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

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.

• Authors: Wei Huang, Xianbo Lv, Chenying Liu, Zhengyu Zha, Heng Zhang, Ying Jiang, Yue Xiong, Qun-Ying Lei, Kun-Liang Guan
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 31 Pg. 26245-53 (Jul 27 2012) ISSN: 1083-351X [Electronic] United States
• PMID: 22692215 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chromones
• Intracellular Signaling Peptides and Proteins
• Morpholines
• Phosphoinositide-3 Kinase Inhibitors
• Trans-Activators
• Transcription Factors
• Transcriptional Coactivator with PDZ-Binding Motif Proteins
• WWTR1 protein, human
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• SKP Cullin F-Box Protein Ligases
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3

Topics

• Animals
• Cell Proliferation
• Chromones (pharmacology)
• Glycogen Synthase Kinase 3 (metabolism)
• HEK293 Cells
• HeLa Cells
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• Mice
• Morpholines (pharmacology)
• NIH 3T3 Cells
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation
• Protein Processing, Post-Translational
• Protein Stability
• Protein Structure, Tertiary
• Proteolysis
• Proto-Oncogene Proteins c-akt (metabolism)
• SKP Cullin F-Box Protein Ligases (metabolism)
• Signal Transduction
• Trans-Activators
• Transcription Factors
• Transcriptional Coactivator with PDZ-Binding Motif Proteins