Distinct Binding Preferences between Ras and Raf Family Members and the Impact on Oncogenic Ras Signaling.
Animals
Cell Proliferation
Cell Transformation, Neoplastic
/ genetics
Female
Gene Expression Regulation, Neoplastic
HEK293 Cells
HeLa Cells
Humans
Male
Mice
Mutation
NIH 3T3 Cells
Neoplasms
/ enzymology
Protein Binding
Protein Interaction Domains and Motifs
Protein Multimerization
Proto-Oncogene Proteins B-raf
/ genetics
Proto-Oncogene Proteins c-raf
/ genetics
Proto-Oncogene Proteins p21(ras)
/ genetics
Signal Transduction
/ genetics
Spheroids, Cellular
raf Kinases
/ genetics
ras Proteins
/ genetics
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
19 12 2019
19 12 2019
Historique:
received:
08
10
2018
revised:
22
07
2019
accepted:
05
09
2019
pubmed:
14
10
2019
medline:
20
2
2020
entrez:
14
10
2019
Statut:
ppublish
Résumé
The Ras GTPases are frequently mutated in human cancer, and, although the Raf kinases are essential effectors of Ras signaling, the tumorigenic properties of specific Ras-Raf complexes are not well characterized. Here, we examine the ability of individual Ras and Raf proteins to interact in live cells using bioluminescence resonance energy transfer (BRET) technology. We find that C-Raf binds all mutant Ras proteins with high affinity, whereas B-Raf exhibits a striking preference for mutant K-Ras. This selectivity is mediated by the acidic, N-terminal segment of B-Raf and requires the K-Ras polybasic region for high-affinity binding. In addition, we find that C-Raf is critical for mutant H-Ras-driven signaling and that events stabilizing B-Raf/C-Raf dimerization, such as Raf inhibitor treatment or certain B-Raf mutations, can allow mutant H-Ras to engage B-Raf with increased affinity to promote tumorigenesis, thus revealing a previously unappreciated role for C-Raf in potentiating B-Raf function.
Identifiants
pubmed: 31606273
pii: S1097-2765(19)30689-6
doi: 10.1016/j.molcel.2019.09.004
pmc: PMC7001861
mid: NIHMS1540003
pii:
doi:
Substances chimiques
KRAS protein, human
0
BRAF protein, human
EC 2.7.11.1
Braf protein, mouse
EC 2.7.11.1
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
Proto-Oncogene Proteins c-raf
EC 2.7.11.1
Raf1 protein, human
EC 2.7.11.1
Raf1 protein, mouse
EC 2.7.11.1
raf Kinases
EC 2.7.11.1
HRAS protein, human
EC 3.6.5.2
Hras protein, mouse
EC 3.6.5.2
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
ras Proteins
EC 3.6.5.2
Types de publication
Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
872-884.e5Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM124233
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC010329-19
Pays : United States
Organisme : CCR NIH HHS
ID : HHSN261200800001C
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261200800001E
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC010329
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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