The Merlin/NF2 Tumor Suppressor Functions through the YAP Oncoprotein to Regulate Tissue Homeostasis in Mammals

Nailing Zhang, Haibo Bai, Karen K. David, Jixin Dong, Yonggang Zheng, Jing Cai, Marco Giovannini, Pentao Liu, Robert A. Anders, Duojia Pan

Research output: Contribution to journalArticle

366 Citations (Scopus)

Abstract

The conserved Hippo signaling pathway regulates organ size in Drosophila and mammals. While a core kinase cascade leading from the protein kinase Hippo (Hpo) (Mst1 and Mst2 in mammals) to the transcription coactivator Yorkie (Yki) (YAP in mammals) has been established, upstream regulators of the Hippo kinase cascade are less well defined, especially in mammals. Using conditional knockout mice, we demonstrate that the Merlin/NF2 tumor suppressor and the YAP oncoprotein function antagonistically to regulate liver development. While inactivation of Yap led to loss of hepatocytes and biliary epithelial cells, inactivation of Nf2 led to hepatocellular carcinoma and bile duct hamartoma. Strikingly, the Nf2-deficient phenotypes in multiple tissues were largely suppressed by heterozygous deletion of Yap, suggesting that YAP is a major effector of Merlin/NF2 in growth regulation. Our studies link Merlin/NF2 to mammalian Hippo signaling and implicate YAP activation as a mediator of pathologies relevant to Neurofibromatosis 2.

Original languageEnglish (US)
Pages (from-to)27-38
Number of pages12
JournalDevelopmental Cell
Volume19
Issue number1
DOIs
StatePublished - Jul 1 2010

Fingerprint

Tissue homeostasis
Neurofibromin 2
Mammals
Oncogene Proteins
Tumors
Homeostasis
Neoplasms
Phosphotransferases
Neurofibromatosis 2
Hamartoma
Organ Size
Pathology
Transcription
Bile Ducts
Knockout Mice
Liver
Ducts
Protein Kinases
Drosophila
Hepatocytes

Keywords

  • Devbio
  • Humdisease

ASJC Scopus subject areas

  • Developmental Biology

Cite this

The Merlin/NF2 Tumor Suppressor Functions through the YAP Oncoprotein to Regulate Tissue Homeostasis in Mammals. / Zhang, Nailing; Bai, Haibo; David, Karen K.; Dong, Jixin; Zheng, Yonggang; Cai, Jing; Giovannini, Marco; Liu, Pentao; Anders, Robert A.; Pan, Duojia.

In: Developmental Cell, Vol. 19, No. 1, 01.07.2010, p. 27-38.

Research output: Contribution to journalArticle

Zhang, N, Bai, H, David, KK, Dong, J, Zheng, Y, Cai, J, Giovannini, M, Liu, P, Anders, RA & Pan, D 2010, 'The Merlin/NF2 Tumor Suppressor Functions through the YAP Oncoprotein to Regulate Tissue Homeostasis in Mammals', Developmental Cell, vol. 19, no. 1, pp. 27-38. https://doi.org/10.1016/j.devcel.2010.06.015
Zhang, Nailing ; Bai, Haibo ; David, Karen K. ; Dong, Jixin ; Zheng, Yonggang ; Cai, Jing ; Giovannini, Marco ; Liu, Pentao ; Anders, Robert A. ; Pan, Duojia. / The Merlin/NF2 Tumor Suppressor Functions through the YAP Oncoprotein to Regulate Tissue Homeostasis in Mammals. In: Developmental Cell. 2010 ; Vol. 19, No. 1. pp. 27-38.
@article{755c647b7e2d4a45a418f291d274e523,
title = "The Merlin/NF2 Tumor Suppressor Functions through the YAP Oncoprotein to Regulate Tissue Homeostasis in Mammals",
abstract = "The conserved Hippo signaling pathway regulates organ size in Drosophila and mammals. While a core kinase cascade leading from the protein kinase Hippo (Hpo) (Mst1 and Mst2 in mammals) to the transcription coactivator Yorkie (Yki) (YAP in mammals) has been established, upstream regulators of the Hippo kinase cascade are less well defined, especially in mammals. Using conditional knockout mice, we demonstrate that the Merlin/NF2 tumor suppressor and the YAP oncoprotein function antagonistically to regulate liver development. While inactivation of Yap led to loss of hepatocytes and biliary epithelial cells, inactivation of Nf2 led to hepatocellular carcinoma and bile duct hamartoma. Strikingly, the Nf2-deficient phenotypes in multiple tissues were largely suppressed by heterozygous deletion of Yap, suggesting that YAP is a major effector of Merlin/NF2 in growth regulation. Our studies link Merlin/NF2 to mammalian Hippo signaling and implicate YAP activation as a mediator of pathologies relevant to Neurofibromatosis 2.",
keywords = "Devbio, Humdisease",
author = "Nailing Zhang and Haibo Bai and David, {Karen K.} and Jixin Dong and Yonggang Zheng and Jing Cai and Marco Giovannini and Pentao Liu and Anders, {Robert A.} and Duojia Pan",
year = "2010",
month = "7",
day = "1",
doi = "10.1016/j.devcel.2010.06.015",
language = "English (US)",
volume = "19",
pages = "27--38",
journal = "Developmental Cell",
issn = "1534-5807",
publisher = "Cell Press",
number = "1",

