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

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

doi:10.1074/jbc.m110.152942

Cited by 447 publications

(455 citation statements)

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“…PP1A Stabilizes TAZ by Decreasing the Interaction between TAZ and ␤-TrCP-Our recent work has shown that LATS and CK1 phosphorylate TAZ and promote TAZ interaction with the SCF E3 ubiquitin ligase and degradation (15). If PP1A dephosphorylates TAZ, it should stabilize TAZ by antagonizing the effect of LATS.…”

Section: Resultsmentioning

confidence: 99%

“…2C). Our recent study identified ␤-TrCP as a TAZ-binding protein to recruit the SCF E3 ubiquitin ligase (15). We then determined the effect of PP1A on the interaction between TAZ and ␤-TrCP.…”

Section: Resultsmentioning

confidence: 99%

“…2E). TAZ phosphorylation at Ser-311 is required for C-terminal phosphodegron-mediated degradation (15). We then determined the effect of PP1A on TAZ phosphorylation at Ser-311.…”

Section: Resultsmentioning

confidence: 99%

“…Phosphorylation of Ser-89 inhibits TAZ by cytoplasmic sequestration, whereas phosphorylation of Ser-311 inactivates TAZ by promoting ubiquitination and degradation (15). Therefore, phosphorylation plays a major role in TAZ regulation.…”

Section: Discussionmentioning

confidence: 99%

“…A dual phosphorylation of TAZ by LATS and CK1 creates a binding site for ␤-TrCP (beta-Transducin repeat containing protein), the substrate-recruiting subunit of the SCF ␤-TrCP E3 ubiquitin ligase (15). Phosphorylation of TAZ at Ser-311 by LATS provides the priming site for subsequent CK1 phosphorylation at Ser-314 in TAZ, therefore creating a functional phosphodegron for ␤-TrCP binding (15). Therefore, phosphorylation plays a major role in TAZ regulation in both subcellular localization and protein levels.…”

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confidence: 99%

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PP1 Cooperates with ASPP2 to Dephosphorylate and Activate TAZ

Liu

et al. 2011

Journal of Biological Chemistry

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The Hippo pathway regulates organ size by controlling both cell proliferation and apoptosis. TAZ functions as a transcriptional co-activator downstream of the Hippo pathway and has been implicated in human cancer development. A key step in the Hippo-TAZ pathway is phosphorylation of TAZ by LATS kinase, which leads to TAZ inhibition by both cytoplasmic retention and degradation. However, the mechanism of TAZ dephosphorylation and the responsible phosphatase are unknown. Here, we identified PP1 as a bona fide TAZ phosphatase. PP1A dephosphorylates TAZ at Ser-89 and Ser-311, promotes TAZ nuclear translocation, and stabilizes TAZ by disrupting the binding to the SCF E3 ubiquitin ligase. Furthermore, ASPP2 facilitates the interaction between TAZ and PP1 to promote TAZ dephosphorylation. As a result, PP1 and ASPP2 increase TAZ-dependent gene expression. This study demonstrates that PP1A and ASPP2 play a critical role in promoting TAZ function by antagonizing the LATS kinase through TAZ dephosphorylation.Genetic screens in Drosophila have delineated a new tumor suppressor pathway, the Hippo pathway, which regulates organ size by controlling both cell proliferation and apoptosis (1). Both the components and functions of the Hippo pathway are conserved from Drosophila to mammals. In mammalian cells, LATS1/2 and MST1/2 are the homologs of Drosophila Warts and Hippo, respectively (2). YAP, the mammalian ortholog of Drosophila Yorkie, has been demonstrated to be phosphorylated and inhibited by LATS (3, 4). TAZ, first identified as a 14-3-3-binding protein, shares ϳ50% sequence identity with YAP and has also been shown to function as a transcriptional co-activator downstream of the Hippo pathway (5, 6). TAZ is involved in the development of multiple organs such as the lung, fat, muscle, bone, limb, and heart, as well as in many cellular, processes including stem cell differentiation, cell proliferation, and epithelial-mesenchymal transition (6 -12). Taz knockout mice develop two severe abnormalities: polycystic kidney disease and emphysema (13,14). Notably, elevated TAZ expression is observed in Ͼ20% of breast cancers, especially invasive ductal carcinomas (12).We previously showed that the activity of TAZ is inhibited by LATS kinase in a mechanism similar to YAP regulation by the Hippo pathway (6). There are four HXRXXS LATS phosphorylation motifs in TAZ. We have demonstrated that phosphorylation of TAZ at Ser-89 by LATS promotes its interaction with 14-3-3, resulting in cytoplasmic sequestration and functional inhibition of TAZ. The S89A mutation makes TAZ partially resistant to inhibition by the Hippo pathway (6). In addition, TAZ stability is also regulated by LATS phosphorylation. A dual phosphorylation of TAZ by LATS and CK1 creates a binding site for ␤-TrCP (beta-Transducin repeat containing protein), the substrate-recruiting subunit of the SCF ␤-TrCP E3 ubiquitin ligase (15). Phosphorylation of TAZ at Ser-311 by LATS provides the priming site for subsequent CK1 phosphorylation at Ser-314 in TAZ, therefore creating a ...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…2E). TAZ phosphorylation at Ser-311 is required for C-terminal phosphodegron-mediated degradation (15). We then determined the effect of PP1A on TAZ phosphorylation at Ser-311.…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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PP1 Cooperates with ASPP2 to Dephosphorylate and Activate TAZ

Liu

et al. 2011

Journal of Biological Chemistry

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123

105

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YAPping about and not forgetting TAZ

et al. 2019

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The Hippo pathway has emerged as a major eukaryotic signalling pathway and is increasingly the subject of intense interest, as are the key effectors of canonical Hippo signalling, YES‐associated protein (YAP) and TAZ. The Hippo pathway has key roles in diverse biological processes, including network signalling regulation, development, organ growth, tissue repair and regeneration, cancer, stem cell regulation and mechanotransduction. YAP and TAZ are multidomain proteins and function as transcriptional coactivators of key genes to evoke their biological effects. YAP and TAZ interact with numerous partners and their activities are controlled by a complex set of processes. This review provides an overview of Hippo signalling and its role in growth. In particular, the functional domains of YAP and TAZ and the complex mechanisms that regulate their protein stability and activity are discussed. Notably, the similarities and key differences are highlighted between the two paralogues including which partner proteins interact with which functional domains to regulate their activity.

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Primary Cilia as Signaling Hubs in Health and Disease

et al. 2018

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Primary cilia detect extracellular cues and transduce these signals into cells to regulate proliferation, migration, and differentiation. Here, the function of primary cilia as signaling hubs of growth factors and morphogens is in focus. First, the molecular mechanisms regulating the assembly and disassembly of primary cilia are described. Then, the role of primary cilia in mediating growth factor and morphogen signaling to maintain human health and the potential mechanisms by which defects in these pathways contribute to human diseases, such as ciliopathy, obesity, and cancer are described. Furthermore, a novel signaling pathway by which certain growth factors stimulate cell proliferation through suppression of ciliogenesis is also described, suggesting novel therapeutic targets in cancer.

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

Cited by 447 publications

References 35 publications

PP1 Cooperates with ASPP2 to Dephosphorylate and Activate TAZ

PP1 Cooperates with ASPP2 to Dephosphorylate and Activate TAZ

YAPping about and not forgetting TAZ

Primary Cilia as Signaling Hubs in Health and Disease

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