KIBRA exhibits MST-independent functional regulation of the Hippo signaling pathway in mammals

Oncogene. 2013 Apr 4;32(14):1821-30. doi: 10.1038/onc.2012.196. Epub 2012 May 21.

Abstract

The Salvador/Warts/Hippo (Hippo) signaling pathway defines a novel signaling cascade regulating cell contact inhibition, organ size control, cell growth, proliferation, apoptosis and cancer development in mammals. The upstream regulation of this pathway has been less well defined than the core kinase cassette. KIBRA has been shown to function as an upstream member of the Hippo pathway by influencing the phosphorylation of LATS and YAP, but functional consequences of these biochemical changes have not been previously addressed. We show that in MCF10A cells, loss of KIBRA expression displays epithelial-to-mesenchymal transition (EMT) features, which are concomitant with decreased LATS and YAP phosphorylation, but not MST1/2. In addition, ectopic KIBRA expression antagonizes YAP via the serine 127 phosphorylation site and we show that KIBRA, Willin and Merlin differentially regulate genes controlled by YAP. Finally, reduced KIBRA expression in primary breast cancer specimens correlates with the recently described claudin-low subtype, an aggressive sub-group with EMT features and a poor prognosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Blotting, Western
  • Breast / cytology
  • Breast / metabolism
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carcinoma, Ductal, Breast / genetics
  • Carcinoma, Ductal, Breast / metabolism
  • Carcinoma, Ductal, Breast / pathology
  • Cell Adhesion
  • Cell Cycle Proteins
  • Cell Movement
  • Cell Proliferation
  • Cells, Cultured
  • Claudin-1 / genetics
  • Claudin-1 / metabolism
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • Epithelial-Mesenchymal Transition*
  • Female
  • Gene Expression Profiling
  • Hepatocyte Growth Factor / antagonists & inhibitors
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / metabolism*
  • Humans
  • Immunoenzyme Techniques
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Neurofibromin 2 / genetics
  • Neurofibromin 2 / metabolism
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Oligonucleotide Array Sequence Analysis
  • Phosphoproteins / antagonists & inhibitors
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Biomarkers, Tumor
  • CLDN1 protein, human
  • Cell Cycle Proteins
  • Claudin-1
  • Cytoskeletal Proteins
  • FRMD6 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Neurofibromin 2
  • Nuclear Proteins
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Transcription Factors
  • WWC1 protein, human
  • YY1AP1 protein, human
  • macrophage stimulating protein
  • Hepatocyte Growth Factor
  • LATS1 protein, human
  • STK3 protein, human
  • Protein-Serine-Threonine Kinases