CCDC6-RET fusion protein regulates Ras/MAPK signaling through the fusion- GRB2-SHC1 signal niche.

Src Homology 2 Domain-Containing, Transforming Protein 1 / metabolism Humans GRB2 Adaptor Protein / metabolism ras Proteins / metabolism Proto-Oncogene Proteins c-ret / metabolism MAP Kinase Signaling System Oncogene Proteins, Fusion / metabolism Signal Transduction Phosphorylation
CCDC6-RET fusion protein kinase liquid–liquid phase separation signal niche

Journal

Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876

Informations de publication

Date de publication:
04 Jun 2024
Historique:
medline: 28 5 2024
pubmed: 28 5 2024
entrez: 28 5 2024
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1073/pnas.2322359121 PMID: 38805286
pubmed: 38805286
doi: 10.1073/pnas.2322359121
doi:

Substances chimiques

Src Homology 2 Domain-Containing, Transforming Protein 1 0
GRB2 Adaptor Protein 0
SHC1 protein, human 0
ras Proteins EC 3.6.5.2
Proto-Oncogene Proteins c-ret EC 2.7.10.1
Oncogene Proteins, Fusion 0
GRB2 protein, human 0
RET protein, human EC 2.7.10.1

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

e2322359121

Subventions

Organisme : MOST | National Natural Science Foundation of China (NSFC)
ID : 32000363
Organisme : MOST | NSFC | NSFC-Zhejiang Joint Fund | | Natural Science Foundation of Zhejiang Province (ZJNSF)
ID : LQ21C060006

Déclaration de conflit d'intérêts

Competing interests statement:The authors declare no competing interest.

Auteurs

Ting Qiu (T)

School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
ORCID: 0000-0001-6299-1004

Yichao Kong (Y)

School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.

Guifeng Wei (G)

School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.

Kai Sun (K)

School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.

Ruijie Wang (R)

School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.

Yang Wang (Y)

School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.

Yiji Chen (Y)

School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.

Wenxin Wang (W)

School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.

Yun Zhang (Y)

School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
School of Life Sciences, Westlake University, Hangzhou 310024, China.

Caihong Jiang (C)

School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.

Peiguo Yang (P)

School of Life Sciences, Westlake University, Hangzhou 310024, China.
ORCID: 0000-0002-2334-5664

Tian Xie (T)

School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.

Xiabin Chen (X)

School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › Protéines adaptatrices de signalisation Shc › Protéine transformante-1 contenant un domaine d'homologie-2 de Src › CCDC6-RET fusion protein regulates Ras/MAPK...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › CCDC6-RET fusion protein regulates Ras/MAPK...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › Protéine adaptatrice GRB2 › CCDC6-RET fusion protein regulates Ras/MAPK...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines G › Protéines G monomériques › Protéines G ras › CCDC6-RET fusion protein regulates Ras/MAPK...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Protéines proto-oncogènes c-ret › CCDC6-RET fusion protein regulates Ras/MAPK...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Système de signalisation des MAP kinases › CCDC6-RET fusion protein regulates Ras/MAPK...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines de fusion oncogènes › CCDC6-RET fusion protein regulates Ras/MAPK...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › CCDC6-RET fusion protein regulates Ras/MAPK...
questionsmedicales.fr › Métabolisme › Phosphorylation › CCDC6-RET fusion protein regulates Ras/MAPK...