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.
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Abbreviations
- ASPP:
-
apoptosis-stimulating protein of p53
- c-Abl (ABL1):
-
Abelson tyrosine protein kinase 1
- Arg (ABL2):
-
Abl-related gene
- EMT:
-
epithelial to mesenchymal transition
- FACS:
-
fluorescence-activated cell sorting
- Lats:
-
large tumor suppressor
- Mdm:
-
mouse double minute
- Mst:
-
mammalian STE20-like protein kinase
- PARP:
-
poly ADP-ribose polymerase
- RASSF:
-
RAS association domain family
- Rb:
-
retinoblastoma
- Taz:
-
transcription coactivator with PDZ-binding motif
- WW45:
-
45 kDa WW domain protein
- Yap:
-
Yes-associated protein
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Acknowledgements
We thank M Oren and Y Aylon for helpful discussion and for the myc-Lats2 constructs and reagents. We thank XJ Yang for the HA-Lats2, Mst1 and WW45 constructs. We thank G Superti-Furga for the pSLX c-Abl constructs. STI571 was kindly provided by Novartis Pharmaceuticals. We thank R Keshet for providing the pBabe Flag-Yap constructs, and M Elbaz for her technical assistance. This work was supported by grants from the Israel Science Foundation (grant no. 551/11), Israel Cancer Research Fund, the Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ) and Israel’s Ministry of Science and Technology (MOST) and from the Minerva Foundation with funding from the Federal German Ministry for Education and Research.
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Reuven, N., Adler, J., Meltser, V. et al. The Hippo pathway kinase Lats2 prevents DNA damage-induced apoptosis through inhibition of the tyrosine kinase c-Abl. Cell Death Differ 20, 1330–1340 (2013). https://doi.org/10.1038/cdd.2013.83
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DOI: https://doi.org/10.1038/cdd.2013.83
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