Abstract
Oncogenic RAS (Rat sarcoma) mutations drive more than half of human cancers, and RAS inhibition is the holy grail of oncology. Thirty years of relentless efforts and harsh disappointments have taught us about the intricacies of oncogenic RAS signalling that allow us to now get a pharmacological grip on this elusive protein. The inhibition of effector pathways, such as the RAF-MEK-ERK pathway, has largely proven disappointing. Thus far, most of these efforts were aimed at blocking the activation of ERK. Here, we discuss RAF-dependent pathways that are regulated through RAF functions independent of catalytic activity and their potential role as targets to block oncogenic RAS signalling. We focus on the now well documented roles of RAF kinase-independent functions in apoptosis, cell cycle progression and cell migration.
Highlights
Genes 2021, 12, 553. https://doi.org/RAS (Rat sarcoma) proteins are mutated in ca. 20% of all human cancers, with prevalent and deadly cancers such as colorectal, lung and pancreatic cancer featuring40%, 20–40%, and >90% RAS mutations [1]
The kinase-independent role of RAF1 as a negative regulator of apoptosis is well characterized, and here, we review how RAF1 regulates the three effector proteins identified so far—Apoptosis Signal-Regulating Kinase 1 (ASK1), Mammalian STE20-Like Kinase 2 (MST2) and BAD
Extensive work from our group using a combination of interaction proteomics experiments with molecular and functional experiments allowed us to map the signalling pathway that is activated by MST2 upon release from RAF1 inhibitory binding (Figure 4)
Summary
RAS (Rat sarcoma) proteins are mutated in ca. 20% of all human cancers, with prevalent and deadly cancers such as colorectal, lung and pancreatic cancer featuring. Oncogenic mutations keep RAS proteins in the GTP bound state resulting in the constitutive activation of pathways that stimulate cell proliferation, survival, invasiveness and drug resistance. A main effector of oncogenic RAS signalling is the RAFMEK-ERK pathway (Figure 1). This pathway is a cascade of three kinases. This mechanism leads to a allostericallythe transactivate the kinase of the other protomer [7,8] This mechanism paradoxical activation of ERK in RAS-mutated cells in response. RAF inhibitors leads to a paradoxical activation of ERK in RAS-mutated cells intoresponse to RAF[9,10,11]. We summarize how these kinase-independent RAF functions contribute toexplore cancer and howbe they could be targeted. We discuss them in relation to their main function
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