Molecular Architecture of Signal Complexes Regulating Immune Cell Function

Abstract

Signals transmitted via multichain immunoreceptors control the development, differentiation and activation of hematopoetic cells. The cytoplasmic parts of these receptors contain immunoreceptor tyrosine-based activation motifs (ITAMs) that upon phosphorylation by members of the Src tyrosine kinase family orchestrate a complex set of signaling events involving tyrosine phosphorylation, generation of second messengers like DAG, IP3 and Ca2+, activation of effector molecules like Ras and MAPKs and the translocation and activation of transcription factors like NFAT, API and NF-kB. Spatial and temporal organization of these signaling events is essential both to connect the receptors to downstream cascades as well as to control the functional outcome of the immune activation. Throughout this process control and fine-tuning of the different signals are necessary both for effective immune function and in order to avoid inappropriate or exaggerated immune activation and autoimmunity. This control includes modulating mechanisms that set the threshold for activation and reset the activation status after an immune response has been launched. One immunomodulating pathway is the cAMP-protein kinase A-Csk pathway scaffolded by a supramolecular complex residing in lipid rafts with the A kinase-anchoring protein (AKAP) ezrin, the Csk-binding protein PAG and a linker between the two, EBP50. Failure of correct scaffolding and loss of spatiotemporal control can potentially have severe consequences, leading to immune failure or autoimmunity. The clinical relevance of supramolecular complexes specifically organized by scaffolding proteins in regulating immune activity and the specter of genetic diseases linked to different signaling components suggest that protein-protein contact surfaces can be potential targets for drug intervention. It is also of interest to note that different pathogens have evolved strategies to specifically modulate signal integration, thereby rewiring the signal in a way beneficial for their survival. In addition to demonstrating the importance of different signal processes, these adaptations are elegant illustrations of the potential for drug targeting of protein assembly. This chapter reviews some of the important scaffolding events downstream of immunoreceptors with focus on signaling transduction through the T-cell receptor (TCR).

Selective inhibition of cell death in malignant vs normal B-cell precursors: implications for cAMP in development and treatment of BCP-ALL

“…In cells of the immune system, cAMP is well established as an important physiological signal transducer. 16 Lymphocytes possess GPCRs for catecholamines and prostaglandin E 2 (PGE 2 ), and engagement of these receptors by their respective ligands has been shown to exert a growth-inhibitory effect mediated by the elevation of cAMP levels. 17,18 ALL blasts have also been demonstrated to express functional PGE 2 receptors 19 ; however, the possible role of cAMP signaling in ALL physiology has yet to be determined.…”

High-resolution mapping of prostaglandin E2–dependent signaling networks identifies a constitutively active PKA signaling node in CD8+CD45RO+ T cells

“…On the basis of the reported immunomodulating role of PGE 2 , it is interesting to note the phosphorylation of proteins important in T-cell activation (reviewed in Torgersen et al 40 ). These include direct phosphorylation of CARMA1, FYN binding protein/ adhesion and degranulation promoting adapter protein, VASP, Nck, phospholipase C ␥, Wiskott-Aldrich syndrome protein-interacting protein, GADS, and nuclear factor of activated T cells cytoplasmic 2 (supplemental Table 2; supplemental data).…”

“…However, our set of phosphoproteomic data identifies PGE 2 -induced phosphorylation changes at previously uncharacterized sites on a series of proteins in the TCR signaling cascade, confirming the inhibitory potential of PGE 2 in respect to TCR signaling. 39 Proteins that are involved in the regulation of enzyme activity as well as protein complex formation downstream of TCR (reviewed in Torgersen et al 40 ) include CARMA1 (Ser441; 11-fold increase), phospholipase C ␥ (Ser1233; 10-fold increase), Wiskott-Aldrich syndrome proteininteracting protein (Ser340; 7-fold increase), VASP (Ser239; 6-fold increase), GADS (Thr262; 5-fold increase), nuclear factor of activated T cells cytoplasmic 2 (Ser236/243; 5-fold increase), FYN binding protein/adhesion and degranulation promoting adapter protein (Ser46; 4-fold increase), and Nck (Ser85; 4-fold increase) all of which constitute previously unnoticed sites of action in the PGE 2 signaling network (supplemental Tables 2-4; supplemental data). …”

Gene expression profiling identifies STAT3 as a novel pathway for immunomodulation by cholera toxin adjuvant

“…This intracellular second messenger is well known to ARTICLES regulate gene expression at the transcriptional level and could be important for the adjuvant function. 8 We, along with others, have previously studied the immunomodulating function of CT on B lymphocytes and found evidence for direct effects on isotype-switch differentiation and expression of costimulatory molecules. 9 Interestingly, CT strongly promoted sterile RNA transcripts and switching to IgG1 and IgE in interleukin (IL)-4 plus LPS-exposed murine IgM + B cells, suggesting that CT affected gene transcription.…”