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

Small GTPases. 2021 May;12(3):209-225. doi: 10.1080/21541248.2020.1724596. Epub 2020 Feb 14.

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.

Keywords: Ras binding domain; cell signalling; network rewiring; proteomics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology*
  • Databases, Factual*
  • Humans
  • Intestine, Large / metabolism*
  • Protein Interaction Domains and Motifs*
  • Signal Transduction
  • Transcription Factors / metabolism*
  • ras Proteins / metabolism*

Substances

  • Transcription Factors
  • ras Proteins

Grants and funding

This work is part of the research program ‘Quantitative and systems analysis of (patho)physiological signalling networks’ with project number [16/FRL/3886], which is financed by Science Foundation Ireland (SFI) (to C. Kiel).