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

Taybor W Parker,Aaron J Rudeen,Kristi L Neufeld

doi:10.3390/cancers12082114

Taybor W Parker, Aaron J Rudeen + Show 1 more

Open Access

https://doi.org/10.3390/cancers12082114

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Journal: Cancers	Publication Date: Jul 30, 2020
Citations: 8	License type: CC BY 4.0

Affiliation: University of Kansas

Abstract

The Wnt/β-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 β-catenin levels. While at a much lower frequency, mutations that result in a β-catenin that is compromised for degradation occur in a subset of human CRCs. Here, we investigate whether one such “stabilized” β-catenin responds to regulatory stimuli, thus allowing β-catenin levels conducive for tumor formation. We utilize cells harboring a single mutant allele encoding Ser45-deleted β-catenin (β-catΔS45) to test the effects of Wnt3a treatment or APC-depletion on β-catΔS45 regulation and activity. We find that APC and β-catΔS45 retain interaction with Wnt receptors. Unexpectedly, β-catΔS45 accumulates and activates TOPflash reporter upon Wnt treatment or APC-depletion, but only accumulates in the nucleus upon APC loss. Finally, we find that β-catenin phosphorylation at GSK-3β sites and proteasomal degradation continue to occur in the absence of Ser45. Our results expand the current understanding of Wnt/β-catenin signaling and provide an example of a β-catenin mutation that maintains some ability to respond to Wnt, a possible key to establishing β-catenin activity that is “just-right” for tumorigenesis.

Highlights

Discovered nearly 40 years ago, the Wnt signaling pathway has proven essential for many cellular functions, including proliferation, polarity, developmental cell-fate determination, and tissue homeostasis [1]
Using data available on cBioPortal, we find that mutations to β-catenin occur in ~6% of human
It has been previously proposed that Adenomatous Polyposis Coli (APC) mutations occur in a “just-right” fashion to allow optimal levels of β-catenin signaling for tumorigenesis

Summary

Introduction

Discovered nearly 40 years ago, the Wnt signaling pathway has proven essential for many cellular functions, including proliferation, polarity, developmental cell-fate determination, and tissue homeostasis [1]. Normal colon tissue homeostasis is dependent on well-controlled Wnt signaling, as Wnt pathway components are mutated in over 90% of colorectal cancers (CRCs) [2,3,4]. In the absence of a Wnt signal, a cytoplasmic β-catenin destruction complex efficiently catalyzes the proteasome-mediated degradation of β-catenin. The core components of the complex include two scaffolding proteins, Adenomatous Polyposis Coli (APC) and Axin, as well as two kinases, GSK-3β and CK1-α [5]. In the absence of ligands, the complex binds and phosphorylates β-catenin, leading to β-TrCP-mediated ubiquitination and proteasomal degradation [6,7,8].

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