The Hippo Tumor Pathway Promotes TAZ Degradation by Phosphorylating a Phosphodegron and Recruiting the SCFβ-TrCP E3 Ligase

Heng Zhang,Tingting Li,Shimin Zhao,Chen-Ying Liu,Wanjin Hong,Yue Xiong,Qun-Ying Lei,Siew Wee Chan,Kun-Liang Guan,Chun Jye Lim,Wei Huang,Zheng-Yu Zha,Xin Zhou,Di Zhao

doi:10.1074/jbc.m110.152942

Abstract

The TAZ transcription co-activator promotes cell proliferation and epithelial-mesenchymal transition. TAZ is inhibited by the Hippo tumor suppressor pathway, which promotes TAZ cytoplasmic localization by phosphorylation. We report here that TAZ protein stability is controlled by a phosphodegron recognized by the F-box protein β-TrCP and ubiquitylated by the SCF/CRL1(β-TrCP) E3 ligase. The interaction between TAZ and β-TrCP is regulated by the Hippo pathway. Phosphorylation of a phosphodegron in TAZ by LATS primes it for further phosphorylation by CK1ε and subsequent binding by β-TrCP. Therefore, the Hippo pathway negatively regulates TAZ function by both limiting its nuclear accumulation and promoting its degradation. The phosphodegron-mediated TAZ degradation plays an important role in negatively regulating TAZ biological functions.

Highlights

Mechanism, Merlin and expanded, two ERM family members, stimulate the Hippo pathway and are regulated by Fat, a transmembrane protocadherin family member [7,8,9,10]
Acting downstream of the Hippo pathway is a transcriptional co-activator Yorkie, which regulates the expression of a number of genes, including cyclin E and Diap1 involved in cell proliferation and apoptosis, respectively [11]
We show that TAZ protein stability is controlled by C-terminal phosphodegron that is phosphorylated by LATS and Casein kinase 1 (CK1), recognized by the F-box protein, ␤-TrCP, and subsequent ubiquitylated by the SCF␤-TrCP E3 ligase

Summary

Hippo Tumor Pathway Promotes TAZ Degradation

We previously showed that the activity of TAZ is inhibited by LATS kinase [15, 21]. There are four HXRXXS LATS phosphorylation motifs in TAZ. Mutation of Ser-311 in another HXRXXS motif confers TAZ a partial resistance to LATS inhibition [15]. The functional significance and mechanism underlying the phosphorylation of Ser-311 and other HXRXXS motifs in TAZ regulation are not clear. We showed that phosphorylation of TAZ Ser311 by LATS primes subsequent phosphorylation on Ser-314 in the phosphodegron by CK1⑀ and recruitment of the SCF␤-TrCP E3 ubiquitin ligase, leads to TAZ ubiquitylation and degradation. This provides a mechanism of temporal regulation of TAZ by the Hippo pathway

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION