Apc And Gsk-3 Regulate Hippo Signaling Through Ajuba

Loading...
Thumbnail Image
Degree type
Doctor of Philosophy (PhD)
Graduate group
Pharmacology
Discipline
Subject
Ajuba
APC
Colorectal Cancer
GSK-3
Hippo
Wnt
Molecular Biology
Pharmacology
Funder
Grant number
License
Copyright date
2022-09-17T20:21:00-07:00
Distributor
Related resources
Author
Myers, Rebecca Lynne
Contributor
Abstract

Mutations in the tumor suppressor Adenomatous Polyposis Coli (APC) are implicated in over 80% of human colorectal cancers. APC suppresses canonical Wnt signaling by enhancing GSK-3 mediated phosphorylation and degradation of -catenin, an activator of Wnt target genes. APC also suppresses the Hippo pathway mediators YAP and TAZ, but the molecular mechanism of this regulation is not well characterized. Here we show that APC acts through GSK-3 to modulate the levels of the LIM domain protein Ajuba, which in turn activates YAP and TAZ by preventing phosphorylation by the upstream protein kinase LATS. Oncogenic mutations in APC or inhibition of GSK-3 causes stabilization and accumulation of Ajuba protein, whereas rescue of wild-type APC expression in APC deficient colorectal carcinoma cells abrogates this accumulation in a GSK-3- dependent manner. GSK-3 directly phosphorylates Ajuba, resulting in its destabilization and suppression of YAP/TAZ-TEAD target genes. Thus GSK-3 phosphorylation and destabilization of Ajuba provides a mechanism linking APC to the suppression of YAP/TAZ-TEAD signaling.

Advisor
Peter S. Klein
Date of degree
2021-01-01
Date Range for Data Collection (Start Date)
Date Range for Data Collection (End Date)
Digital Object Identifier
Series name and number
Volume number
Issue number
Publisher
Publisher DOI
Journal Issue
Comments
Recommended citation