Proximal Protein Interaction Landscape of RAS Paralogs
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Published on: July 17, 2019
Benoît Béganton1,2, Etienne Coyaud3, Estelle M N Laurent3
1CHU Montpellier, Department of Pathology and Onco-Biology, Univ Montpellier, 34295 Montpellier, France.
Abstract:
RAS proteins (KRAS, NRAS and HRAS) are frequently activated in different cancer types (e.g., non-small cell lung cancer, colorectal cancer, melanoma and bladder cancer). For many years, their activities were considered redundant due to their high degree of sequence homology (80% identity) and their shared upstream and downstream protein partners. However, the high conservation of the Hyper-Variable-Region across mammalian species, the preferential activation of different RAS proteins in specific tumor types and the specific post-translational modifications and plasma membrane-localization of each paralog suggest they could ensure discrete functions. To gain insights into RAS proteins specificities, we explored their proximal protein-protein interaction landscapes using the proximity-dependent biotin identification technology (BioID) in Flp-In T-REx 293 cell lines stably transfected and inducibly expressing wild type KRAS4B, NRAS or HRAS. We identified more than 800 high-confidence proximal interactors, allowing us to propose an unprecedented comparative analysis of wild type RAS paralogs protein networks. These data bring novel information on poorly characterized RAS functions, e.g., its putative involvement in metabolic pathways, and on shared as well as paralog-specific protein networks that could partially explain the complexity of RAS functions. These networks of protein interactions open numerous avenues to better understand RAS paralogs biological activities.
Insights
RAS proteins (KRAS, NRAS, HRAS) have distinct functions despite sequence similarity. Proximity-dependent biotin identification revealed unique protein interaction networks for each RAS paralog, offering insights into their specific roles in cancer.
Area of Science:
- Molecular Biology
- Oncology
- Proteomics
Background:
- RAS proteins (KRAS, NRAS, HRAS) are frequently activated in various cancers.
- Despite high sequence homology, discrete functions are suggested by specific tumor activation and localization.
- Previous studies often considered RAS paralog activities redundant.
Purpose of the Study:
- To investigate the specific protein-protein interaction landscapes of wild-type KRAS4B, NRAS, and HRAS.
- To identify paralog-specific and shared interactors to understand RAS functional diversities.
- To uncover novel functions of RAS proteins, including potential roles in metabolic pathways.
Main Methods:
- Utilized proximity-dependent biotin identification (BioID) technology.
- Employed Flp-In T-REx 293 cell lines with inducible expression of wild-type RAS paralogs.
- Performed comparative analysis of proximal protein-protein interaction networks.
Main Results:
- Identified over 800 high-confidence proximal interactors for KRAS4B, NRAS, and HRAS.
- Generated a comprehensive comparative map of wild-type RAS paralog protein networks.
- Uncovered novel insights into poorly characterized RAS functions, including metabolic pathway involvement.
Conclusions:
- RAS paralogs possess distinct protein interaction networks, contributing to their specific biological activities.
- These identified networks provide a foundation for understanding the complexity of RAS functions in normal and cancerous cells.
- The findings open new avenues for therapeutic strategies targeting specific RAS paralogs in cancer treatment.
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