CCDC6-RET fusion protein regulates Ras/MAPK signaling through the fusion- GRB2-SHC1 signal niche.
Proc Natl Acad Sci U S A
; 121(23): e2322359121, 2024 Jun 04.
Article
em En
| MEDLINE
| ID: mdl-38805286
ABSTRACT
Rearranged during transfection (RET) rearrangement oncoprotein-mediated Ras/MAPK signaling cascade is constitutively activated in cancers. Here, we demonstrate a unique signal niche. The niche is a ternary complex based on the chimeric RET liquid-liquid phase separation. The complex comprises the rearranged kinase (RET fusion); the adaptor (GRB2), and the effector (SHC1). Together, they orchestrate the Ras/MAPK signal cascade, which is dependent on tyrosine kinase. CCDC6-RET fusion undergoes LLPS requiring its kinase domain and its fusion partner. The CCDC6-RET fusion LLPS promotes the autophosphorylation of RET fusion, with enhanced kinase activity, which is necessary for the formation of the signaling niche. Within the signal niche, the interactions among the constituent components are reinforced, and the signal transduction efficiency is amplified. The specific RET fusion-related signal niche elucidates the mechanism of the constitutive activation of the Ras/MAPK signaling pathway. Beyond just focusing on RET fusion itself, exploration of the ternary complex potentially unveils a promising avenue for devising therapeutic strategies aimed at treating RET fusion-driven diseases.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Fusão Oncogênica
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Proteínas ras
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Sistema de Sinalização das MAP Quinases
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Proteínas Proto-Oncogênicas c-ret
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Proteína Adaptadora GRB2
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Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src
Limite:
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article