Leucine-rich nuclear-export signals: born to be weak

Kutay, Ulrike; Güttinger, Stephan

doi:10.1016/j.tcb.2005.01.005

Cited by 297 publications

(329 citation statements)

References 27 publications

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“…Because CRM1 interacts directly with a leucine-rich NES motif, we next examined the primary amino-acid sequences of PP2Aca to determine whether it contains an NES. We found that sequence between 149 and 158 conforms to this motif, as indicated by its similarity to other known NESs such as MAPKK, PKI-a, IkB, TFIIIA, hDM2, p53 and p73 (Gama-Carvalho and Carmo-Fonseca, 2001;Kutay and Guttinger, 2005). On the other hand, we did not find any NES-like sequence in other PP2A subunits.…”

Section: Inhibition Of Cyclin D1 Expression By Leptomycin Bmentioning

confidence: 43%

“…These include cellular proteins, many of which are involved in transcription, cell signaling cascades, oncogenic transformation and regulation of the cell cycle. Examples include PKI, mitogen-activated protein kinase kinase (MAPKK), TFIIIA, Mdm2, p53, IkBa, NMD3, cyclin B1, c-Abl and 14-3-3s (Gama-Carvalho and Carmo-Fonseca, 2001; Kutay and Guttinger, 2005). The activities of these proteins are tightly regulated by their NESs.…”

Section: Introductionmentioning

confidence: 99%

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Involvement of protein phosphatase 2A nuclear accumulation and subsequent inactivation of activator protein-1 in leptomycin B-inhibited cyclin D1 expression

et al. 2006

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Leptomycin B (LMB) is a Streptomyces metabolite that causes the specific inhibition of the nuclear export of proteins containing a nuclear export signal (NES). LMB was reported to inhibit cell cycle progression in fission yeast and mammalian cells, however, the mechanism underlying LMB-induced cell cycle arrest is still obscure. In this study, we found that in serum-starved NIH3T3 cells, LMB inhibited serum-induced cyclin D1 expression at the level of transcription. However, this inhibition was reversed by inhibitors of protein phosphatase 2A (PP2A). Furthermore, we found that PP2A accumulated in the nucleus upon treatment with LMB. The finding prompted us to identify the functional NES in PP2A catalytic subunit a. These results indicated that LMB inhibited the chromosomal region maintenance 1 (CRM1)-dependent nuclear export of PP2A, resulting in sustained dephosphorylation in the nucleus. Although phosphorylation of c-Jun at Ser-63 is required for activator protein 1 (AP-1)-dependent expression of cyclin D1, it decreased in LMBtreated cells compared to untreated cells. Moreover, the inhibitors of PP2A restored the levels of c-Jun phosphorylated at Ser-63. We propose that inhibition of cyclin D1 expression by LMB is mediated by the LMB-induced nuclear accumulation of PP2A, leading to sustained dephosphorylation of c-Jun at Ser-63, which leads to inactivation of the transcription of the AP-1-responsive cyclin D1 gene.

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Section: Inhibition Of Cyclin D1 Expression By Leptomycin Bmentioning

confidence: 43%

Section: Introductionmentioning

confidence: 99%

Involvement of protein phosphatase 2A nuclear accumulation and subsequent inactivation of activator protein-1 in leptomycin B-inhibited cyclin D1 expression

et al. 2006

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“…Surprisingly, however, the deletion of the C-terminal region (residues 1523-1675) on CHC leads to elevated nuclear accumulation, suggesting that CHC has the potential to enter the nucleus and that there might be strong nuclear export or cytoplasmic retention sequences in the C-terminal region containing the trimerization domain of CHC. So far, seven nuclear export factors including CRM1, CAS, Exp-t, Exp-4, -5, -6 and -7 have been identified (Kutay and Guttinger, 2005). Also, some transcription factors are retained in the cytoplasm by certain proteins associated with actin and microtubule cytoskeletons (Ziegler and Ghosh, 2005).…”

Section: Discussionmentioning

confidence: 99%

Monomeric but not trimeric clathrin heavy chain regulates p53-mediated transcription

et al. 2007

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“…Cytonuclear trafficking of proteins larger than 40 kDa results from an active transport mediated by karyopherins, which facilitate translocation of cargos through the nuclear pore and release them in the nucleus, in the case of importins, or in the cytoplasm in the case of exportins [28,29]. The best characterized mechanisms for nuclear import and export are based on the association of cargos that contain nuclear localization signal (NLS) or a hydrophobic nuclear export sequence (NES) with importins and the exportin chromosome region maintenance 1 (CRM1), respectively [30][31][32]. Here we characterize the role of NLS, NES, and other sequences in Pyk2 cytonuclear trafficking and its control by S778 phosphorylation by PKA and dephosphorylation by calcineurin.…”

Section: Introductionmentioning

confidence: 99%

Pyk2 cytonuclear localization: mechanisms and regulation by serine dephosphorylation

Faure

Ramos

Girault

2012

Cell. Mol. Life Sci.

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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 Ca 2? -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 depolarizationinduced 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 Ca 2? -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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Leucine-rich nuclear-export signals: born to be weak

Cited by 297 publications

References 27 publications

Involvement of protein phosphatase 2A nuclear accumulation and subsequent inactivation of activator protein-1 in leptomycin B-inhibited cyclin D1 expression

Involvement of protein phosphatase 2A nuclear accumulation and subsequent inactivation of activator protein-1 in leptomycin B-inhibited cyclin D1 expression

Monomeric but not trimeric clathrin heavy chain regulates p53-mediated transcription

Pyk2 cytonuclear localization: mechanisms and regulation by serine dephosphorylation

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