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

Toshiro Moroishi, Hyun Woo Park, Baodong Qin, Qian Chen, Zhipeng Meng, Steven W. Plouffe, Koji Taniguchi, Fa Xing Yu, Michael Karin, Duojia Pan, Kun Liang Guan

Research output: Contribution to journalArticle

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/TAZactivity 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.

Original languageEnglish (US)
Pages (from-to)1271-1284
Number of pages14
JournalGenes & development
Volume29
Issue number12
DOIs
StatePublished - Jun 15 2015

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Keywords

  • Cancer
  • Hippo pathway
  • Negative feedback
  • Phosphorylation
  • TAZ
  • YAP

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Moroishi, T., Park, H. W., Qin, B., Chen, Q., Meng, Z., Plouffe, S. W., Taniguchi, K., Yu, F. X., Karin, M., Pan, D., & Guan, K. L. (2015). A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis. Genes & development, 29(12), 1271-1284. https://doi.org/10.1101/gad.262816.115