Oncogenic Serine 45-Deleted ?-Catenin Remains Susceptible to Wnt Stimulation and APC Regulation in Human Colonocytes.

ABSTRACT: The Wnt/?-catenin signaling pathway is deregulated in nearly all colorectal cancers (CRCs), predominantly through mutation of the tumor suppressor Adenomatous Polyposis Coli (APC). APC mutation is thought to allow a "just-right" amount of Wnt pathway activation by fine-tuning ?-catenin levels. While at a much lower frequency, mutations that result in a ?-catenin that is compromised for degradation occur in a subset of human CRCs. Here, we investigate whether one such "stabilized" ?-catenin responds to regulatory stimuli, thus allowing ?-catenin levels conducive for tumor formation. We utilize cells harboring a single mutant allele encoding Ser45-deleted ?-catenin (?-cat?S45) to test the effects of Wnt3a treatment or APC-depletion on ?-cat?S45 regulation and activity. We find that APC and ?-cat?S45 retain interaction with Wnt receptors. Unexpectedly, ?-cat?S45 accumulates and activates TOPflash reporter upon Wnt treatment or APC-depletion, but only accumulates in the nucleus upon APC loss. Finally, we find that ?-catenin phosphorylation at GSK-3? sites and proteasomal degradation continue to occur in the absence of Ser45. Our results expand the current understanding of Wnt/?-catenin signaling and provide an example of a ?-catenin mutation that maintains some ability to respond to Wnt, a possible key to establishing ?-catenin activity that is "just-right" for tumorigenesis.

SUBMITTER: Parker TW 

PROVIDER: S-EPMC7464804 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature