Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded

Dev Cell. 2010 Feb 16;18(2):288-99. doi: 10.1016/j.devcel.2009.12.012.

Abstract

The Hippo signaling pathway regulates organ size and tissue homeostasis from Drosophila to mammals. Central to this pathway is a kinase cascade wherein Hippo (Hpo), in complex with Salvador (Sav), phosphorylates and activates Warts (Wts), which in turn phosphorylates and inactivates the Yorkie (Yki) oncoprotein, known as the YAP coactivator in mammalian cells. The FERM domain proteins Merlin (Mer) and Expanded (Ex) are upstream components that regulate Hpo activity through unknown mechanisms. Here we identify Kibra as another upstream component of the Hippo signaling pathway. We show that Kibra functions together with Mer and Ex in a protein complex localized to the apical domain of epithelial cells, and that this protein complex regulates the Hippo kinase cascade via direct binding to Hpo and Sav. These results shed light on the mechanism of Ex and Mer function and implicate Kibra as a potential tumor suppressor with relevance to neurofibromatosis.

Publication types

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

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Cell Line
  • Cell Polarity
  • Drosophila / genetics
  • Drosophila / growth & development*
  • Drosophila / physiology*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / physiology*
  • Female
  • Genes, Insect
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology*
  • Multiprotein Complexes
  • Neurofibromin 2 / genetics
  • Neurofibromin 2 / physiology*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology
  • Oocytes / cytology
  • Oocytes / physiology
  • Phosphoproteins
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology*
  • Proteins / genetics
  • Proteins / physiology
  • Receptors, Notch / genetics
  • Receptors, Notch / physiology
  • Signal Transduction
  • Trans-Activators / genetics
  • Trans-Activators / physiology
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / physiology*

Substances

  • Drosophila Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Multiprotein Complexes
  • N protein, Drosophila
  • Neurofibromin 2
  • Nuclear Proteins
  • Phosphoproteins
  • Proteins
  • Receptors, Notch
  • Trans-Activators
  • Tumor Suppressor Proteins
  • WWC1 protein, human
  • Yki protein, Drosophila
  • ex protein, Drosophila
  • kibra protein, Drosophila
  • merlin, Drosophila
  • Protein-Serine-Threonine Kinases
  • hpo protein, Drosophila