The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to expanded

Chen Ling, Yonggang Zheng, Feng Yin, Jianzhong Yu, Juan Huang, Yang Hong, Shian Wu, Duojia Pan

Research output: Contribution to journalArticle

216 Citations (Scopus)

Abstract

The Hippo signaling pathway regulates organ size and tissue homeostasis from Drosophila to mammals. At the core of the Hippo pathway is a kinase cascade extending from the Hippo (Hpo) tumor suppressor to the Yorkie (Yki) oncoprotein. The Hippo kinase cascade, in turn, is regulated by apical membrane-associated proteins such as the FERM domain proteins Merlin and Expanded (Ex), and the WW- and C2-domain protein Kibra. How these apical proteins are themselves regulated remains poorly understood. Here, we identify the transmembrane protein Crumbs (Crb), a determinant of epithelial apical-basal polarity in Drosophila embryos, as an upstream component of the Hippo pathway in imaginal disk growth control. Loss of Crb leads to tissue overgrowth and target gene expression characteristic of defective Hippo signaling. Crb directly binds to Ex through its juxtamembrane FERM-binding motif (FBM). Loss of Crb or mutation of its FBM leads to mislocalization of Ex to basolateral domain of imaginal disk epithelial cells. These results shed light on the mechanism of Ex regulation and provide a molecular link between apical-basal polarity and tissue growth. Furthermore, our studies implicate Crb as a putative cell surface receptor for Hippo signaling by uncovering a transmembrane protein that directly binds to an apical component of the Hippo pathway.

Original languageEnglish (US)
Pages (from-to)10532-10537
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number23
DOIs
StatePublished - Jun 8 2010

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Imaginal Discs
Drosophila
Neoplasms
Proteins
Phosphotransferases
Neurofibromin 2
Organ Size
Oncogene Proteins
Cell Surface Receptors
Growth
Mammals
Membrane Proteins
Homeostasis
Embryonic Structures
Epithelial Cells
Gene Expression
Mutation
C2 Domains
Protein Domains

Keywords

  • Apical-basal polarity
  • Development
  • Drosophila
  • Organ size
  • Signal transduction

ASJC Scopus subject areas

  • General

Cite this

The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to expanded. / Ling, Chen; Zheng, Yonggang; Yin, Feng; Yu, Jianzhong; Huang, Juan; Hong, Yang; Wu, Shian; Pan, Duojia.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 23, 08.06.2010, p. 10532-10537.

Research output: Contribution to journalArticle

Ling, Chen ; Zheng, Yonggang ; Yin, Feng ; Yu, Jianzhong ; Huang, Juan ; Hong, Yang ; Wu, Shian ; Pan, Duojia. / The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to expanded. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 23. pp. 10532-10537.
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