A comprehensive manually curated reaction map of RANKL/RANK-signaling pathway

Abstract

Receptor activator of nuclear factor-kappa B ligand (RANKL) is a member of tumor necrosis factor (TNF) superfamily that plays a key role in the regulation of differentiation, activation and survival of osteoclasts and also in tumor cell migration and bone metastasis. Osteoclast activation induced by RANKL regulates hematopoietic stem cell mobilization as part of homeostasis and host defense mechanisms thereby linking regulation of hematopoiesis with bone remodeling. Binding of RANKL to its receptor, Receptor activator of nuclear factor-kappa B (RANK) activates molecules such as NF-kappa B, mitogen activated protein kinase (MAPK), nuclear factor of activated T cells (NFAT) and phosphatidyl 3-kinase (PI3K). Although the molecular and cellular roles of these molecules have been reported previously, a systematic cataloging of the molecular events induced by RANKL/RANK interaction has not been attempted. Here, we present a comprehensive reaction map of the RANKL/RANK-signaling pathway based on an extensive manual curation of the published literature. We hope that the curated RANKL/RANK-signaling pathway model would enable new biomedical discoveries, which can provide novel insights into disease processes and development of novel therapeutic interventions.

Figure 1.

An overview of the RANKL pathway page in NetPath. RANKL pathway page in NetPath hosts the information on the number of molecules curated for RANKL pathway, statistics of the total number of molecules, link to RANKL pathway reactions and the list of genes which are differentially upregulated by RANKL/RANK pathway. Every molecule in the pathway page is linked to the corresponding NetPath molecule page which is further linked to Entrez gene, HPRD, OMIM and Swiss-Prot identifiers. The reaction page of the RANKL pathway contains the list of each type of reactions such as physical interactions, enzyme catalysis and transport with a brief description about the reactions with their PTM dependence or interacting regions/domains/motifs whenever it was available in literature. The list of curators and reviewers are provided in the RANKL pathway page with the details of the pathway authority. A comments tab is provided in the pathway page to invite the queries and suggestions from the community so as to update and improve RANKL pathway alike other pathways in NetPath.

Figure 2.

A high-confidence RANKL/RANK pathway reaction map using PathVisio. The RANKL/RANK pathway reaction map represents the high-confidence molecular reactions induced by the binding of RANKL homotrimer to its homotrimer receptor complex. The presented map of RANKL/RANK contains 43 proteins involved in 17 molecular associations, 24 enzyme catalysis reactions and four translocation events. The nodes and edges represent the molecules and their reactions respectively. A detailed legend representative of the information of different types of edges distinguished with various colors is provided. A downloadable version of this map is available with the description for each of the reactions and the inclusion criteria for selection of the reaction in the map at http://www.netpath.org/netslim/rankl_pathway.html.