Nesprin interchain associations control nuclear size

Lu, Wenshu; Schneider, Maria; Neumann, Sandra; Jaeger, Verena; Taranum, Surayya; Munck, Martina; Cartwright, Sarah; Richardson, Christine; Carthew, James; Noh, Kowoon; Goldberg, Martin D.; Noegel, Angelika A.; Karakesisoglou, Iakowos

doi:10.1007/s00018-012-1034-1

Cited by 84 publications

(83 citation statements)

References 70 publications

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“…A Nesprin-1α siRNA mediated knockdown also results in enlarged cell sizes [ 19 ]. Furthermore, morphometric analysis of cells expressing different Nesprin-2 domains shows alterations in nuclear areas as well as cellular sizes [ 21 ] (Fig. 2 ).…”

Section: Nuclear and Cellular Sizementioning

confidence: 96%

“…In addition to the changes in nuclear size, the cell size changed in the same manner. The overexpression of N-or C-term Nesprin-2 polypeptides led to enlarged cells, and the expression of Nesprin-2 mini to cellular compaction [ 21 ]. Whether Nesprins are also crucial factors for nuclear and cellular sizes or the ratio of both in different cancer types is not yet known.…”

Section: Nuclear and Cellular Sizementioning

confidence: 99%

“…Furthermore, Nesprins control nuclear shape and size by forming a protein lattice that covers the NE comparable to the meshwork of lamin proteins residing at the inner surface of the NE to stabilize nuclear morphology [ 21 ]. Based on their structure and size, Nesprins were originally depicted as stiff molecules that are connected to the NE by their C-terminus whereas their N-terminus reaches into the cytoplasm over a distance of 300-500 nm.…”

Section: Nesprins Function As Guardians Of Nuclear Shapementioning

confidence: 99%

“…Interestingly, these interactions do not interfere with the abilities of the Nesprins to interact with their cytoskeletal interaction partners. Based on these fi ndings a novel model was predicted in which the giant Nesprin-1 and -2 molecules form a fi lamentous meshwork encasing the nucleus [ 21 ]. This is achieved through "anchorage" of the giant Nesprins in the NE at two sites, the C-terminus via the KASH domain and the N-terminus by the interaction with the ~100 kDa rather small Nesprin-3.…”

Section: Nesprins Function As Guardians Of Nuclear Shapementioning

confidence: 99%

“…Beside morphological changes nuclear and cellular sizes are modulated as well and tend to be increased upon a loss of Nesprins. ( b ) Overview about Nesprin-2 giant, the biggest Nesprin-2 isoform and the polypeptides used to identify the role of Nesprin-2 in nuclear scaling [ 21 ]. Nesprin-2 N-term aa 1-459 form the calponin homology domains that act as actin binding domains.…”

Section: Nesprins Function As Guardians Of Nuclear Shapementioning

confidence: 99%

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Nesprins in Cell Stability and Migration

Neumann

Noegel

2014

Cancer Biology and the Nuclear Envelope

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Nesprins are a family of proteins that are primarily known for their localization along the nuclear envelope. Together with inner nuclear membrane SUN proteins, they form the core of the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex that traverses both nuclear membranes to connect the cytoplasm and the nuclear interior. Based on their structure and interactions, Nesprins integrate the nucleus into the cytoskeleton of a cell. Mutations in Nesprins have been identified in a group of human diseases that have been summarized as laminopathies. Cellular functions of the Nesprins and recent studies on different cancer types additionally draw interest on Nesprins in the field of cancer research. Here we summarize recent findings about the structural arrangements of Nesprins along the nuclear envelope, and highlight Nesprin functions in basic cellular processes like maintenance of nuclear shape and size, and of nuclear and cellular or cytoskeletal organization, centrosomal positioning, cell migration, and signal transduction. In summary, Nesprins are involved in critical cellular processes, which in case of malfunction contribute to the formation of cancer and might represent novel targets in cancer diagnosis or for therapeutic intervention.

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Section: Nuclear and Cellular Sizementioning

confidence: 96%

Section: Nuclear and Cellular Sizementioning

confidence: 99%

Section: Nesprins Function As Guardians Of Nuclear Shapementioning

confidence: 99%

Section: Nesprins Function As Guardians Of Nuclear Shapementioning

confidence: 99%

Section: Nesprins Function As Guardians Of Nuclear Shapementioning

confidence: 99%

See 3 more Smart Citations

Nesprins in Cell Stability and Migration

Neumann

Noegel

2014

Cancer Biology and the Nuclear Envelope

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Nesprin‐1 and nesprin‐2 regulate endothelial cell shape and migration

et al. 2014

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Nesprins are large multi-domain proteins that link the nuclear envelope to the cytoskeleton and nucleoskeleton. Here we show that nesprin-1 and nesprin-2 play important roles in regulating cell shape and migration in endothelial cells. Nesprin-1 or nesprin-2 depletion by RNAi increased endothelial cell spread area and the length of cellular protrusions, as well as stimulating stress fibre assembly which correlated with an increase in F-actin levels. Nuclear area was also increased by nesprin depletion, and localization of the inner nuclear membrane protein emerin to the nuclear envelope was reduced. Depletion of nesprin-1 or nesprin-2 reduced migration of endothelial cells into a cell-free area, and decreased loop formation in an in vitro angiogenesis assay. Taken together, our results indicate that nesprin-1 and nesprin-2 both regulate nuclear and cytoplasmic architecture, which we propose leads to their effects on endothelial cell migration and angiogenic loop formation.

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Cell Mechanosensitivity to Extremely Low-Magnitude Signals Is Enabled by a LINCed Nucleus

et al. 2015

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A cell’s ability to recognize and adapt to the physical environment is central to its survival and function, but how mechanical cues are perceived and transduced into intracellular signals remains unclear. In mesenchymal stem cells (MSC), high magnitude substrate strain (HMS, ≥2%) effectively suppresses adipogenesis via induction of FAK/mTORC2/Akt signaling generated at focal adhesions [1]. Physiologic systems also rely on a persistent barrage of low level signals to regulate behavior [2]. Exposing MSC to extremely low magnitude mechanical signals (LMS) suppresses adipocyte formation [3] despite the virtual absence of substrate strain (<0.001%) [2], suggesting that LMS-induced dynamic accelerations can generate force within the cell. Here we show that MSC response to LMS is enabled through mechanical coupling between the cytoskeleton and the nucleus, in turn activating focal adhesion kinase (FAK) and Akt signaling followed by FAK-dependent induction of RhoA. While LMS and HMS synergistically regulated FAK activity at the focal adhesions, LMS-induced actin remodeling was concentrated at the perinuclear domain. Preventing nuclear-actin cytoskeleton mechanocoupling by disrupting LINC (Linker of Nucleoskeleton and Cytoskeleton) complexes inhibited these LMS-induced signals as well as prevented LMS repression of adipogenic differentiation, highlighting that LINC connections are critical for sensing LMS. In contrast, FAK activation by high magnitude strain (HMS) was unaffected by LINC decoupling, consistent with signal initiation at the focal adhesion (FA) mechanosome. These results indicate that the MSC responds to its dynamic physical environment not only with “outside-in” signaling initiated by substrate strain, but vibratory signals enacted through the LINC complex enable matrix independent “inside-inside” signaling.

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Nesprin interchain associations control nuclear size

Cited by 84 publications

References 70 publications

Nesprins in Cell Stability and Migration

Nesprins in Cell Stability and Migration

Nesprin‐1 and nesprin‐2 regulate endothelial cell shape and migration

Cell Mechanosensitivity to Extremely Low-Magnitude Signals Is Enabled by a LINCed Nucleus

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