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<p>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 <i>CTNNB1</i>, <i>AXIN1</i>, <i>APC</i> and <i>GSK3B</i>. 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.</p>

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Mutational scanning reveals substrate-assisted autoregulation of the WNT destruction complex

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月2日

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  • Murugesh Padmanarayana,
  • Saira Sakalas,
  • Parijat Sarkar,
  • Mengxiao Ma,
  • Ethan R. Garvin,
  • Ethan Lee,
  • Steven M. Corsello,
  • Sebastian Guettler,
  • Ganesh V. Pusapati,
  • Rajat Rohatgi

摘要

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.