NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway

J Cell Biol. 2011 May 16;193(4):633-42. doi: 10.1083/jcb.201009069. Epub 2011 May 9.

Abstract

The conserved Hippo signaling pathway regulates organ size in Drosophila melanogaster and mammals and has an essential role in tumor suppression and the control of cell proliferation. Recent studies identified activators of Hippo signaling, but antagonists of the pathway have remained largely elusive. In this paper, we show that NPHP4, a known cilia-associated protein that is mutated in the severe degenerative renal disease nephronophthisis, acts as a potent negative regulator of mammalian Hippo signaling. NPHP4 directly interacted with the kinase Lats1 and inhibited Lats1-mediated phosphorylation of the Yes-associated protein (YAP) and TAZ (transcriptional coactivator with PDZ-binding domain), leading to derepression of these protooncogenic transcriptional regulators. Moreover, NPHP4 induced release from 14-3-3 binding and nuclear translocation of YAP and TAZ, promoting TEA domain (TEAD)/TAZ/YAP-dependent transcriptional activity. Consistent with these data, knockdown of NPHP4 negatively affected cellular proliferation and TEAD/TAZ activity, essentially phenocopying loss of TAZ function. These data identify NPHP4 as a negative regulator of the Hippo pathway and suggest that NPHP4 regulates cell proliferation through its effects on Hippo signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / metabolism
  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Proliferation*
  • Female
  • Genes, Reporter
  • HEK293 Cells
  • Humans
  • Immunoprecipitation
  • Kidney / metabolism*
  • Kidney / pathology
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteins / genetics
  • Proteins / metabolism*
  • RNA Interference
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction*
  • Transcription Factors / metabolism
  • Transfection

Substances

  • 14-3-3 Proteins
  • Cell Cycle Proteins
  • NPHP4 protein, human
  • Nuclear Proteins
  • Proteins
  • Recombinant Fusion Proteins
  • TAZ protein, human
  • Transcription Factors
  • YY1AP1 protein, human
  • LATS1 protein, human
  • Protein-Serine-Threonine Kinases