Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Pharmacology

First Advisor

Peter S. Klein

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.

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