期刊
CELLULAR AND MOLECULAR LIFE SCIENCES
卷 70, 期 1, 页码 137-152出版社
SPRINGER BASEL AG
DOI: 10.1007/s00018-012-1075-5
关键词
Non-receptor tyrosine kinase; Cytonuclear localization; Nucleus; Phosphorylation; Protein phosphatase; Calcineurin
资金
- Inserm
- UPMC
- Agence nationale de la recherche [ANR-08-BLAN-0287-02]
- Fondation pour la recherche medicale (FRM)
- Association pour la recherche contre le cancer (ARC)
- Fondation pour la recherche sur le cerveau (FRC)
- Framework Program 7 (SynSys)
- European research council (ERC)
- Agence Nationale de la Recherche (ANR) [ANR-08-BLAN-0287] Funding Source: Agence Nationale de la Recherche (ANR)
Cytonuclear signaling is essential for long-term alterations of cellular properties. Several pathways involving regulated nuclear accumulation of Ser/Thr kinases have been described but little is known about cytonuclear trafficking of tyrosine kinases. Proline-rich tyrosine kinase 2 (Pyk2) is a cytoplasmic non-receptor tyrosine kinase enriched in neurons and involved in functions ranging from synaptic plasticity to bone resorption, as well as in cancer. We previously showed the Ca2+-induced, calcineurin-dependent, nuclear localization of Pyk2. Here, we characterize the molecular mechanisms of Pyk2 cytonuclear localization in transfected PC12 cells. The 700-841 linker region of Pyk2 recapitulates its depolarization-induced nuclear accumulation. This region includes a nuclear export motif regulated by phosphorylation at residue S778, a substrate of cAMP-dependent protein kinase and calcineurin. Nuclear import is controlled by a previously identified sequence in the N-terminal domain and by a novel nuclear targeting signal in the linker region. Regulation of cytonuclear trafficking is independent of Pyk2 activity. The region regulating nuclear localization is absent from the non-neuronal shorter splice isoform of Pyk2. Our results elucidate the mechanisms of Ca2+-induced nuclear accumulation of Pyk2. They also suggest that Pyk2 nuclear accumulation is a novel type of signaling response that may contribute to specific long-term adaptations in neurons.
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