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The nuclear envelope protein Nesprin-2 has roles in cell proliferation and differentiation during wound healing.

Rashmi RN, Eckes B, Glöckner G, Groth M, Neumann S, Gloy J, Sellin L, Walz G, Schneider M, Karakesisoglou I, Eichinger L, Noegel AA - Nucleus (2012)

Bottom Line: When we probed for an interaction of Nesprin-2 Giant with chromatin we observed in ChIP Seq experiments an association of the protein with heterochromatic and centromeric DNA.Through this activity Nesprin-2 can affect the nuclear landscape and gene regulation.Our findings suggest functions for Nesprin-2 at the nuclear envelope (NE) in gene regulation and in regulation of the actin cytoskeleton which impact on wound healing.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.

ABSTRACT
Nesprin-2, a type II transmembrane protein of the nuclear envelope, is a component of the LINC complex that connects the nuclear lamina with the actin cytoskeleton. To elucidate its physiological role we studied wound healing in Nesprin-2 Giant deficient mice and found that a loss of the protein affected wound healing particularly at later stages during fibroblast differentiation and keratinocyte proliferation leading to delayed wound closure. We identified altered expression and localization of transcription factors as one of the underlying mechanisms. Furthermore, the actin cytoskeleton which surrounds the nucleus was altered and keratinocyte migration was slowed down and focal adhesion formation enhanced. We also uncovered a new activity of Nesprin-2. When we probed for an interaction of Nesprin-2 Giant with chromatin we observed in ChIP Seq experiments an association of the protein with heterochromatic and centromeric DNA. Through this activity Nesprin-2 can affect the nuclear landscape and gene regulation. Our findings suggest functions for Nesprin-2 at the nuclear envelope (NE) in gene regulation and in regulation of the actin cytoskeleton which impact on wound healing.

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Proposed mechanisms of Nesprin-2 involvement in cell migration, proliferation and transcription regulation. In WT Nesprin-2 at the ONM together with other NE proteins connects the nucleus to the actin cytoskeleton (LINC complex). The LINC complex (Nesprin-SUN) and associated proteins can transduce signals from the cytoplasm to the nucleus. Nesprins can transduce either mechanic signals through the LINC complex to the nucleoplasm and are also involved in signal transduction processes through interaction with transcription factors. Gene transcription may also be affected through interactions of NE proteins with chromatin thereby altering the status of chromatin from being inactive or being actively transcribed and vice versa. In KO cells F-actin distribution and status of heterochromatin is altered. Expression and availability of transcription factors is reduced and leads to reduced cell proliferation.
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Figure 10: Proposed mechanisms of Nesprin-2 involvement in cell migration, proliferation and transcription regulation. In WT Nesprin-2 at the ONM together with other NE proteins connects the nucleus to the actin cytoskeleton (LINC complex). The LINC complex (Nesprin-SUN) and associated proteins can transduce signals from the cytoplasm to the nucleus. Nesprins can transduce either mechanic signals through the LINC complex to the nucleoplasm and are also involved in signal transduction processes through interaction with transcription factors. Gene transcription may also be affected through interactions of NE proteins with chromatin thereby altering the status of chromatin from being inactive or being actively transcribed and vice versa. In KO cells F-actin distribution and status of heterochromatin is altered. Expression and availability of transcription factors is reduced and leads to reduced cell proliferation.

Mentions: From our study we propose that Nesprin-2G has two major roles in wound healing; one through its capacity as an actin-binding protein and a further one through its interaction with lamina components and with chromatin. At the ONM it interacts with F-actin and is responsible for the correct formation of the actin cytoskeleton around the nucleus in WT. Through the actin cytoskeleton interaction it is also connected to the plasma membrane and the extracellular matrix and can affect focal adhesion formation. At the NE, Nesprin-2 interacts with SUN proteins and the underlying nuclear lamina. Loss of Nesprin-2G leads to a loss of F-actin around the nucleus, and signals from the extracellular matrix are less efficiently transmitted to the NE and the nuclear lamina (Fig. 10). Nuclear lamina components themselves can interact with transcription factors and through this chain of interactions Nesprin-2 may affect transcription. Interestingly, the binding sites of LaminA/C for Rb protein and c-Fos overlap with the binding site for Nesprin-2 and a competition for binding sites might be a further mechanism to explain Nesprin-2 action in addition to its effects on transcription through heterochromatin interactions.7,14 Finally, actin, the interaction partner of Nesprin-2 Giant is also a nuclear protein and has roles in gene regulation.53 Therefore an impact of Nesprin-2 on transcription via actin could also be considered.


