Analysis and prediction of leucine-rich nuclear export signals

Cour, Tanja la; Kiemer, Lars; Mølgaard, Anne; Gupta, Ramneek; Skriver, Karen; Brunak, Søren

doi:10.1093/protein/gzh062

Cited by 706 publications

(665 citation statements)

References 72 publications

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“…This indicated the presence of one or several LMB-sensitive NES in GFP-Pyk2 700-841 . The L 730 LAPKLQFQVP sequence of Pyk2A was identified as putative NES by the NetNES 1.1 server [41]. We mutated the 3 hydrophobic residues (L735A/F737A/V739A, i.e.…”

Section: Resultsmentioning

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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Section: Resultsmentioning

confidence: 99%

Pyk2 cytonuclear localization: mechanisms and regulation by serine dephosphorylation

Faure

Ramos

Girault

2012

Cell. Mol. Life Sci.

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“…The RASSF1A/p120 E4F association was found to enhance G1 cell-cycle arrest and S-phase inhibition and promote the stabilization of cyclins (Fajas et al, 2001;Fenton et al, 2004). Within the primary sequence of RASSF1A, two potential nuclear export sequences can be found that follow the consensus sequence, LxxxLxxL (la Cour et al, 2004): 10 LIELREL and 301 LHNFLRIL (numbers denote amino-acid number within the primary sequence of human RASSF1A). It is interesting that 17/35 (48%) of the leucine residues within the primary sequence are found within the last 100 amino acids.…”

Section: Discussionmentioning

confidence: 99%

Functional importance of RASSF1A microtubule localization and polymorphisms

2010

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Ras association domain family protein 1A (RASSF1A) is one of the more heavily methylated genes in human cancers. In addition to promoter-specific methylation, RASSF1A polymorphisms have been identified in cancer patients. RASSF1A is a tumor suppressor protein involved in death receptor-dependent apoptosis and it is localized to microtubules. Currently, the biological importance of RASSF1A microtubule localization and the functional consequences of RASSF1A polymorphisms is not understood. In this study, we have investigated both RASSF1A microtubule association and polymorphisms. Loss of RASSF1A microtubule association resulted in the nuclear appearance of RASSF1A and the loss of association with a-, c-and b-tubulin. Moreover, the loss of microtubule localization of RASSF1A resulted in enhanced tumorpromoting potential, as determined by a xenograft transplantation model in nude mice. It is surprising that, several RASSF1A polymorphisms also lost the ability to associate with a-, c-and b-tubulin and lost the ability to prevent tumor formation in a xenograft nude mouse model when compared with wild-type RASSF1A. Our results demonstrate a role for RASSF1A microtubule localization in eliciting its tumor suppressor function. In addition, some RASSF1A polymorphisms lack the tumor suppressor function of RASSF1A and, if present in patients, may be tumorigenic.

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“…Fluc-EGFP and FlucDM-EGFP were tagged with either a nuclear export signal (NES) (shown in yellow) or a nuclear localization signal (NLS) (shown in red) at the N-terminus to study proteostasis of the cytoplasm and the nucleus respectively. whereas, NES was derived from a consensus sequence obtained from prediction algorithm program (The NES predictor, NetNES) (http://www.cbs.dtu.dk/services/NetNES/) using experimentally validated sequences rich in leucine residues (la Cour et al, 2004).…”

Section: Egfp Variantsmentioning

confidence: 99%