Abstract
RAS oncogenes are among the most commonly mutated proteins in human cancers. They regulate a wide range of effector pathways that control cell proliferation, survival, differentiation, migration and metabolic status. Including aberrations in these pathways, RAS-dependent signaling is altered in more than half of human cancers. Targeting mutant RAS proteins and their downstream oncogenic signaling pathways has been elusive. However, recent results comprising detailed molecular studies, large scale omics studies and computational modeling have painted a new and more comprehensive portrait of RAS signaling that helps us to understand the intricacies of RAS, how its physiological and pathophysiological functions are regulated, and how we can target them. Here, we review these efforts particularly trying to relate the detailed mechanistic studies with global functional studies. We highlight the importance of computational modeling and data integration to derive an actionable understanding of RAS signaling that will allow us to design new mechanism-based therapies for RAS mutated cancers.
Highlights
Since the discovery of retroviruses transducing RAS oncogenes in 1964 [1], huge research efforts have been spent on understanding what RAS does [2]
guanosine triphosphate (GTP) binding is stimulated by Guanine nucleotide Exchange Factors (GEFs), while GTP hydrolysis is accelerated by GTPase Activating Proteins (GAPs)
We have shown previously that increasing the concentration of the effector RIN1 in cultured cells decreased the phosphorylation of CRAF and its downstream targets, which was enhanced even further when RIN1 was artificially localized to the plasma membrane (PM) using a CAAX box [24]
Summary
Since the discovery of retroviruses transducing RAS oncogenes in 1964 [1], huge research efforts have been spent on understanding what RAS does [2]. In the GTP bound form, RAS switches into a conformation where it can bind and activate effector proteins which transduce a wide range of signals that regulate almost any aspect of cellular physiology [6]. The oncogenic mutations are thought to lock RAS in the active conformation, causing constitutive signaling through these downstream effector pathways, most prominently the RAF and phosphoinositide-3 kinase (PI3K) pathways [6]. The take-home lesson was that we need to understand RAS signaling in much want greater successfully target it.
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
