{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T19:03:45Z","timestamp":1790103825470,"version":"4.0.1"},"posted":{"date-parts":[[2026,9,18]]},"group-title":"Biochemistry","reference-count":81,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["P30CA124435"],"award-info":[{"award-number":["P30CA124435"]}]},{"name":"NIH","award":["5F31CA196170-02"],"award-info":[{"award-number":["5F31CA196170-02"]}]},{"name":"NIH","award":["S10RR027425"],"award-info":[{"award-number":["S10RR027425"]}]},{"name":"NIH","award":["R35GM131747"],"award-info":[{"award-number":["R35GM131747"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,18]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  Wnt signaling controls cellular development by regulating levels of \u03b2-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 \u03b2-catenin degradation. Mutations in APC cause deregulation of Wnt\/\u03b2-catenin signaling contributing to the development of several types of cancer, especially colorectal cancers. Tumors are not null mutant for APC\u2014instead they accumulate truncated proteins. Many APC proteins are truncated between the second and third 20-amino acid repeats, a region known as the \u03b2-catenin inhibition domain (CID), which is essential for \u03b2-catenin destruction, but its mechanism of action is unclear. Here we find that cyclin dependent kinases and GSK3\u03b2 phosphorylate the CID region of APC\n                  <jats:italic>in vitro<\/jats:italic>\n                  . This allows the APC CID to bind to the E3 ubiquitin ligase component \u03b2-TrCP1 in a phosphorylation dependent manner and this in turn regulates the rate of \u03b2-catenin ubiquitylation. \u03b2-TrCP1 binding to the phosphorylated CID favors the retention and stabilization of the SCF\n                  <jats:sup>\u03b2-TrCP1<\/jats:sup>\n                  E3 ligase in the destruction complex and ensures that SCF\n                  <jats:sup>\u03b2-TrCP1<\/jats:sup>\n                  remains available for \u03b2-catenin ubiquitylation. These findings provide a mechanism for the vital role of APC\u2019s CID region in \u03b2-catenin destruction.\n                <\/jats:p>","DOI":"10.64898\/2026.09.16.751897","type":"posted-content","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T14:10:13Z","timestamp":1789740613000},"source":"Crossref","is-referenced-by-count":0,"title":["Phosphorylation-dependent binding of the Adenomatous Polyposis Coli protein to \u03b2-TrCP1 regulates \u03b2-catenin destruction"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7302-0115","authenticated-orcid":false,"given":"Darius M.","family":"Johnston","sequence":"first","affiliation":[{"name":"Department of Molecular Cellular Physiology, Stanford University School of Medicine, Stanford, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4708-6473","authenticated-orcid":false,"given":"Crissy L.","family":"Tarver","sequence":"additional","affiliation":[{"name":"Department of Structural Biology, Stanford University School of Medicine, Stanford, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Leib","sequence":"additional","affiliation":[{"name":"Vincent Coates Foundation Mass Spectrometry Laboratory, Stanford University, Stanford, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4691-6930","authenticated-orcid":false,"given":"Mardo","family":"K\u00f5ivom\u00e4gi","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, NIH, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Liu","sequence":"additional","affiliation":[{"name":"Vincent Coates Foundation Mass Spectrometry Laboratory, Stanford University, Stanford, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Adams","sequence":"additional","affiliation":[{"name":"Vincent Coates Foundation Mass Spectrometry Laboratory, Stanford University, Stanford, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5583-6150","authenticated-orcid":false,"given":"William I.","family":"Weis","sequence":"additional","affiliation":[{"name":"Department of Molecular Cellular Physiology, Stanford University School of Medicine, Stanford, CA"},{"name":"Department of Structural Biology, Stanford University School of Medicine, Stanford, 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