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PreprintCC BYbioRxiv

Phosphorylation-dependent binding of the Adenomatous Polyposis Coli protein to β-TrCP1 regulates β-catenin destruction

  • D. M. Johnston1
  • C. L. Tarver
  • R. D. Leib
  • M. Koivomägi
  • F. Liu
  • C. M. Adams
  • W. I. Weis
  1. 1Stanford University
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Abstract

Wnt signaling controls cellular development by regulating levels of {beta}-catenin, a dual transcription factor and adhesion protein. The tumor suppressor gene Adenomatous Polyposis coli (APC) is a negative regulator of Wnt signaling that acts by interacting with multiple proteins in the destruction complex to drive {beta}-catenin degradation. Mutations in APC cause deregulation of Wnt/{beta}-catenin signaling contributing to the development of several types of cancer, especially colorectal cancers. Tumors are not null mutant for APC - instead they accumulate truncated proteins. Many APC proteins are truncated between the second and third 20-amino acid repeats, a region known as the {beta}-catenin inhibition domain (CID), which is essential for {beta}-catenin destruction, but its mechanism of action is unclear. Here we find that cyclin dependent kinases and GSK3{beta} phosphorylate the CID region of APC in vitro. This allows the APC CID to bind to the E3 ubiquitin ligase component {beta}-TrCP1 in a phosphorylation dependent manner and this in turn regulates the rate of {beta}-catenin ubiquitylation. {beta} TrCP1 binding to the phosphorylated CID favors the retention and stabilization of the SCF {beta}-TrCP1 E3 ligase in the destruction complex and ensures that SCF {beta}-TrCP1 remains available for {beta}-catenin ubiquitylation. These findings provide a mechanism for the vital role of APCs CID region in {beta}-catenin destruction.

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Cite

BibTeXRIS
BibTeX
@misc{johnston2026phosphorylationdependent,
  title = {{Phosphorylation-dependent binding of the Adenomatous Polyposis Coli protein to β-TrCP1 regulates β-catenin destruction}},
  author = {D. M. Johnston and C. L. Tarver and R. D. Leib and M. Koivomägi and F. Liu and C. M. Adams and W. I. Weis},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.16.751897},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.16.751897v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - Phosphorylation-dependent binding of the Adenomatous Polyposis Coli protein to β-TrCP1 regulates β-catenin destruction
AU  - D. M. Johnston
AU  - C. L. Tarver
AU  - R. D. Leib
AU  - M. Koivomägi
AU  - F. Liu
AU  - C. M. Adams
AU  - W. I. Weis
PY  - 2026
DA  - 2026/09/16
PB  - bioRxiv
DO  - 10.64898/2026.09.16.751897
UR  - https://www.biorxiv.org/content/10.64898/2026.09.16.751897v1
AB  - Wnt signaling controls cellular development by regulating levels of {beta}-catenin, a dual transcription factor and adhesion protein. The tumor suppressor gene Adenomatous Polyposis coli (APC) is a negative regulator of Wnt signaling that acts by interacting with multiple proteins in the destruction complex to drive {beta}-catenin degradation. Mutations in APC cause deregulation of Wnt/{beta}-catenin signaling contributing to the development of several types of cancer, especially colorectal cancers. Tumors are not null mutant for APC - instead they accumulate truncated proteins. Many APC proteins are truncated between the second and third 20-amino acid repeats, a region known as the {beta}-catenin inhibition domain (CID), which is essential for {beta}-catenin destruction, but its mechanism of action is unclear. Here we find that cyclin dependent kinases and GSK3{beta} phosphorylate the CID region of APC in vitro. This allows the APC CID to bind to the E3 ubiquitin ligase component {beta}-TrCP1 in a phosphorylation dependent manner and this in turn regulates the rate of {beta}-catenin ubiquitylation. {beta} TrCP1 binding to the phosphorylated CID favors the retention and stabilization of the SCF {beta}-TrCP1 E3 ligase in the destruction complex and ensures that SCF {beta}-TrCP1 remains available for {beta}-catenin ubiquitylation. These findings provide a mechanism for the vital role of APCs CID region in {beta}-catenin destruction.
ER  -