Differential ligand-signaling network of CCL19/CCL21-CCR7 system

Abstract

Chemokine (C-C motif) receptor 7 (CCR7), a class A subtype G-Protein Coupled Receptor (GPCR), is involved in the migration, activation and survival of multiple cell types including dendritic cells, T cells, eosinophils, B cells, endothelial cells and different cancer cells. Together, CCR7 signaling system has been implicated in diverse biological processes such as lymph node homeostasis, T cell activation, immune tolerance, inflammatory response and cancer metastasis. CCL19 and CCL21, the two well-characterized CCR7 ligands, have been established to be differential in their signaling through CCR7 in multiple cell types. Although the differential ligand signaling through single receptor have been suggested for many receptors including GPCRs, there exists no resource or platform to analyse them globally. Here, first of its kind, we present the cell-type-specific differential signaling network of CCL19/CCL21-CCR7 system for effective visualization and differential analysis of chemokine/GPCR signaling. Database URL: http:// www. netpath. org/ pathways? path_ id= NetPath_ 46.

Figure 1.

Cell-type-specific differential-ligand network map of CCL19/CCL21-CCR7 signaling. The network map of CCR7 signaling pathway reactions induced by its ligands CCL19 and CCL21 that are experimentally identified in multiple cell types are represented using PathVisio. The topology of the network is devised based on the mutants, inhibitors, activators and silencing approaches. The edges represent the reactions and nodes represent the molecules. Molecules italicized represent the genes transcriptionally regulated by CCR7 signaling with red indicating the upregulated genes and green, the downregulated genes. The edges are distinguished by colors to differentiate different types of reactions such as protein–protein interactions, Post-translational modifications (PTMs) and translocation reactions. The PTMs of each protein are represented with the site and residue of modification mapped to the corresponding RefSeq accessions. The differential signaling by CCL19 and CCL21 in multiple cell types are also represented using colored square (CCL19), triangle (CCL21) and circle (not differential for both CCL19 and CCL21) shapes. Blue represent the reactions to be unique to one of them but not induced by the other whereas red indicates higher for one and the green indicates studied only in one of them and not the other and hence not to be considered differential.