A novel role for the nuclear membrane protein emerin in association of the centrosome to the outer nuclear membrane

Salpingidou, Georgia; Smertenko, Andrei; Hausmanowa-Petrucewicz, Irena; Hussey, Patrick J.; Hutchison, Chris

doi:10.1083/jcb.200702026

Cited by 177 publications

(186 citation statements)

References 29 publications

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“…Indeed, values of 40-50 m are not unusual. To put these numbers in perspective, loss of emerin or A-type lamins leads to a 3-to 4-m separation between the centrosome and nucleus (37,38). Our findings suggest that Nesp4 expression does not simply disrupt centrosome tethering, but actively drives the separation of these structures.…”

Section: Resultsmentioning

confidence: 91%

Nesprin 4 is an outer nuclear membrane protein that can induce kinesin-mediated cell polarization

Roux

Crisp

Liu

et al. 2009

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

319

348

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Nucleocytoplasmic coupling is mediated by outer nuclear membrane (ONM) nesprin proteins and inner nuclear membrane Sun proteins. Interactions spanning the perinuclear space create nesprin-Sun complexes connecting the cytoskeleton to nuclear components. A search for proteins displaying a conserved C-terminal sequence present in nesprins 1-3 identified nesprin 4 (Nesp4), a new member of this family. Nesp4 is a kinesin-1-binding protein that displays Sun-dependent localization to the ONM. Expression of Nesp4 is associated with dramatic changes in cellular organization involving relocation of the centrosome and Golgi apparatus relative to the nucleus. These effects can be accounted for entirely by Nesp4's kinesin-binding function. The implication is that Nesp4 may contribute to microtubule-dependent nuclear positioning.centrosome ͉ LINC complex ͉ nuclear envelope T he nuclear envelope (NE) forms the interface between the nucleus and cytoplasm acting as a selective barrier that regulates nucleo-cytoplasmic traffic (1). In addition to this partition function, accumulating evidence reveals an essential role for the NE as a determinant of higher-order nuclear and chromatin organization (2). More surprising are findings that the NE directly impacts cytoskeletal architecture and in this way may help define the mechanical properties of the cell as a whole (3). The molecular bases for these effects are now emerging, uniting aspects of cellular physiology from mechanotransduction to nuclear positioning during differentiation and development (4).The NE is assembled from several elements, the most prominent being inner nuclear membranes (INMs) and outer nuclear membranes (ONMs) separated by a Ϸ40-nm gap or perinuclear space (PNS). The INM and ONM are joined where they are spanned by nuclear pore complexes (NPCs), the mediators of trafficking across the NE. The ONM also displays connections to the peripheral endoplasmic reticulum (ER). Accordingly, the INM, ONM, and ER represent a single membrane system with the PNS forming an extension of the ER lumen.The final feature of the NE is the nuclear lamina, a protein meshwork composed primarily of A-and B-type lamins that lines the nuclear face of the INM (2). The lamina is required for NE integrity and provides chromatin-anchoring sites at the nuclear periphery. Remarkably, aberrant A-type lamin expression, which is linked to several human diseases (5), is associated with altered cytoskeletal mechanics (3). The mechanisms underlying this phenomenon represent an intriguing biological problem.At least 60 NE membrane proteins are known (6). Although most likely reside in the INM, several ONM proteins have been identified (7). These include members of the mammalian nesprin (or syne) family (8, 9), Klarsicht (10) and 12) in Drosophila melanogaster, Anc-1 (13), and 16) in Caenorhabditis elegans, and Kms2 in the fission yeast Schizosaccharomyces pombe (17). A property that each of these has in common is that they interact with cytoskeletal components. They are also united in possessing a...

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Section: Resultsmentioning

confidence: 91%

Nesprin 4 is an outer nuclear membrane protein that can induce kinesin-mediated cell polarization

Roux

Crisp

Liu

et al. 2009

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

319

348

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“…(31,32) In human dermal fibroblasts, it is shown that emerin and microtubules both are necessary for the association of the centrosome with the nuclear envelope. (33) From our results, we inferred the mechanism by which this interaction connects the centrosome and nucleus. We accordingly propose a model in which the centrosome is localized close to the nuclear membrane via the BRCA2-plectin interaction (Fig.…”

