Analysis of context-specific KRAS-effector (sub)complexes in Caco-2 cells.
Journal
Life science alliance
ISSN: 2575-1077
Titre abrégé: Life Sci Alliance
Pays: United States
ID NLM: 101728869
Informations de publication
Date de publication:
05 2023
05 2023
Historique:
received:
12
08
2022
revised:
24
02
2023
accepted:
27
02
2023
entrez:
9
3
2023
pubmed:
10
3
2023
medline:
14
3
2023
Statut:
epublish
Résumé
Ras is a key switch controlling cell behavior. In the GTP-bound form, Ras interacts with numerous effectors in a mutually exclusive manner, where individual Ras-effectors are likely part of larger cellular (sub)complexes. The molecular details of these (sub)complexes and their alteration in specific contexts are not understood. Focusing on KRAS, we performed affinity purification (AP)-mass spectrometry (MS) experiments of exogenously expressed FLAG-KRAS WT and three oncogenic mutants ("genetic contexts") in the human Caco-2 cell line, each exposed to 11 different culture media ("culture contexts") that mimic conditions relevant in the colon and colorectal cancer. We identified four effectors present in complex with KRAS in all genetic and growth contexts ("context-general effectors"). Seven effectors are found in KRAS complexes in only some contexts ("context-specific effectors"). Analyzing all interactors in complex with KRAS per condition, we find that the culture contexts had a larger impact on interaction rewiring than genetic contexts. We investigated how changes in the interactome impact functional outcomes and created a Shiny app for interactive visualization. We validated some of the functional differences in metabolism and proliferation. Finally, we used networks to evaluate how KRAS-effectors are involved in the modulation of functions by random walk analyses of effector-mediated (sub)complexes. Altogether, our work shows the impact of environmental contexts on network rewiring, which provides insights into tissue-specific signaling mechanisms. This may also explain why KRAS oncogenic mutants may be causing cancer only in specific tissues despite KRAS being expressed in most cells and tissues.
Identifiants
pubmed: 36894174
pii: 6/5/e202201670
doi: 10.26508/lsa.202201670
pmc: PMC9998658
pii:
doi:
Substances chimiques
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
KRAS protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2023 Ternet et al.
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