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 crossregulation 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.The ITAM is a conserved signaling motif preferentially used by hematopoietic cells 1 . The ITAM motif (consensus sequence YXXLX 6-8 YXXL/I) is contained in the cytoplasmic domain of transmembrane adaptor molecules that are associated with and transmit signals from various immunoreceptors. ITAM-coupled receptors include the T cell and B cell antigen receptors (TCR and BCR) and Fc receptors (FcRs), which bind immunoglobulins. In lymphocytes, ITAM-containing adaptors transmit antigen receptor signals that lead to cell activation or tolerance, depending on the intensity of receptor stimulation and the presence or absence of co-stimulatory signals 2 . Myeloid cells express approximately 20 ITAM-associated receptors, including FcRs, TREMs, ILTs (also called LILRs), MAIRs, PIR-A, MDL-1, DCAR, OSCAR, CD200 receptors and c-Fms (refs. 3,4 ). These receptors signal through two main ITAM-containing adaptors expressed by myeloid cells, termed . Except for FcRs, which bind immunoglobulins and immune complexes, the ligands for myeloid ITAM-coupled receptors are not well defined; they include MHC class I molecules and other, as yet unknown ligands that are expressed on myeloid cells or on tissue cells with which myeloid cells interact. Thus, in myeloid cells ITAM-coupled receptors are constitutively engaged, which leads to tonic low-level ITAM-mediated signaling (reviewed in ref. 5 ). More recently, it has become clear that FcRγ and DAP12 associate with β 2 and β 3 integrins and contribute to signaling by these receptors [6][7][8] . Thus, ITAM signaling is also induced by cell-cell and cell-extracellular matrix (ECM) interactions that are mediated by these integrins.The ligation of ITAM-associated receptors in myeloid cells leads to a signaling cascade that begins with phosphorylation of ITAM tyrosine residues by Src-family kinases, followed by the recruitment and activation of the spleen tyrosine kinase (Syk) 1,5 Integration with TLR responsesMany microbial products and complex inflammatory stimuli contain ligands for...

The Toll-like receptor 2/1 (TLR2/1) complex initiates human platelet activation via the src/Syk/LAT/PLCγ2 signalling cascade

“…This was found not to be due to a general impairment of dense granule secretion, as platelets released prominent and almost normal amounts of ATP (3 µM) when subsequently challenged with 0.1 U/ml thrombin. Under all tested conditions platelet aggregation, as expected, was prominently precluded by abciximab ( Figure 5B FcRs or β integrins for PLC activation and, in turn, Ca 2+ and DAG signalling (for review see [19]). Using isolated platelets from a Glanzmann's thrombasthenia patient ( Figure 6) we found that convulxin (7.5 ng/ml) as well as Pam3CSK4 (7.5 and 30 µg/ml) evoked both LAT Tyr191 and PLC2 Tyr759 phosphorylation ( Figure 6A).…”

“…Unlike in some other 'classical' immune cells this cascade was not indirectly induced via  3 integrins [19,20] as demonstrated by the use of platelets from a patient with…”

“…When we mimicked the lack of integrin  3 signalling by precluding fibrinogen-binding and integrin  IIa  3 outside-in signalling with abciximab we observed a similar lack of Pam3CSK4-and convulxin-provoked dense granule secretion. Along this line, a most interesting aspect of TLR-induced cell activation is the integration and even orchestration of ITAM-associated receptors such as Fc receptors or  2 and  3 integrins to simultaneously activate PLC-mediated pathways [19]. In this context, in monocytes from Glanzmann's thrombasthenia patients lacking  3 integrins it has been shown that Pam3CSK4-provoked production of TNF and IL-8 completely relied on concomitant signalling via the vitronectin-receptor integrin  V  3 [20].…”

High affinity soluble ILT2 receptor: a potent inhibitor of CD8+ T cell activation

“…Their extracellular regions contain either four or two immunoglobulin-like domains arranged linearly. Natural ILT2 consists of four extracellular domains and a cytoplasmic tail of four ITIMs, which mediate its cell-signaling effects (Hamerman and Lanier, 2006;Ivashkiv, 2009). Engagement of ILT2 triggers tyrosine phosphorylation of ITIMs and the subsequent recruitment of a number of protein tyrosine phosphatases (Binstadt et al, 1996), leading to downregulation of the signaling mediated by activating receptors (Colonna et al, 1997).…”

IL-3 Inhibits Human Osteoclastogenesis and Bone Resorption through Downregulation of c-Fms and Diverts the Cells to Dendritic Cell Lineage

“…M-CSF as well as RANKL-deficient mice show severe osteopetrosis (5,6,12). In addition to these molecules, several transcription factors, such as NF-kB, NFAT cytoplasmic 1 (NFATc1), micropthalmia transcription factor (MITF), PU.1, and c-Fos, are vital for osteoclast formation (13)(14)(15). PU.1 is essential for development of myeloid cells.…”