The Hippo pathway kinase Lats2 prevents DNA damage-induced apoptosis through inhibition of the tyrosine kinase c-Abl

Cell Death Differ. 2013 Oct;20(10):1330-40. doi: 10.1038/cdd.2013.83. Epub 2013 Jul 12.

Abstract

The Hippo pathway is an evolutionarily conserved pathway that controls cell proliferation, organ size, tissue regeneration and stem cell self-renewal. Here we show that it also regulates the DNA damage response. At high cell density, when the Hippo pathway is active, DNA damage-induced apoptosis and the activation of the tyrosine kinase c-Abl were suppressed. At low cell density, overexpression of the Hippo pathway kinase large tumor suppressor 2 (Lats2) inhibited c-Abl activity. This led to reduced phosphorylation of downstream c-Abl substrates, the transcription coactivator Yes-associated protein (Yap) and the tumor suppressor p73. Inhibition of c-Abl by Lats2 was mediated through Lats2 interaction with and phosphorylation of c-Abl. Lats2 knockdown, or expression of c-Abl mutants that escape inhibition by Lats2, enabled DNA damage-induced apoptosis of densely plated cells, while Lats2 overexpression inhibited apoptosis in sparse cells. These findings explain a long-standing enigma of why densely plated cells are radioresistant. Furthermore, they demonstrate that the Hippo pathway regulates cell fate decisions in response to DNA damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics*
  • Cell Count
  • Cell Cycle Proteins
  • Cell Growth Processes / drug effects
  • Cell Growth Processes / genetics
  • DNA Damage*
  • HEK293 Cells
  • Humans
  • Mice
  • NIH 3T3 Cells
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / biosynthesis
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-abl / antagonists & inhibitors*
  • Signal Transduction
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / biosynthesis
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Cell Cycle Proteins
  • Nuclear Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • YY1AP1 protein, human
  • LATS2 protein, human
  • Proto-Oncogene Proteins c-abl
  • Hippo protein, human
  • Protein-Serine-Threonine Kinases