期刊
FEBS JOURNAL
卷 -, 期 -, 页码 -出版社
WILEY
DOI: 10.1111/febs.16800
关键词
PP1C; RAF; RAS; RASopathy; SHOC2
RAF activation is a crucial step for signal transduction in the MAPK pathway. The SHOC2-MRAS-PP1C (SMP) holoenzyme complex, consisting of SHOC2, MRAS, and PP1C, plays a key role in activating RAF kinases. Recent research has provided valuable insights into the structure and function of the SMP complex, including its assembly, the impact of the nucleotide state of MRAS, and the involvement of SHOC2 and MRAS in PP1C activity and specificity. Understanding the SMP complex could lead to potential therapeutic strategies for RAS/RAF-driven cancers and RASopathies.
RAF activation is a key step for signalling through the mitogen-activated protein kinase (MAPK) pathway. The SHOC2 protein, along with MRAS and PP1C, forms a high affinity, heterotrimeric holoenzyme that activates RAF kinases by dephosphorylating a specific phosphoserine. Recently, our research, along with that of three other teams, has uncovered valuable structural and functional insights into the SHOC2-MRAS-PP1C (SMP) holoenzyme complex. In this structural snapshot, we review SMP complex assembly, the dependency on the bound-nucleotide state of MRAS, the substitution of MRAS by the canonical RAS proteins and the roles of SHOC2 and MRAS on PP1C activity and specificity. Furthermore, we discuss the effect of several RASopathy mutations identified within the SMP complex and explore potential therapeutic approaches for targeting the SMP complex in RAS/RAF-driven cancers and RASopathies.
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