The nuclear envelope protein Nesprin-2 has roles in cell proliferation and differentiation during wound healing.

Rashmi RN, Eckes B, Glöckner G, Groth M, Neumann S, Gloy J, Sellin L, Walz G, Schneider M, Karakesisoglou I, Eichinger L, Noegel AA - Nucleus (2012)

Proposed mechanisms of Nesprin-2 involvement in cell migration, proliferation and transcription regulation. In WT Nesprin-2 at the ONM together with other NE proteins connects the nucleus to the actin cytoskeleton (LINC complex). The LINC complex (Nesprin-SUN) and associated proteins can transduce signals from the cytoplasm to the nucleus. Nesprins can transduce either mechanic signals through the LINC complex to the nucleoplasm and are also involved in signal transduction processes through interaction with transcription factors. Gene transcription may also be affected through interactions of NE proteins with chromatin thereby altering the status of chromatin from being inactive or being actively transcribed and vice versa. In KO cells F-actin distribution and status of heterochromatin is altered. Expression and availability of transcription factors is reduced and leads to reduced cell proliferation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3383573&req=5

Figure 10: Proposed mechanisms of Nesprin-2 involvement in cell migration, proliferation and transcription regulation. In WT Nesprin-2 at the ONM together with other NE proteins connects the nucleus to the actin cytoskeleton (LINC complex). The LINC complex (Nesprin-SUN) and associated proteins can transduce signals from the cytoplasm to the nucleus. Nesprins can transduce either mechanic signals through the LINC complex to the nucleoplasm and are also involved in signal transduction processes through interaction with transcription factors. Gene transcription may also be affected through interactions of NE proteins with chromatin thereby altering the status of chromatin from being inactive or being actively transcribed and vice versa. In KO cells F-actin distribution and status of heterochromatin is altered. Expression and availability of transcription factors is reduced and leads to reduced cell proliferation.
Mentions: From our study we propose that Nesprin-2G has two major roles in wound healing; one through its capacity as an actin-binding protein and a further one through its interaction with lamina components and with chromatin. At the ONM it interacts with F-actin and is responsible for the correct formation of the actin cytoskeleton around the nucleus in WT. Through the actin cytoskeleton interaction it is also connected to the plasma membrane and the extracellular matrix and can affect focal adhesion formation. At the NE, Nesprin-2 interacts with SUN proteins and the underlying nuclear lamina. Loss of Nesprin-2G leads to a loss of F-actin around the nucleus, and signals from the extracellular matrix are less efficiently transmitted to the NE and the nuclear lamina (Fig. 10). Nuclear lamina components themselves can interact with transcription factors and through this chain of interactions Nesprin-2 may affect transcription. Interestingly, the binding sites of LaminA/C for Rb protein and c-Fos overlap with the binding site for Nesprin-2 and a competition for binding sites might be a further mechanism to explain Nesprin-2 action in addition to its effects on transcription through heterochromatin interactions.7,14 Finally, actin, the interaction partner of Nesprin-2 Giant is also a nuclear protein and has roles in gene regulation.53 Therefore an impact of Nesprin-2 on transcription via actin could also be considered.

Bottom Line: When we probed for an interaction of Nesprin-2 Giant with chromatin we observed in ChIP Seq experiments an association of the protein with heterochromatic and centromeric DNA.Through this activity Nesprin-2 can affect the nuclear landscape and gene regulation.Our findings suggest functions for Nesprin-2 at the nuclear envelope (NE) in gene regulation and in regulation of the actin cytoskeleton which impact on wound healing.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.

ABSTRACT
Nesprin-2, a type II transmembrane protein of the nuclear envelope, is a component of the LINC complex that connects the nuclear lamina with the actin cytoskeleton. To elucidate its physiological role we studied wound healing in Nesprin-2 Giant deficient mice and found that a loss of the protein affected wound healing particularly at later stages during fibroblast differentiation and keratinocyte proliferation leading to delayed wound closure. We identified altered expression and localization of transcription factors as one of the underlying mechanisms. Furthermore, the actin cytoskeleton which surrounds the nucleus was altered and keratinocyte migration was slowed down and focal adhesion formation enhanced. We also uncovered a new activity of Nesprin-2. When we probed for an interaction of Nesprin-2 Giant with chromatin we observed in ChIP Seq experiments an association of the protein with heterochromatic and centromeric DNA. Through this activity Nesprin-2 can affect the nuclear landscape and gene regulation. Our findings suggest functions for Nesprin-2 at the nuclear envelope (NE) in gene regulation and in regulation of the actin cytoskeleton which impact on wound healing.

Show MeSH
Related in: MedlinePlus