The peptide repeat domain of nucleoporin Nup98 functions as a docking site in transport across the nuclear pore complex

Radu, Aurelian; Moore, Mary Shannon; Blobel, Günter

doi:10.1016/0092-8674(95)90331-3

Cited by 430 publications

(440 citation statements)

References 42 publications

Supporting

Mentioning

424

Contrasting

Unclassified

Order By: Relevance

“…Over the last decades the pioneering work of Gu¨nter Blobel and colleagues has deciphered the fundamental role of KPNA2 proteins in nuclear protein transport (Radu et al, 1995;Chook and Blobel, 2001). It has further been shown that malfunctions in nuclearcytoplasmic shuttling may contribute to carcinogenesis, for example, of breast and colon (Flamini et al, 1996;Lu et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Nuclear transport receptor karyopherin-α2 promotes malignant breast cancer phenotypes in vitro

et al. 2011

View full text Add to dashboard Cite

Tumorigenesis and tumor progression are associated with dysfunction of the nuclear transport machinery at the level of import and export receptors (karyopherins). Recent studies have shown that the nuclear import factor karyopherin-a2 (KPNA2) is a novel prognostic marker for poor prognosis in human breast cancer. Based on the well-defined hallmarks of cancer progression, we performed a detailed in vitro characterization of the phenotypic effects caused by KPNA2 overexpression and KPNA2 silencing in benign and malignant human breast cells. KPNA2 overexpression clearly increased proliferation of MCF7 tumor cells and further led to a reduction of cell-matrix adhesion in benign MCF10A cells, whereas cell migration was significantly increased (Po0.0001) in both tumor models. Remarkably, these individual effects of KPNA2 overexpression on proliferation, cell-matrix adhesion and migration resulted in an increased colony spreading of benign MCF10A breast cells and malignant MCF7 tumor cells (Po0.001), which is a hallmark of cancer progression. Conversely, RNA interference-mediated KPNA2 silencing caused a complete inhibition of MCF7 tumor cell proliferation and migration (Po0.0001). In addition, in these experiments apoptosis was increased (Po0.05) and formation of tumor cell colonies was reduced (Po0.01). Thus, KPNA2 overexpression provoked increased aggressiveness of malignant MCF7 breast tumor cells and induced a shift in benign MCF10A breast cells toward a malignant breast cancer phenotype. In conclusion, we demonstrate for the first time in experimental tumor models that forced KPNA2 expression drives malignant features relevant for breast cancer progression, while its silencing is required for the remission of those progressive phenotypes. This study gives clear evidence that KPNA2 acts as a novel oncogenic factor in human breast cancer, in vitro.

show abstract

Section: Discussionmentioning

confidence: 99%

Nuclear transport receptor karyopherin-α2 promotes malignant breast cancer phenotypes in vitro

et al. 2011

View full text Add to dashboard Cite

show abstract

“…1). At the N-terminal end of each of these appendages are FG-repeat motifs, which are known to function as binding sites for [cargo•transport-factor] complexes (8).…”

Section: Discussionmentioning

confidence: 99%

“…7). Projecting from the scaffold to the center as well as to the cytoplasmic and nucleoplasmic side of the central transport conduit, these FG repeats have a dual function: to capture [cargo•transport-factor] complexes for transport across the central transport conduit (8) and, in an unoccupied state, to also form a permeability barrier (7).…”

