TSLP signaling pathway map: a platform for analysis of TSLP-mediated signaling

Abstract

Thymic stromal lymphopoietin (TSLP) is a four-helix bundle cytokine that plays a critical role in the regulation of immune responses and in the differentiation of hematopoietic cells. TSLP signals through a heterodimeric receptor complex consisting of an interleukin-7 receptor α chain and a unique TSLP receptor (TSLPR) [also known as cytokine receptor-like factor 2 (CRLF2)]. Cellular targets of TSLP include dendritic cells, B cells, mast cells, regulatory T (Treg) cells and CD4+ and CD8+ T cells. The TSLP/TSLPR axis can activate multiple signaling transduction pathways including the JAK/STAT pathway and the PI-3 kinase pathway. Aberrant TSLP/TSLPR signaling has been associated with a variety of human diseases including asthma, atopic dermatitis, nasal polyposis, inflammatory bowel disease, eosinophilic eosophagitis and, most recently, acute lymphoblastic leukemia. A centralized resource of the TSLP signaling pathway cataloging signaling events is not yet available. In this study, we present a literature-annotated resource of reactions in the TSLP signaling pathway. This pathway map is publicly available through NetPath (http://www.netpath.org/), an open access signal transduction pathway resource developed previously by our group. This map includes 236 molecules and 252 reactions that are involved in TSLP/TSLPR signaling pathway. We expect that the TSLP signaling pathway map will provide a rich resource to study the biology of this important cytokine as well as to identify novel therapeutic targets for diseases associated with dysregulated TSLP/TSLPR signaling. Database URL: http://www.netpath.org/pathways?path_id=NetPath_24.

Figure 1.

An overview of the TSLP pathway page in NetPath. The TSLP pathway page in NetPath provides statistics pertaining to the number of molecules curated, links to TSLP pathway reactions and a list of genes that are differentially regulated by TSLP. Each 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 TSLP pathway contains a list of each type of reaction such as physical interactions, enzyme catalysis or transport with a brief description of the reactions including their PTM dependence or interacting regions/domains/motifs whenever available in literature. The list of curators and reviewers are provided in the TSLP pathway page with the details of the pathway authority. A comments tab is also provided.

Figure 2.

A high-confidence reaction map of the TSLP signaling pathway. The pathway reaction map contains 37 proteins involved in 9 molecular associations, 21 enzyme catalysis reactions and 7 translocation events. Apart from the reactions selected based on NetSlim criteria, we have also included 2 enzyme complexes namely MTORC1 and PI3-kinase complex based on the inhibitor assays that confirmed their role in TSLP signaling and our phosphoproteomics study (the nodes highlighted in green). The edges representing the relationships between nodes are explained in the legend.