ArticleProceedings of the National Academy of Sciences of the United States of America2019
SHOC2 complex-driven RAF dimerization selectively contributes to ERK pathway dynamics.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 51 citations in OpenAlex.
- Restoring the 14-3-3/CRAF regulatory interaction in Noonan syndrome using molecular glues.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- A naturally synonymous mutation modulates an ERK-centered regulatory network to mediate thermotolerance divergence in Crassostrea oysters.Communications biology · 2026Article
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- Targeting Kinase Suppressor of Ras 1 (KSR1) for Cancer Therapy.Pharmaceutics · 2025Review
- The Raf/LIN-45 C-terminal distal tail segment negatively regulates signaling in Caenorhabditis elegans.Genetics · 2024Article
- The expression of congenital Shoc2 variants induces AKT-dependent crosstalk activation of the ERK1/2 pathway.Human molecular genetics · 2024Article
- SIRT4 as a novel interactor and candidate suppressor of C-RAF kinase in MAPK signaling.Life science alliance · 2024Article
- Targeting RAF dimers in RAS mutant tumors: From biology to clinic.Acta pharmaceutica Sinica. B · 2024Review
- The role of CRAF in cancer progression: from molecular mechanisms to precision therapies.Nature reviews. Cancer · 2024Review
- The evolution of BRAF-targeted therapies in melanoma: overcoming hurdles and unleashing novel strategies.Frontiers in oncology · 2024Review
- A guide to ERK dynamics, part 1: mechanisms and models.The Biochemical journal · 2023Article
- Targeting protein methylation in pancreatic cancer cells results in KRAS signaling imbalance and inhibition of autophagy.Cell death & disease · 2023Article
- Biological insights in non-small cell lung cancer.Cancer biology & medicine · 2023Review
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- Localized immune surveillance of primary melanoma in the skin deciphered through executable modeling.Science advances · 2023Article
- Targeted therapies for KRAS-mutant non-small cell lung cancer: from preclinical studies to clinical development-a narrative review.Translational lung cancer research · 2023Review
- Hyperphosphorylation of hepatic proteome characterizes nonalcoholic fatty liver disease in S-adenosylmethionine deficiency.iScience · 2023Article
- Article
- Targeting KRAS in PDAC: A New Way to Cure It?Cancers · 2022Review
- Structure of the SHOC2-MRAS-PP1C complex provides insights into RAF activation and Noonan syndrome.Nature structural & molecular biology · 2022Article
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Authors and funding
11 authors at 2 institutions in 2 countries.
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Abstract
Despite the crucial role of RAF kinases in cell signaling and disease, we still lack a complete understanding of their regulation. Heterodimerization of RAF kinases as well as dephosphorylation of a conserved "S259" inhibitory site are important steps for RAF activation but the precise mechanisms and dynamics remain unclear. A ternary complex comprised of SHOC2, MRAS, and PP1 (SHOC2 complex) functions as a RAF S259 holophosphatase and gain-of-function mutations in SHOC2, MRAS, and PP1 that promote complex formation are found in Noonan syndrome. Here we show that SHOC2 complex-mediated S259 RAF dephosphorylation is critically required for growth factor-induced RAF heterodimerization as well as for MEK dissociation from BRAF. We also uncover SHOC2-independent mechanisms of RAF and ERK pathway activation that rely on N-region phosphorylation of CRAF. In DLD-1 cells stimulated with EGF, SHOC2 function is essential for a rapid transient phase of ERK activation, but is not required for a slow, sustained phase that is instead driven by palmitoylated H/N-RAS proteins and CRAF. Whereas redundant SHOC2-dependent and -independent mechanisms of RAF and ERK activation make SHOC2 dispensable for proliferation in 2D, KRAS mutant cells preferentially rely on SHOC2 for ERK signaling under anchorage-independent conditions. Our study highlights a context-dependent contribution of SHOC2 to ERK pathway dynamics that is preferentially engaged by KRAS oncogenic signaling and provides a biochemical framework for selective ERK pathway inhibition by targeting the SHOC2 holophosphatase.
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