mentioning

confidence: 99%

Ring cycle for dilating and constricting the nuclear pore

Solmaz

Blobel

Melčák

2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

We recently showed that the three "channel" nucleoporins, Nup54, Nup58, and Nup62, interact with each other through only four distinct sites and established the crystal structures of the two resulting "interactomes," Nup54•Nup58 and Nup54•Nup62. We also reported instability of the Nup54•Nup58 interactome and previously determined the atomic structure of the relevant Nup58 segment by itself, demonstrating that it forms a twofold symmetric tetramer. Here, we report the crystal structure of the relevant free Nup54 segment and show that it forms a tetrameric, helical bundle that is structurally "conditioned" for instability by a central patch of polar hydrogen-bonded residues. Integrating these data with our previously reported results, we propose a "ring cycle" for dilating and constricting the nuclear pore. In essence, three homooligomeric rings, one consisting of eight modules of Nup58 tetramers, and two, each consisting of eight modules of Nup54 tetramers, are stacked in midplane and characterize a constricted pore of 10-to 20-nm diameter. In going to the dilated state, segments of one Nup58 and two Nup54 tetrameric modules reassort into a dodecameric module, eight of which form a single, heterooligomeric midplane ring, which is flexible in a diameter range of 40-50 nm. The ring cycle would be regulated by phenylalanineglycine regions ("FG repeats") of channel nups. Akin to ligandgated channels, the dilated state of the midplane ring may be stabilized by binding of [cargo•transport-factor] complexes to FG repeats, thereby linking the ratio of constricted to dilated nuclear pores to cellular transport need.ligand gating | X-ray crystallography | nucleo-cytoplasmic transport I n evolution from prokaryotes to eukaryotes, the myriad of reactions yielding cotranscriptional and posttranscriptional assembly of ribonucleoproteins was largely confined to the nuclear compartment. This required the concomitant evolution of transport conduits of a sufficiently large diameter to allow passage of assembled ribonucleoproteins to the cytoplasm. Among these, newly assembled ribosomal subunits presented a special challenge, as they are relatively rigid bodies; the eukaryotic large ribosomal subunit, for example, has a diameter of about 30 nm. Hence, a correspondingly large nuclear pore had to evolve to accommodate the passage of ribosomal subunits, but also to protect against concomitant bidirectional leakage of the myriad of proteins, which are generally much smaller than ribonucleoproteins, to help maintain distinct nucleoplasmic and cytoplasmic proteomes. One way for meeting the challenge to transport diverse substrates of a large size range would be to endow the nuclear pore with the ability to have its central transport channel undergo dilation and constriction. However, as has been argued elsewhere (1), diameter changes in the 30-nm range might buckle the membrane, if channel proteins were directly embedded into the membrane's lipid bilayer. It could be conjectured that evolution of the nuclear pore into the massive protein...

show abstract

“…In contrast, the FG domains of the Nup62 complex and possibly also Nup98 and POM121 are symmetrically anchored into the inner ring (Fig 1A). Although the exact role of the different types of FG‐Nups has to be further investigated, it has been well established that FG‐Nups interact with the soluble phase of the nuclear transport system thereby enabling active nucleocytoplasmic exchange (Fig 1B; Radu et al , 1995; Strawn et al , 2004). This soluble phase consists of the small GTPase RAN, a number of auxiliary factors as well as nuclear transport receptors (NTRs) that transiently interact with FG‐repeats but also explore the open space of cytoplasm and nucleoplasm to recruit cargos.…”

Section: Introductionmentioning

confidence: 99%

Landscape of nuclear transport receptor cargo specificity

Mackmull

Klaus

Heinze

et al. 2017

Molecular Systems Biology

View full text Add to dashboard Cite

Nuclear transport receptors (NTRs) recognize localization signals of cargos to facilitate their passage across the central channel of nuclear pore complexes (NPCs). About 30 different NTRs constitute different transport pathways in humans and bind to a multitude of different cargos. The exact cargo spectrum of the majority of NTRs, their specificity and even the extent to which active nucleocytoplasmic transport contributes to protein localization remains understudied because of the transient nature of these interactions and the wide dynamic range of cargo concentrations. To systematically map cargo–NTR relationships in situ, we used proximity ligation coupled to mass spectrometry (BioID). We systematically fused the engineered biotin ligase BirA* to 16 NTRs. We estimate that a considerable fraction of the human proteome is subject to active nuclear transport. We quantified the specificity and redundancy in NTR interactions and identified transport pathways for cargos. We extended the BioID method by the direct identification of biotinylation sites. This approach enabled us to identify interaction interfaces and to discriminate direct versus piggyback transport mechanisms. Data are available via ProteomeXchange with identifier PXD007976.

show abstract

The peptide repeat domain of nucleoporin Nup98 functions as a docking site in transport across the nuclear pore complex

Cited by 430 publications

References 42 publications

Nuclear transport receptor karyopherin-α2 promotes malignant breast cancer phenotypes in vitro

Nuclear transport receptor karyopherin-α2 promotes malignant breast cancer phenotypes in vitro

Ring cycle for dilating and constricting the nuclear pore

Landscape of nuclear transport receptor cargo specificity

Contact Info

Product

Resources

About