hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts

Cell. 2003 Aug 22;114(4):445-56. doi: 10.1016/s0092-8674(03)00549-x.

Abstract

The coordination between cell proliferation and cell death is essential to maintain homeostasis within multicellular organisms. The mechanisms underlying this regulation are yet to be completely understood. Here, we report the identification of hippo (hpo) as a gene that regulates both cell proliferation and cell death in Drosophila. hpo encodes a Ste-20 family protein kinase that binds to and phosphorylates the tumor suppressor protein Salvador (Sav), which is known to interact with the Warts (Wts) protein kinase. Loss of hpo results in elevated transcription of the cell cycle regulator cyclin E and the cell-death inhibitor diap1, leading to increased proliferation and reduced apoptosis. Further, we show that hpo, sav, and wts define a pathway that regulates diap1 at the transcriptional level. A human homolog of hpo completely rescues the overgrowth phenotype of Drosophila hpo mutants, suggesting that hpo might play a conserved role for growth control in mammals.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis / physiology*
  • Cell Cycle Proteins / metabolism*
  • Cell Division / physiology*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / physiology
  • Drosophila melanogaster / ultrastructure
  • Genes, Insect
  • Genes, Tumor Suppressor
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • MAP Kinase Kinase Kinases
  • Molecular Sequence Data
  • Phenotype
  • Phosphorylation
  • Protein Kinases*
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Saccharomyces cerevisiae Proteins*
  • Two-Hybrid System Techniques
  • Wings, Animal / anatomy & histology

Substances

  • Cell Cycle Proteins
  • Drosophila Proteins
  • Intracellular Signaling Peptides and Proteins
  • Saccharomyces cerevisiae Proteins
  • sav protein, Drosophila
  • Protein Kinases
  • LATS1 protein, human
  • wts protein, Drosophila
  • Protein-Serine-Threonine Kinases
  • hpo protein, Drosophila
  • MAP Kinase Kinase Kinases
  • STE20 protein, S cerevisiae