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Updated: Feb 3, 2026
Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
Structural snapshots of RAF kinase interactions
Soheila Rezaei Adariani1, Marcel Buchholzer1, Mohammad Akbarzadeh1
1Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
Abstract:
RAF (rapidly accelerated fibrosarcoma) Ser/Thr kinases (ARAF, BRAF, and CRAF) link the RAS (rat sarcoma) protein family with the MAPK (mitogen-activated protein kinase) pathway and control cell growth, differentiation, development, aging, and tumorigenesis. Their activity is specifically modulated by protein-protein interactions, post-translational modifications, and conformational changes in specific spatiotemporal patterns via various upstream regulators, including the kinases, phosphatase, GTPases, and scaffold and modulator proteins. Dephosphorylation of Ser-259 (CRAF numbering) and dissociation of 14-3-3 release the RAF regulatory domains RAS-binding domain and cysteine-rich domain for interaction with RAS-GTP and membrane lipids. This, in turn, results in RAF phosphorylation at Ser-621 and 14-3-3 reassociation, followed by its dimerization and ultimately substrate binding and phosphorylation. This review focuses on structural understanding of how distinct binding partners trigger a cascade of molecular events that induces RAF kinase activation.
Insights
RAF kinases regulate cell growth and tumorigenesis by linking RAS proteins to the MAPK pathway. This review details how protein interactions and modifications activate RAF kinase signaling.
Area of Science:
- Molecular Biology
- Cell Signaling
- Biochemistry
Background:
- RAF (rapidly accelerated fibrosarcoma) kinases (ARAF, BRAF, CRAF) are key regulators of the RAS-MAPK pathway.
- This pathway controls fundamental cellular processes including growth, differentiation, and tumorigenesis.
- RAF kinase activity is precisely controlled by various upstream regulators and post-translational modifications.
Purpose of the Study:
- To provide a structural understanding of RAF kinase activation.
- To elucidate the molecular events triggered by distinct binding partners.
- To detail the cascade leading to RAF kinase activation.
Main Methods:
- This review synthesizes existing structural and biochemical data.
- Focuses on the interplay between RAF proteins, RAS-GTP, 14-3-3 proteins, and regulatory lipids.
- Examines the conformational changes and post-translational modifications involved.
Main Results:
- Dephosphorylation at Ser-259 and 14-3-3 dissociation enable RAS-GTP binding.
- Subsequent phosphorylation at Ser-621 and reassociation with 14-3-3 promote dimerization.
- Dimerization is essential for substrate binding and downstream signaling.
Conclusions:
- Distinct binding partners initiate a cascade of molecular events leading to RAF kinase activation.
- Understanding these structural mechanisms is crucial for deciphering RAF-mediated cellular processes.
- This knowledge may inform therapeutic strategies targeting RAF-driven diseases.
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