The fat cadherin acts through the hippo tumor-suppressor pathway to regulate tissue size

Curr Biol. 2006 Nov 7;16(21):2090-100. doi: 10.1016/j.cub.2006.09.005. Epub 2006 Sep 21.

Abstract

Background: The Hippo tumor-suppressor pathway has emerged as a key signaling pathway that controls tissue size in Drosophila. Merlin, the Drosophila homolog of the human Neurofibromatosis type-2 (NF2) tumor-suppressor gene, and the related protein Expanded are the most upstream components of the Hippo pathway identified so far. However, components acting upstream of Expanded and Merlin, such as transmembrane receptors, have not yet been identified.

Results: Here, we report that the protocadherin Fat acts as an upstream component in the Hippo pathway. Fat is a known tumor-suppressor gene in Drosophila, and fat mutants have severely overgrown imaginal discs. We found that the overgrowth phenotypes of fat mutants are similar to those of mutants in Hippo pathway components: fat mutant cells continued to proliferate after wild-type cells stopped proliferating, and fat mutant cells deregulated Hippo target genes such as cyclin E and diap1. Fat acts genetically and biochemically upstream of other Hippo pathway components such as Expanded, the Hippo and Warts kinases, and the transcriptional coactivator Yorkie. Fat is required for the stability of Expanded and its localization to the plasma membrane. In contrast, Fat is not required for Merlin localization, and Fat and Merlin act in parallel in growth regulation.

Conclusions: Taken together, our data identify a cell-surface molecule that may act as a receptor of the Hippo signaling pathway.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cadherins / genetics
  • Cadherins / physiology
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / physiology*
  • Cell Proliferation
  • Drosophila / embryology
  • Drosophila / genetics
  • Drosophila / physiology*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila Proteins / physiology*
  • Eye / embryology
  • Eye / ultrastructure
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins / metabolism
  • Neurofibromin 2 / metabolism
  • Nuclear Proteins / metabolism
  • Phenotype
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction*
  • Trans-Activators / metabolism
  • Wings, Animal / anatomy & histology

Substances

  • Cadherins
  • Cell Adhesion Molecules
  • Drosophila Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Neurofibromin 2
  • Nuclear Proteins
  • Trans-Activators
  • Yki protein, Drosophila
  • ex protein, Drosophila
  • ft protein, Drosophila
  • merlin, Drosophila
  • Protein Kinases
  • wts protein, Drosophila
  • Protein-Serine-Threonine Kinases
  • hpo protein, Drosophila