

Figure 3

Integration of ITAM and cytokine Jak–STAT signaling. Low-avidity ligation of ITAM-associated receptors leads to tonic calcium signaling that maintains basal activity of a CaMK–Pyk2 pathway that amplifies Jak activity and enhances downstream activation of STAT1. Cytokine receptors and Jaks also activate Pyk2, and Pyk2 can thus relay signals between ITAM-associated receptors and cytokine receptors bidirectionally. ITAM-containing DAP12 also modulates cell responses to IL-4. Cytokines such as IFN-γ, IFN-α, IL-4, IL-10 and IL-27 regulate expression of ITAM-associated receptors and STAT1, and thus cytokine and ITAM-associated receptor signaling pathways are tightly integrated. Adapted from Nat. Immunol. 9, 186–193 (2008).

Figure 4

Indirect activation of calcium signaling by TLRs and TNFR through integrins. Engagement of TLRs and TNFRs activates signaling pathways that induce a conformational change in integrins (in a process termed inside-out signaling), leading to high-affinity ligand binding and associated high-avidity ligation of integrins. High-avidity integrin ligation results in outside-in signaling that activates integrin-mediated signaling pathways (which in the case of β₂ and β₃ integrins includes activation of DAP12- and FcRγ-mediated signaling).