The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research. Previously known as our Top 10 Cancer Research Publications, it is curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.
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Hauseman, Z.J., Fodor, M., Dhembi, A. et al. Nature 609, 416–423 (2022).
doi: 10.1038/s41586-022-05086-1.
Summary of findings
Given its central role in cell signaling and oncogenesis, Ras is one of the most studied molecules in biology and many RAS-interacting effector proteins have been described. However, only a handful of structures are available for RAS/effector complexes, limiting our understanding of intricate RAS functions in pathogenic conditions. In a recent Nature paper, Hauseman et al. provide a high-resolution X-ray structure of the SHOC2-MRAS-PP1 (SMP) holophosphatase complex responsible for an essential step in the activation of the MAPK signaling pathway, via dephosphorylation of a key regulatory site in RAF proteins that enables RAF dimerization and subsequent activation. The importance of the SMP complex has been discovered in the context of germline gain-of-function mutations that cause Rasopathies, a family of developmental syndromes with aberrant MAPK pathway activation. Recently, the SMP complex has become the focus of intense interest as a potential pharmacologic target in oncology. The authors reveal a highly cooperative assembly between the three members of the complex, with Rasopathy mutations mapping to protein-protein interfaces resulting in increased complex formation, RAF de-phosphorylation and MAPK pathway activity. Significantly, they show that not only the preferred non-canonical MRAS but also the canonical RAS isoforms can also form, albeit with reduced cooperativity, functional ternary complexes with SHOC2-PP1. Since the SMP complex assembly is dependent on the nucleotide-loading state of RAS, which is influenced by upstream pathway activation but also, in a constitutive manner, by oncogenic mutations on canonical RAS proteins, the authors suggest that in such conditions the activated or oncogenic canonical RAS isoforms can substitute for the non-canonical wild-type MRAS in the complex.
Future Impact of the Findings
An important implication arising from this work is that constitutively activated RAS-mutant proteins could simultaneously act on and recruit separate subunits of RAF and SHOC2-PP1 to sustain oncogenic proliferation. Publicly available large cancer genetic screens support these findings showing significant co-dependencies between SHOC2 and canonical RAS proteins within cancer models expressing RAS oncogenic mutations. In summary, this publication provides molecular insights on important aspects of RAS biology and offer a resource for possible therapeutic interventions in both Rasopathies and RAS-mutated cancers.
