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

ABSTRACT: The β-catenin destruction complex (BDC) is a central node in WNT/β-catenin signaling, governing embryonic development and adult tissue homeostasis. Although recognized as a prime therapeutic target in colorectal cancer (CRC) for three decades, its dynamic architecture and biochemical complexity have hindered mechanistic understanding. Here, we systematically mapped the sequence-function landscape of the BDC using tiled base editor screens across four endogenous components-CTNNB1, AXIN1, APC, and GSK3B. Validation studies identified ~150 previously unreported mutations across these genes that affected WNT/β-catenin signaling. In addition to known cancer-associated mutations, we discovered rare gain-of-function and separation-of-function alleles of AXIN1 an

SUBMITTER: Padmanarayana M 

PROVIDER: S-EPMC12633535 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature