Abstract
c-Jun N-terminal kinase (JNK) is activated by dual phosphorylation of both threonine and tyrosine residues in the phosphorylation loop of the protein in response to several stress factors. However, the precise molecular mechanisms for activation after phosphorylation remain elusive. Here we show that Pin1, a peptidyl-prolyl isomerase, has a key role in the JNK1 activation process by modulating a phospho-Thr-Pro motif in the phosphorylation loop. Pin1 overexpression in human breast cancer cell lines correlates with increased JNK activity. In addition, small interfering RNA (siRNA) analyses showed that knockdown of Pin1 in a human breast cancer cell line decreased JNK1 activity. Pin1 associates with JNK1, and then catalyzes prolyl isomerization of the phospho-Thr-Pro motif in JNK1 from trans- to cis-conformation. Furthermore, Pin1 enhances the association of JNK1 with its substrates. As a result, Pin1−/− cells are defective in JNK activation and resistant to oxidative stress. These results provide novel insights that, following stress-induced phosphorylation of Thr in the Thr-Pro motif of JNK1, JNK1 associates with Pin1 and undergoes conformational changes to promote the binding of JNK1 to its substrates, resulting in cellular responses from extracellular signals.
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Abbreviations
- JNK:
-
c-Jun N-terminal kinase
- Pin1:
-
peptidyl-prolyl cis/trans-isomerase
- MEF:
-
mouse embryonic fibroblast
- TCFβ1:
-
T-cell factor β1
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Acknowledgements
We thank Roger Davis, Insug Kang, Jong-Tae Kim, and Seung-Chul Choi for generously providing reagents or technical assistance. This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST; no. 2011-0003139) and by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A01-0385-A70604-07M7-00040B).
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Park, J., Lee, J., Park, S. et al. A critical step for JNK activation: isomerization by the prolyl isomerase Pin1. Cell Death Differ 19, 153–161 (2012). https://doi.org/10.1038/cdd.2011.82
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DOI: https://doi.org/10.1038/cdd.2011.82
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