Cargando…

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...

Descripción completa

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
_version_ 1784681987919839232
author Simanshu, Dhirendra K.
Morrison, Deborah K.
author_facet Simanshu, Dhirendra K.
Morrison, Deborah K.
author_sort Simanshu, Dhirendra K.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-8983508
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher American Association for Cancer Research
record_format MEDLINE/PubMed
spelling pubmed-89835082022-04-06 A Structure is Worth a Thousand Words: New Insights for RAS and RAF Regulation Simanshu, Dhirendra K. Morrison, Deborah K. Cancer Discov Reviews 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. American Association for Cancer Research 2022-04-01 2022-01-19 /pmc/articles/PMC8983508/ /pubmed/35046094 http://dx.doi.org/10.1158/2159-8290.CD-21-1494 Text en ©2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs International 4.0 License.
spellingShingle Reviews
Simanshu, Dhirendra K.
Morrison, Deborah K.
A Structure is Worth a Thousand Words: New Insights for RAS and RAF Regulation
title A Structure is Worth a Thousand Words: New Insights for RAS and RAF Regulation
title_full A Structure is Worth a Thousand Words: New Insights for RAS and RAF Regulation
title_fullStr A Structure is Worth a Thousand Words: New Insights for RAS and RAF Regulation
title_full_unstemmed A Structure is Worth a Thousand Words: New Insights for RAS and RAF Regulation
title_short A Structure is Worth a Thousand Words: New Insights for RAS and RAF Regulation
title_sort structure is worth a thousand words: new insights for ras and raf regulation
topic Reviews
url 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
work_keys_str_mv AT simanshudhirendrak astructureisworthathousandwordsnewinsightsforrasandrafregulation
AT morrisondeborahk astructureisworthathousandwordsnewinsightsforrasandrafregulation
AT simanshudhirendrak structureisworthathousandwordsnewinsightsforrasandrafregulation
AT morrisondeborahk structureisworthathousandwordsnewinsightsforrasandrafregulation