Section: Discussionmentioning

confidence: 92%

BRCA2 interacts with the cytoskeletal linker protein plectin to form a complex controlling centrosome localization

et al. 2009

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The breast cancer susceptibility gene (BRCA2) is localized mainly in the nucleus where it plays an important role in DNA damage repair. Some BRCA2 protein is also present in the centrosome. Here, we demonstrate that BRCA2 interacts with plectin, a cytoskeletal cross-linker protein, and that this interaction controls the position of the centrosome. Phosphorylation of plectin by cyclindependent kinase 1 ⁄ cyclin B (CDK1 ⁄ CycB) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of HeLa cells by adding activated CDK1 ⁄ CycB kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane. Plectin has six homologous ankyrin-like repeat domains (termed PLEC M1-M6). Using a pull-down assay, we found that GST-PLEC M1 and a GST-C-terminal region fusion protein (which comprised PLEC M6, along with an adjacent vimentin site) interacted with BRCA2. Since each PLEC module exhibits high homology to the others, the possibility of all six domains participating in this interaction was indicated. Moreover, when PLEC M1 was overexpressed in HeLa cells, it competed with endogenous plectin and inhibited the BRCA2-plectin interaction. This inhibitory effect resulted in dissociation of the centrosomes from the nucleus and increased the rate of micronuclei formation which may lead to carcinogenesis. In addition, when either BRCA2 or plectin was suppressed by the appropriate siRNA, a similar change in centrosomal positioning was observed. We suggest that the BRCA2-plectin interaction plays an important role in the regulation of centrosome localization and also that displacement of the centrosome may result in genomic instability and cancer development. (Cancer Sci 2009; 100: 2115-2125 M utations of breast cancer susceptibility gene (BRCA2), a tumor suppressor gene, are associated with an increased susceptibility to breast and ovarian carcinomas.(1,2) The BRCA2 protein plays important roles in both transcriptional regulation and DNA damage repair mediated by homologous recombination.(3,4) BRCA2 forms complexes with Rad51 that are important for the maintenance of genomic stability during DNA recombination and double-strand break repair.(5,6) Murine embryo fibroblasts that are homozygous for a targeted mutation of Brca2 (BRCA2Tr2014) show centrosome amplification, spontaneous accumulation of chromosomal abnormalities, and defective cytokinesis. (7,8) Recently, we reported that BRCA2 interacts with c-tubulin (a component of the centrosome), has nuclear export and centrosome localization signals, and localizes to the centrosomes during the S and early M phases of the cell cycle.(9,10) Moreover, suppression of BRCA2 using small interfering RNA (siRNA) causes abnormalities in the position or duplication of the centrosome.(7,10) Nevertheless, despite these observations, the function of BRCA2 with respect to the centrosome remains uncertain.Here, we demonstrate that plectin, a cytoskeletal cross-linker protein widel...

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“…The nuclear envelope (NE) consists of the outer and inner nuclear membranes (ONM & INM) (the former being continuous with the rough endoplasmic reticulum, ER), the nuclear pore complexes (NPCs) and the nuclear lamina (NL), which together bridge the cytoskeleton and the various cytosolic organelles in the cytoplasm with the chromatin, the nuclear bodies and the nucleoskeleton inside the nucleus (Salpingidou et al 2007) (see Fig. 2).…”

Section: The Nuclear Lamina As a Stress-resistant Filamentous Networkmentioning

confidence: 99%

Adult stem cell maintenance and tissue regeneration in the ageing context: the role for A‐type lamins as intrinsic modulators of ageing in adult stem cells and their niches

Pekovic

Hutchison

2008

Journal of Anatomy

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Adult stem cells have been identified in most mammalian tissues of the adult body and are known to support the continuous repair and regeneration of tissues. A generalized decline in tissue regenerative responses associated with age is believed to result from a depletion and/or a loss of function of adult stem cells, which itself may be a driving cause of many age-related disease pathologies. Here we review the striking similarities between tissue phenotypes seen in many degenerative conditions associated with old age and those reported in age-related nuclear envelope disorders caused by mutations in the LMNA gene. The concept is beginning to emerge that nuclear filament proteins, A-type lamins, may act as signalling receptors in the nucleus required for receiving and/ or transducing upstream cytosolic signals in a number of pathways central to adult stem cell maintenance as well as adaptive responses to stress. We propose that during ageing and in diseases caused by lamin A mutations, dysfunction of the A-type lamin stress-resistant signalling network in adult stem cells, their progenitors and/or stem cell niches leads to a loss of protection against growth-related stress. This in turn triggers an inappropriate activation or a complete failure of self-renewal pathways with the consequent initiation of stress-induced senescence. As such, A-type lamins should be regarded as intrinsic modulators of ageing within adult stem cells and their niches that are essential for survival to old age.

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A novel role for the nuclear membrane protein emerin in association of the centrosome to the outer nuclear membrane

Cited by 177 publications

References 29 publications

Nesprin 4 is an outer nuclear membrane protein that can induce kinesin-mediated cell polarization

Nesprin 4 is an outer nuclear membrane protein that can induce kinesin-mediated cell polarization

BRCA2 interacts with the cytoskeletal linker protein plectin to form a complex controlling centrosome localization

Adult stem cell maintenance and tissue regeneration in the ageing context: the role for A‐type lamins as intrinsic modulators of ageing in adult stem cells and their niches

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