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A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis.

ABSTRACT: YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) are major downstream effectors of the Hippo pathway that influences tissue homeostasis, organ size, and cancer development. Aberrant hyperactivation of YAP/TAZ causes tissue overgrowth and tumorigenesis, whereas their inactivation impairs tissue development and regeneration. Dynamic and precise control of YAP/TAZ activity is thus important to ensure proper physiological regulation and homeostasis of the cells. Here, we show that YAP/TAZ activation results in activation of their negative regulators, LATS1/2 (large tumor suppressor 1/2) kinases, to constitute a negative feedback loop of the Hippo pathway in both cultured cells and mouse tissues. YAP/TAZ in complex with the transcription factor TEAD (TEA domain family member) directly induce LATS2 expression. Furthermore, YAP/TAZ also stimulate the kinase activity of LATS1/2 through inducing NF2 (neurofibromin 2). This feedback regulation is responsible for the transient activation of YAP upon lysophosphatidic acid (LPA) stimulation and the inhibition of YAP-induced cell migration. Thus, this LATS-mediated feedback loop provides an efficient mechanism to establish the robustness and homeostasis of YAP/TAZ regulation.

SUBMITTER: Moroishi T

PROVIDER: S-EPMC4495398 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis.

Moroishi Toshiro T Park Hyun Woo HW Qin Baodong B Chen Qian Q Meng Zhipeng Z Plouffe Steven W SW Taniguchi Koji K Yu Fa-Xing FX Karin Michael M Pan Duojia D Guan Kun-Liang KL

Genes & development 20150601 12

YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) are major downstream effectors of the Hippo pathway that influences tissue homeostasis, organ size, and cancer development. Aberrant hyperactivation of YAP/TAZ causes tissue overgrowth and tumorigenesis, whereas their inactivation impairs tissue development and regeneration. Dynamic and precise control of YAP/TAZ activity is thus important to ensure proper physiological regulation and homeostasis of the cel ...[more]

PMID: 26109050

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Project description:YAP and TAZ are essential transcriptional co-activators and downstream effectors of the Hippo pathway, regulating cell proliferation, organ growth, and tissue homeostasis. To ask how the Hippo pathway affects mineralized tissue homeostasis in a tissue that is highly reliant on a tight homeostatic control of mineralized deposition and resorption, we determined the effects of YAP/TAZ dysregulation on the periodontal tissues alveolar bone, root cementum, and periodontal ligament. Loss of YAP/TAZ was associated with a reduction of mineralized tissue density in cellular cementum and alveolar bone, a downregulation in collagen I, alkaline phosphatase, and RUNX2 gene expression, an increase in the resorption markers TRAP and cathepsin K, and elevated numbers of TRAP-stained osteoclasts. Cyclic strain applied to periodontal ligament cells resulted in YAP nuclear localization, an effect that was abolished after blocking YAP. The rescue of YAP signaling with the heparan sulfate proteoglycan agrin resulted in a return of the nuclear YAP signal. Illustrating the key role of YAP on mineralization gene expression, the YAP inhibition-related downregulation of mineralization-associated genes was reversed by the extracellular matrix YAP activator agrin. Application of the unopposed mouse molar model to transform the periodontal ligament into an unloaded state and facilitate the distal drift of teeth resulted in an overall increase in mineralization-associated gene expression, an effect that was 10-20% diminished in Wnt1Cre/YAP/TAZ mutant mice. The unloaded state of the unopposed molar model in Wnt1Cre/YAP/TAZ mutant mice also caused a significant three-fold increase in osteoclast numbers, a substantial increase in bone/cementum resorption, pronounced periodontal ligament hyalinization, and thickened periodontal fiber bundles. Together, these data demonstrated that YAP/TAZ signaling is essential for the microarchitectural integrity of the periodontium by regulating mineralization gene expression and preventing excessive resorption during bodily movement of the dentoalveolar complex.

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A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis.

Publications

A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis.

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