Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control

Bin Zhao, Xiaomu Wei, Weiquan Li, Ryan S. Udan, Qian Yang, Joungmok Kim, Joe Xie, Tsuneo Ikenoue, Jindan Yu, Li Li, Pan Zheng, Keqiang Ye, Arul Chinnaiyan, Georg Halder, Zhi-chun Lai, Kun Liang Guan

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Abstract

The Hippo pathway plays a key role in organ size control by regulating cell proliferation and apoptosis in Drosophila. Although recent genetic studies have shown that the Hippo pathway is regulated by the NF2 and Fat tumor suppressors, the physiological regulations of this pathway are unknown. Here we show that in mammalian cells, the transcription coactivator YAP (Yes-associated protein), is inhibited by cell density via the Hippo pathway. Phosphorylation by the Lats tumor suppressor kinase leads to cytoplasmic translocation and inactivation of the YAP oncoprotein. Furthermore, attenuation of this phosphorylation of YAP or Yorkie (Yki), the Drosophila homolog of YAP, potentiates their growth-promoting function in vivo. Moreover, YAP overexpression regulates gene expression in a manner opposite to cell density, and is able to overcome cell contact inhibition. Inhibition of YAP function restores contact inhibition in a human cancer cell line bearing deletion of Salvador (Sav), a Hippo pathway component. Interestingly, we observed that YAP protein is elevated and nuclear localized in some human liver and prostate cancers. Our observations demonstrate that YAP plays a key role in the Hippo pathway to control cell proliferation in response to cell contact.

Original languageEnglish (US)
Pages (from-to)2747-2761
Number of pages15
JournalGenes and Development
Volume21
Issue number21
DOIs
StatePublished - Nov 1 2007

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Contact Inhibition
Oncogene Proteins
Growth
Proteins
Cell Count
Phosphorylation
Cell Proliferation
Neoplasms
Organ Size
Liver Neoplasms
Drosophila
Prostatic Neoplasms
Phosphotransferases
Fats
Apoptosis
Gene Expression
Cell Line

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

Cite this

Zhao, Bin ; Wei, Xiaomu ; Li, Weiquan ; Udan, Ryan S. ; Yang, Qian ; Kim, Joungmok ; Xie, Joe ; Ikenoue, Tsuneo ; Yu, Jindan ; Li, Li ; Zheng, Pan ; Ye, Keqiang ; Chinnaiyan, Arul ; Halder, Georg ; Lai, Zhi-chun ; Guan, Kun Liang. / Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. In: Genes and Development. 2007 ; Vol. 21, No. 21. pp. 2747-2761.
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author = "Bin Zhao and Xiaomu Wei and Weiquan Li and Udan, {Ryan S.} and Qian Yang and Joungmok Kim and Joe Xie and Tsuneo Ikenoue and Jindan Yu and Li Li and Pan Zheng and Keqiang Ye and Arul Chinnaiyan and Georg Halder and Zhi-chun Lai and Guan, {Kun Liang}",
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Zhao, B, Wei, X, Li, W, Udan, RS, Yang, Q, Kim, J, Xie, J, Ikenoue, T, Yu, J, Li, L, Zheng, P, Ye, K, Chinnaiyan, A, Halder, G, Lai, Z & Guan, KL 2007, 'Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control', Genes and Development, vol. 21, no. 21, pp. 2747-2761. https://doi.org/10.1101/gad.1602907

Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. / Zhao, Bin; Wei, Xiaomu; Li, Weiquan; Udan, Ryan S.; Yang, Qian; Kim, Joungmok; Xie, Joe; Ikenoue, Tsuneo; Yu, Jindan; Li, Li; Zheng, Pan; Ye, Keqiang; Chinnaiyan, Arul; Halder, Georg; Lai, Zhi-chun; Guan, Kun Liang.

In: Genes and Development, Vol. 21, No. 21, 01.11.2007, p. 2747-2761.

Research output: Contribution to journalArticle

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T1 - Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control

AU - Zhao, Bin

AU - Wei, Xiaomu

AU - Li, Weiquan

AU - Udan, Ryan S.

AU - Yang, Qian

AU - Kim, Joungmok

AU - Xie, Joe

AU - Ikenoue, Tsuneo

AU - Yu, Jindan

AU - Li, Li

AU - Zheng, Pan

AU - Ye, Keqiang

AU - Chinnaiyan, Arul

AU - Halder, Georg

AU - Lai, Zhi-chun

AU - Guan, Kun Liang

PY - 2007/11/1

Y1 - 2007/11/1

N2 - The Hippo pathway plays a key role in organ size control by regulating cell proliferation and apoptosis in Drosophila. Although recent genetic studies have shown that the Hippo pathway is regulated by the NF2 and Fat tumor suppressors, the physiological regulations of this pathway are unknown. Here we show that in mammalian cells, the transcription coactivator YAP (Yes-associated protein), is inhibited by cell density via the Hippo pathway. Phosphorylation by the Lats tumor suppressor kinase leads to cytoplasmic translocation and inactivation of the YAP oncoprotein. Furthermore, attenuation of this phosphorylation of YAP or Yorkie (Yki), the Drosophila homolog of YAP, potentiates their growth-promoting function in vivo. Moreover, YAP overexpression regulates gene expression in a manner opposite to cell density, and is able to overcome cell contact inhibition. Inhibition of YAP function restores contact inhibition in a human cancer cell line bearing deletion of Salvador (Sav), a Hippo pathway component. Interestingly, we observed that YAP protein is elevated and nuclear localized in some human liver and prostate cancers. Our observations demonstrate that YAP plays a key role in the Hippo pathway to control cell proliferation in response to cell contact.

AB - The Hippo pathway plays a key role in organ size control by regulating cell proliferation and apoptosis in Drosophila. Although recent genetic studies have shown that the Hippo pathway is regulated by the NF2 and Fat tumor suppressors, the physiological regulations of this pathway are unknown. Here we show that in mammalian cells, the transcription coactivator YAP (Yes-associated protein), is inhibited by cell density via the Hippo pathway. Phosphorylation by the Lats tumor suppressor kinase leads to cytoplasmic translocation and inactivation of the YAP oncoprotein. Furthermore, attenuation of this phosphorylation of YAP or Yorkie (Yki), the Drosophila homolog of YAP, potentiates their growth-promoting function in vivo. Moreover, YAP overexpression regulates gene expression in a manner opposite to cell density, and is able to overcome cell contact inhibition. Inhibition of YAP function restores contact inhibition in a human cancer cell line bearing deletion of Salvador (Sav), a Hippo pathway component. Interestingly, we observed that YAP protein is elevated and nuclear localized in some human liver and prostate cancers. Our observations demonstrate that YAP plays a key role in the Hippo pathway to control cell proliferation in response to cell contact.

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U2 - 10.1101/gad.1602907

DO - 10.1101/gad.1602907

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