Analysis of Ras-effector interaction competition in large intestine and colorectal cancer context

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Title: Analysis of Ras-effector interaction competition in large intestine and colorectal cancer context
Authors: Ibáňez Gaspar, VerónicaCatozzi, SimonaTernet, CamilleLuthert, Philip J.Kiel, Christina
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Date: 14-Feb-2020
Online since: 2021-01-25T07:05:45Z
Abstract: Cancer is the second leading cause of death globally, and colorectal cancer (CRC) is among the five most common cancers. The small GTPase KRAS is an oncogene that is mutated in ~30% of all CRCs. Pharmacological treatments of CRC are currently unsatisfactory, but much hope rests on network-centric approaches to drug development and cancer treatment. These approaches, however, require a better understanding of how networks downstream of Ras oncoproteins are connected in a particular tissue context–here colon and CRC. Previously we have shown that competition for binding to a ‘hub’ protein, such as Ras, can induce a rewiring of signal transduction networks. In this study, we analysed 56 established and predicted effectors that contain a structural domain with the potential ability to bind to Ras oncoproteins and their link to pathways coordinating intestinal homoeostasis and barrier function. Using protein concentrations in colon tissue and Ras-effector binding affinities, a computational network model was generated that predicted how effectors differentially and competitively bind to Ras in colon context. The model also predicted both qualitative and quantitative changes in Ras-effector complex formations with increased levels of active Ras–to simulate its upregulation in cancer–simply as an emergent property of competition for the same binding interface on the surface of Ras. We also considered how the number of Ras-effector complexes at the membrane can be increased by additional domains present in some effectors that are recruited to the membrane in response to specific conditions (inputs/stimuli/growth factors) in colon context and CRC.
Funding Details: Science Foundation Ireland
Type of material: Journal Article
Publisher: Taylor & Francis
Journal: Small GTPases
Volume: 12
Issue: 3
Start page: 209
End page: 225
Copyright (published version): 2020 the Authors
Keywords: Colo-rectal cancerCancerDigestive diseasesRas binding domainProteomicCell signallingNetwork rewiring
DOI: 10.1080/21541248.2020.1724596
Language: en
Status of Item: Peer reviewed
ISSN: 2154-1248
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Appears in Collections:Conway Institute Research Collection
SBI Research Collection
Medicine Research Collection

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