SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF
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Updated: Aug 15, 2025
Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
Kai Feng1,2, Qing Shi1, Dongyue Jiao1
1Shanghai Stomatological Hospital & School of Stomatology, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan University, Shanghai, 200438, China.
Background:
The gene encoding the E3 ubiquitin ligase substrate-binding adapter Speckle-type BTB/POZ protein (SPOP) is frequently mutated in prostate cancer (PCa) and endometrial cancer (EC); however, the molecular mechanisms underlying the contribution of SPOP mutations to tumorigenesis remain poorly understood.
Methods:
BRAF harbors a potential SPOP-binding consensus motif (SBC) motif. Co-immunoprecipitation assays demonstrated that BRAF interacts with SPOP. A series of functional analyses in cell lines were performed to investigate the biological significance of MAPK/ERK activation caused by SPOP mutations.
Results:
Cytoplasmic SPOP binds to and induces non-degradative ubiquitination of BRAF, thereby reducing the interaction between BRAF and other core components of the MAPK/ERK pathway. SPOP ablation increased MAPK/ERK activation. EC- or PCa-associated SPOP mutants showed a reduced capacity to bind and ubiquitinate BRAF. Moreover, cancer-associated BRAF mutations disrupted the BRAF-SPOP interaction and allowed BRAF to evade SPOP-mediated ubiquitination, thereby upregulating MAPK/ERK signaling and enhancing the neoplastic phenotypes of cancer cells.
Conclusions:
Our findings provide new insights into the molecular link between SPOP mutation-driven tumorigenesis and aberrant BRAF-dependent activation of the MAPK/ERK pathway.
Insights
Speckle-type BTB/POZ protein (SPOP) mutations in cancer disrupt its interaction with BRAF, leading to increased MAPK/ERK signaling. This study reveals a novel mechanism linking SPOP mutations to cancer development.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Speckle-type BTB/POZ protein (SPOP) is frequently mutated in prostate cancer (PCa) and endometrial cancer (EC).
- The molecular mechanisms by which SPOP mutations contribute to tumorigenesis are not well understood.
Purpose of the Study:
- To investigate the interaction between SPOP and BRAF.
- To elucidate the role of SPOP mutations in the activation of the MAPK/ERK pathway in cancer.
Main Methods:
- Co-immunoprecipitation assays to confirm BRAF-SPOP interaction.
- Functional analyses in cell lines to assess MAPK/ERK pathway activation.
- Analysis of cancer-associated SPOP and BRAF mutations.
Main Results:
- Cytoplasmic SPOP binds to BRAF, inducing non-degradative ubiquitination and reducing MAPK/ERK pathway component interaction.
- SPOP ablation or mutations impair BRAF binding and ubiquitination, leading to increased MAPK/ERK activation.
- Cancer-associated BRAF mutations disrupt the BRAF-SPOP interaction, promoting neoplastic phenotypes.
Conclusions:
- SPOP mutations contribute to tumorigenesis through aberrant activation of the BRAF-dependent MAPK/ERK pathway.
- This study uncovers a critical molecular link between SPOP mutations and cancer progression.
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