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Mutational scanning reveals substrate-assisted autoregulation of the WNT destruction complex
Murugesh Padmanarayana1,2,3, Saira Sakalas4, Parijat Sarkar1,2,3
1Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA.
Abstract:
The β-catenin destruction complex (BDC) regulates WNT-β-catenin signaling and is a prime therapeutic target in colorectal cancer, yet its biochemical complexity has hindered mechanistic understanding. We mapped the sequence-function landscape of the BDC using tiled base editor screens across its components CTNNB1, AXIN1, APC and GSK3B. Amongst ~150 previously unreported mutations that affected WNT signaling, we discovered gain-of-function and separation-of-function alleles that reveal mechanisms of complex assembly, including a β-catenin region regulating TCF/LEF transcription factor binding. Critically, we found that the AXIN1-β-catenin interface controls signaling flux through the oncogenic BDC found in APC-mutant cancers. In cells expressing truncated APC, β-catenin itself scaffolds BDC assembly, establishing a substrate-assisted autoregulatory mechanism. This architecture represents an unexploited therapeutic vulnerability: strengthening the AXIN1-β-catenin interaction restores destruction complex function and impairs the growth of colorectal cancer cells. Our mutational resource provides a foundation for mechanistic understanding and therapeutic targeting of the WNT pathway.
Insights
Scientists mapped mutations in the β-catenin destruction complex (BDC) to understand WNT signaling in colorectal cancer. Strengthening a key interaction within the BDC offers a new therapeutic strategy for cancer treatment.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- The β-catenin destruction complex (BDC) is crucial for regulating WNT-β-catenin signaling.
- Dysregulation of this pathway is implicated in colorectal cancer (CRC) development.
- The complexity of the BDC has limited mechanistic understanding and therapeutic targeting.
Purpose of the Study:
- To map the sequence-function landscape of the BDC components (CTNNB1, AXIN1, APC, GSK3B).
- To identify novel mutations affecting WNT signaling and understand BDC assembly mechanisms.
- To explore therapeutic vulnerabilities within the BDC for CRC treatment.
Main Methods:
- Utilized tiled base editor screens across key BDC genes.
- Analyzed approximately 150 novel mutations impacting WNT signaling.
- Investigated the role of the AXIN1-β-catenin interface and APC mutations.
Main Results:
- Discovered gain-of-function and separation-of-function mutations.
- Identified a β-catenin region critical for TCF/LEF transcription factor binding.
- Revealed that the AXIN1-β-catenin interface regulates signaling flux in APC-mutant CRC.
- Demonstrated that β-catenin acts as a scaffold in truncated APC contexts, forming a substrate-assisted autoregulatory mechanism.
Conclusions:
- The study provides a comprehensive mutational resource for understanding BDC mechanisms.
- Targeting the AXIN1-β-catenin interaction represents a potential therapeutic strategy to restore BDC function.
- This approach could impair the growth of colorectal cancer cells by reactivating the destruction complex.
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