Delineation of a Fat tumor suppressor pathway

Nat Genet. 2006 Oct;38(10):1142-50. doi: 10.1038/ng1887. Epub 2006 Sep 17.

Abstract

Recent studies in Drosophila melanogaster of the protocadherins Dachsous and Fat suggest that they act as ligand and receptor, respectively, for an intercellular signaling pathway that influences tissue polarity, growth and gene expression, but the basis for signaling downstream of Fat has remained unclear. Here, we characterize functional relationships among D. melanogaster tumor suppressors and identify the kinases Discs overgrown and Warts as components of a Fat signaling pathway. fat, discs overgrown and warts regulate a common set of downstream genes in multiple tissues. Genetic experiments position the action of discs overgrown upstream of the Fat pathway component dachs, whereas warts acts downstream of dachs. Warts protein coprecipitates with Dachs, and Warts protein levels are influenced by fat, dachs and discs overgrown in vivo, consistent with its placement as a downstream component of the pathway. The tumor suppressors Merlin, expanded, hippo, salvador and mob as tumor suppressor also share multiple Fat pathway phenotypes but regulate Warts activity independently. Our results functionally link what had been four disparate groups of D. melanogaster tumor suppressors, establish a basic framework for Fat signaling from receptor to transcription factor and implicate Warts as an integrator of multiple growth control signals.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Cell Cycle Proteins / genetics
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster
  • Gene Expression Regulation
  • Genes, Tumor Suppressor*
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins / genetics
  • Myosins / genetics
  • Myosins / metabolism
  • Neurofibromin 2 / genetics
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Signal Transduction*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism

Substances

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