The gastrin and cholecystokinin receptors mediated signaling network: a scaffold for data analysis and new hypotheses on regulatory mechanisms

Abstract

BackgroundThe gastrointestinal peptide hormones cholecystokinin and gastrin exert their biological functions via cholecystokinin receptors CCK1R and CCK2R respectively. Gastrin, a central regulator of gastric acid secretion, is involved in growth and differentiation of gastric and colonic mucosa, and there is evidence that it is pro-carcinogenic. Cholecystokinin is implicated in digestion, appetite control and body weight regulation, and may play a role in several digestive disorders.ResultsWe performed a detailed analysis of the literature reporting experimental evidence on signaling pathways triggered by CCK1R and CCK2R, in order to create a comprehensive map of gastrin and cholecystokinin-mediated intracellular signaling cascades. The resulting signaling map captures 413 reactions involving 530 molecular species, and incorporates the currently available knowledge into one integrated signaling network. The decomposition of the signaling map into sub-networks revealed 18 modules that represent higher-level structures of the signaling map. These modules allow a more compact mapping of intracellular signaling reactions to known cell behavioral outcomes such as proliferation, migration and apoptosis. The integration of large-scale protein-protein interaction data to this literature-based signaling map in combination with topological analyses allowed us to identify 70 proteins able to increase the compactness of the map. These proteins represent experimentally testable hypotheses for gaining new knowledge on gastrin- and cholecystokinin receptor signaling. The CCKR map is freely available both in a downloadable, machine-readable SBML-compatible format and as a web resource through PAYAO (http://sblab.celldesigner.org:18080/Payao11/bin/).ConclusionWe have demonstrated how a literature-based CCKR signaling map together with its protein interaction extensions can be analyzed to generate new hypotheses on molecular mechanisms involved in gastrin- and cholecystokinin-mediated regulation of cellular processes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-015-0181-z) contains supplementary material, which is available to authorized users.

IL-1β-induced modulation of gene expression profile in human dermal fibroblasts: the effects of Thai herbal Sahatsatara formula, piperine and gallic acid possessing antioxidant properties

“…Previous evidence showed that IL-1β had the potential to upregulate important genes including NFKBIA and IL-8 involved in activation of NF-кB cascade associated with CCKR signaling [34, 35], as well as IL-6 and IL-8, the critical pro-inflammatory mediators, involved in interleukin signaling. Our findings also indicated the effects of IL-1β on CCKR and prostaglandins (Additional file 3: Table 1) postulated to be involved in pain sensitization [36].…”

Neuropilin‐2 contributes to tumor progression in preclinical models of small intestinal neuroendocrine tumors

“…Lastly, CCKR pathway enrichment hints a novel role of NRP-2 in regulating hormone signaling in neuroendocrine cells. Indeed CCKR signaling pathway is activated by gastrin and cholecystokinin to ultimately promote cell proliferation and migration [49]. This finding could obviously have clinical significance in the context of NETs.…”

Scientific knowledge in the age of computation: Explicated, computable and manageable?

“…To better understand what happens inside mammalian cells stimulated by gastrin (Figure 1), the molecular biologist and GABI member 'Luke' collected "published knowledge" about all cellular components (genes, proteins, RNAs, metabolites) described to respond to gastrin in different experimental systems (different mammalian cell lines, from different organisms, at different conditions) (field notes, September 2012). Luke created a "knowledge assembly" model, operating with assumptions about the extractability and compose-ability of biological "knowledge", across experimental contexts (Tripathi et al 2015). In publications the model is referred to as a "signalling network" and "signalling map" primarily, instead of a "knowledge assembly" model, which was how the model was described in conversation.…”

“…The model encompasses a total of 530 proteins and genes (various shapes) linked by 413 interactions (lines). The entity names are hyperlinked to standard bioontologies and databases, and causal regulatory information is connected to PubMed IDs of the scientific articles from which the information was collected (Tripathi et al 2015).…”

“…On the left hand panel we see a coding of map "points" tagging model components that group members discussed: the tagsets used are 'OK' (green),'DISCUSSION' (yellow), 'INCORRECT' (red) and 'IMPLEMENTED' (blue). (Reproduced with permission, Tripathi et al 2015 , figure 1) 2.5. KM as epistemically productive and practice-dependent Sabina Leonelli (2014) argues that the prospects of fully automating and replacing the capacities of scientists to assess and interpret data are highly doubtful but that computational tools facilitate collaborative thinking among working teams of scientists (399)(400).…”