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JNK phosphorylation of 14-3-3 proteins regulates nuclear targeting of c-Abl in the apoptotic response to DNA damage

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Abstract

The ubiquitously expressed c-Abl tyrosine kinase localizes to the cytoplasm and nucleus1,2. Nuclear c-Abl is activated by diverse genotoxic agents and induces apoptosis3,4; however, the mechanisms that are responsible for nuclear targeting of c-Abl remain unclear. Here, we show that cytoplasmic c-Abl is targeted to the nucleus in the DNA damage response. The results show that c-Abl is sequestered into the cytoplasm by binding to 14-3-3 proteins. Phosphorylation of c-Abl on Thr 735 functions as a site for direct binding to 14-3-3 proteins. We also show that, in response to DNA damage, activation of the c-Jun N-terminal kinase (Jnk) induces phosphorylation of 14-3-3 proteins and their release from c-Abl. Together with these results, expression of an unphosphorylated 14-3-3 mutant attenuates DNA-damage-induced nuclear import of c-Abl and apoptosis. These findings indicate that 14-3-3 proteins are pivotal regulators of intracellular c-Abl localization and of the apoptotic response to genotoxic stress.

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Acknowledgements

This work was supported by grants from the Ministry of Education, Science and Culture of Japan (K.Y. and Y.M.), the Mitsubishi Pharma Research Foundation (K.Y.), the Tokyo Biochemical Research Foundation (K.Y.), Uehara Memorial Foundation (K.Y.) and also by grants CA29431 and CA98628 from the National Cancer Institute (D.K.).

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Competing interests

The authors declare no competing financial interests.

Correspondence to Kiyotsugu Yoshida or Yoshio Miki.

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    Supplementary Figures S1, S2, S3, S4 (PDF 111 kb)

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https://doi.org/10.1038/ncb1228

Further reading

Figure 1: Nuclear translocation of c-ABL in response to DNA damage.
Figure 2: c-ABL interacts with 14-3-3 proteins in the cytoplasm.
Figure 3: Phosphorylated Thr 735 of c-ABL is the binding site for 14-3-3 proteins.
Figure 4: c-Jun N-terminal kinase (JNK) induces release of c-ABL from 14-3-3 proteins in response to DNA damage.
Figure 5: 14-3-3 proteins attenuate c-ABL-mediated apoptosis in response to DNA damage.