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      The N-terminal phosphodegron targets TAZ/WWTR1 protein for SCFβ-TrCP-dependent degradation in response to phosphatidylinositol 3-kinase inhibition.

      The Journal of Biological Chemistry
      Animals, Cell Proliferation, Chromones, pharmacology, Glycogen Synthase Kinase 3, metabolism, HEK293 Cells, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins, Mice, Morpholines, NIH 3T3 Cells, Phosphatidylinositol 3-Kinases, antagonists & inhibitors, Phosphorylation, Protein Processing, Post-Translational, Protein Stability, Protein Structure, Tertiary, Proteolysis, Proto-Oncogene Proteins c-akt, SKP Cullin F-Box Protein Ligases, Signal Transduction

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          Abstract

          The Hippo tumor suppressor pathway plays a major role in development and organ size control, and its dysregulation contributes to tumorigenesis. TAZ (transcriptional co-activator with PDZ-binding motif; also known as WWTR1) is a transcription co-activator acting downstream of the Hippo pathway, and increased TAZ protein levels have been associated with human cancers, such as breast cancer. Previous studies have shown that TAZ is inhibited by large tumor suppressor (LATS)-dependent phosphorylation, leading to cytoplasmic retention and ubiquitin-dependent degradation. The LATS kinase, a core component of the Hippo pathway, phosphorylates the C-terminal phosphodegron in TAZ to promote its degradation. In this study, we have found that the N-terminal phosphodegron of TAZ also plays a role in TAZ protein level regulation, particularly in response to different status of cellular PI3K signaling. GSK3, which can be inhibited by high PI3K via AKT-dependent inhibitory phosphorylation, phosphorylates the N-terminal phosphodegron in TAZ, and the phosphorylated TAZ binds to β-TrCP subunit of the SCF(β-TrCP) E3 ubiquitin ligase, thereby leading to TAZ ubiquitylation and degradation. We observed that the TAZ protein level is elevated in tumor cells with high PI3K signaling, such as in PTEN mutant cancer cells. This study provides a novel mechanism of TAZ regulation and suggests a role of TAZ in modulating tissue growth and tumor development in response to PI3K signaling.

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