Molecular evolution of the Yap/Yorkie proto-oncogene and elucidation of its core transcriptional program

Mol Biol Evol. 2014 Jun;31(6):1375-90. doi: 10.1093/molbev/msu071. Epub 2014 Feb 8.

Abstract

Throughout Metazoa, developmental processes are controlled by a surprisingly limited number of conserved signaling pathways. Precisely how these signaling cassettes were assembled in early animal evolution remains poorly understood, as do the molecular transitions that potentiated the acquisition of their myriad developmental functions. Here we analyze the molecular evolution of the proto-oncogene yes-associated protein (Yap)/Yorkie, a key effector of the Hippo signaling pathway that controls organ size in both Drosophila and mammals. Based on heterologous functional analysis of evolutionarily distant Yap/Yorkie orthologs, we demonstrate that a structurally distinct interaction interface between Yap/Yorkie and its partner TEAD/Scalloped became fixed in the eumetazoan common ancestor. We then combine transcriptional profiling of tissues expressing phylogenetically diverse forms of Yap/Yorkie with ChIP-seq validation to identify a common downstream gene expression program underlying the control of tissue growth in Drosophila. Intriguingly, a subset of the newly identified Yorkie target genes are also induced by Yap in mammalian tissues, thus revealing a conserved Yap-dependent gene expression signature likely to mediate organ size control throughout bilaterian animals. Combined, these experiments provide new mechanistic insights while revealing the ancient evolutionary history of Hippo signaling.

Keywords: Metazoa; Yap; evolution; growth control; target genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Drosophila Proteins / chemistry
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / growth & development
  • Evolution, Molecular*
  • Eye / growth & development
  • Eye / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mammals / metabolism
  • Molecular Sequence Data
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phylogeny
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / metabolism*
  • Sequence Analysis, RNA
  • Trans-Activators / chemistry
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism

Substances

  • Drosophila Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Trans-Activators
  • Yki protein, Drosophila
  • Protein-Serine-Threonine Kinases
  • hpo protein, Drosophila

Associated data

  • GEO/GSE54603