}

TY - JOUR

T1 - The Merlin/NF2 Tumor Suppressor Functions through the YAP Oncoprotein to Regulate Tissue Homeostasis in Mammals

AU - Zhang, Nailing

AU - Bai, Haibo

AU - David, Karen K.

AU - Dong, Jixin

AU - Zheng, Yonggang

AU - Cai, Jing

AU - Giovannini, Marco

AU - Liu, Pentao

AU - Anders, Robert A.

AU - Pan, Duojia

PY - 2010/7/1

Y1 - 2010/7/1

N2 - The conserved Hippo signaling pathway regulates organ size in Drosophila and mammals. While a core kinase cascade leading from the protein kinase Hippo (Hpo) (Mst1 and Mst2 in mammals) to the transcription coactivator Yorkie (Yki) (YAP in mammals) has been established, upstream regulators of the Hippo kinase cascade are less well defined, especially in mammals. Using conditional knockout mice, we demonstrate that the Merlin/NF2 tumor suppressor and the YAP oncoprotein function antagonistically to regulate liver development. While inactivation of Yap led to loss of hepatocytes and biliary epithelial cells, inactivation of Nf2 led to hepatocellular carcinoma and bile duct hamartoma. Strikingly, the Nf2-deficient phenotypes in multiple tissues were largely suppressed by heterozygous deletion of Yap, suggesting that YAP is a major effector of Merlin/NF2 in growth regulation. Our studies link Merlin/NF2 to mammalian Hippo signaling and implicate YAP activation as a mediator of pathologies relevant to Neurofibromatosis 2.

AB - The conserved Hippo signaling pathway regulates organ size in Drosophila and mammals. While a core kinase cascade leading from the protein kinase Hippo (Hpo) (Mst1 and Mst2 in mammals) to the transcription coactivator Yorkie (Yki) (YAP in mammals) has been established, upstream regulators of the Hippo kinase cascade are less well defined, especially in mammals. Using conditional knockout mice, we demonstrate that the Merlin/NF2 tumor suppressor and the YAP oncoprotein function antagonistically to regulate liver development. While inactivation of Yap led to loss of hepatocytes and biliary epithelial cells, inactivation of Nf2 led to hepatocellular carcinoma and bile duct hamartoma. Strikingly, the Nf2-deficient phenotypes in multiple tissues were largely suppressed by heterozygous deletion of Yap, suggesting that YAP is a major effector of Merlin/NF2 in growth regulation. Our studies link Merlin/NF2 to mammalian Hippo signaling and implicate YAP activation as a mediator of pathologies relevant to Neurofibromatosis 2.

KW - Devbio

KW - Humdisease

UR - http://www.scopus.com/inward/record.url?scp=77954945373&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954945373&partnerID=8YFLogxK

U2 - 10.1016/j.devcel.2010.06.015

DO - 10.1016/j.devcel.2010.06.015

M3 - Article

VL - 19

SP - 27

EP - 38

JO - Developmental Cell

JF - Developmental Cell

SN - 1534-5807

IS - 1

ER -