Molecular Cell
Volume 76, Issue 6, 19 December 2019, Pages 872-884.e5
Journal home page for Molecular Cell

Article
Distinct Binding Preferences between Ras and Raf Family Members and the Impact on Oncogenic Ras Signaling

https://doi.org/10.1016/j.molcel.2019.09.004Get rights and content
Under an Elsevier user license
open archive

Highlights

  • C-Raf binds all Ras proteins equivalently, but B-Raf exhibits selectivity for K-Ras

  • Raf N-terminal segments and Ras HVR sequences determine binding preferences

  • C-Raf is critical for downstream transmission of H-Ras-driven signaling

  • Events that increase B-Raf/C-Raf dimerization augment the B-Raf/H-Ras interaction

Summary

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.

Cited by (0)

5

Lead Contact