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Does Ras Activate Raf and PI3K Allosterically?
Ruth Nussinov1,2, Chung-Jung Tsai1, Hyunbum Jang1
1Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, United States.
Abstract:
The mechanism through which oncogenic Ras activates its effectors is vastly important to resolve. If allostery is at play, then targeting allosteric pathways could help in quelling activation of MAPK (Raf/MEK/ERK) and PI3K (PI3K/Akt/mTOR) cell proliferation pathways. On the face of it, allosteric activation is reasonable: Ras binding perturbs the conformational ensembles of its effectors. Here, however, we suggest that at least for Raf, PI3K, and NORE1A (RASSF5), that is unlikely. Raf's long disordered linker dampens effective allosteric activation. Instead, we suggest that the high-affinity Ras-Raf binding relieves Raf's autoinhibition, shifting Raf's ensemble from the inactive to the nanocluster-mediated dimerized active state, as Ras also does for NORE1A. PI3K is recruited and allosterically activated by RTK (e.g., EGFR) at the membrane. Ras restrains PI3K's distribution and active site orientation. It stabilizes and facilitates PIP2 binding at the active site and increases the PI3K residence time at the membrane. Thus, RTKs allosterically activate PI3Kα; however, merging their action with Ras accomplishes full activation. Here we review their activation mechanisms in this light and draw attention to implications for their pharmacology.
Insights
Oncogenic Ras activation of Raf and PI3K is not primarily allosteric. Ras binding relieves Raf
Area of Science:
- Molecular Biology
- Cell Signaling
- Oncology
Background:
- Oncogenic Ras signaling pathways, including MAPK and PI3K, drive cell proliferation.
- Understanding Ras effector activation is crucial for developing targeted cancer therapies.
- Allosteric activation by Ras has been proposed as a key mechanism for effector engagement.
Purpose of the Study:
- To investigate the precise mechanisms by which oncogenic Ras activates its key effectors, Raf, PI3K, and NORE1A.
- To evaluate the role of allosteric regulation versus other mechanisms in Ras-mediated effector activation.
- To inform the development of novel pharmacological strategies targeting Ras-driven cancers.
Main Methods:
- Review of existing literature on Ras-effector interactions.
- Analysis of structural and biochemical data related to Ras, Raf, PI3K, and NORE1A.
- Mechanistic interpretation of Ras-mediated effector activation pathways.
Main Results:
- Ras-effector interactions, particularly with Raf and NORE1A, are unlikely to be primarily allosteric.
- Ras binding to Raf relieves autoinhibition, promoting a shift to an active dimerized state.
- Ras restrains PI3K distribution and enhances membrane residence time, contributing to full activation in concert with RTKs.
Conclusions:
- Ras activation of Raf and NORE1A involves relieving autoinhibition rather than direct allosteric modulation.
- Ras collaborates with RTKs to fully activate PI3K, influencing its localization and activity.
- These mechanistic insights have significant implications for the targeted therapy of Ras-mutated cancers.