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A Structure is Worth a Thousand Words: New Insights for RAS and RAF Regulation

The RAS GTPases are frequently mutated in human cancer, with KRAS being the predominant tumor driver. For many years, it has been known that the structure and function of RAS are integrally linked, as structural changes induced by GTP binding or mutational events determine the ability of RAS to inte...

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Detalles Bibliográficos
Autores principales: Simanshu, Dhirendra K., Morrison, Deborah K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8983508/
https://www.ncbi.nlm.nih.gov/pubmed/35046094
http://dx.doi.org/10.1158/2159-8290.CD-21-1494
Descripción
Sumario:The RAS GTPases are frequently mutated in human cancer, with KRAS being the predominant tumor driver. For many years, it has been known that the structure and function of RAS are integrally linked, as structural changes induced by GTP binding or mutational events determine the ability of RAS to interact with regulators and effectors. Recently, a wealth of information has emerged from structures of specific KRAS mutants and from structures of multiprotein complexes containing RAS and/or RAF, an essential effector of RAS. These structures provide key insights regarding RAS and RAF regulation as well as promising new strategies for therapeutic intervention. SIGNIFICANCE: The RAS GTPases are major drivers of tumorigenesis, and for RAS proteins to exert their full oncogenic potential, they must interact with the RAF kinases to initiate ERK cascade signaling. Although binding to RAS is typically a prerequisite for RAF to become an activated kinase, determining the molecular mechanisms by which this interaction results in RAF activation has been a challenging task. A major advance in understanding this process and RAF regulation has come from recent structural studies of various RAS and RAF multiprotein signaling complexes, revealing new avenues for drug discovery.