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Nesprin-3, a novel outer nuclear membrane protein, associates with the cytoskeletal linker protein plectin.

Wilhelmsen K, Litjens SH, Kuikman I, Tshimbalanga N, Janssen H, van den Bout I, Raymond K, Sonnenberg A - J. Cell Biol. (2005)

Bottom Line: This is primarily the result of an incomplete knowledge of the proteins in the outer nuclear membrane (ONM) that are able to associate with the different cytoskeletal systems.Overexpression of nesprin-3 results in a dramatic recruitment of plectin to the nuclear perimeter, which is where these two molecules are colocalized with both keratin-6 and -14.Importantly, plectin binds to the integrin alpha6beta4 at the cell surface and to nesprin-3 at the ONM in keratinocytes, suggesting that there is a continuous connection between the nucleus and the extracellular matrix through the IF cytoskeleton.

View Article: PubMed Central - PubMed

Affiliation: Division of Cell Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.

ABSTRACT
Despite their importance in cell biology, the mechanisms that maintain the nucleus in its proper position in the cell are not well understood. This is primarily the result of an incomplete knowledge of the proteins in the outer nuclear membrane (ONM) that are able to associate with the different cytoskeletal systems. Two related ONM proteins, nuclear envelope spectrin repeat (nesprin)-1 and -2, are known to make direct connections with the actin cytoskeleton through their NH2-terminal actin-binding domain (ABD). We have now isolated a third member of the nesprin family that lacks an ABD and instead binds to the plakin family member plectin, which can associate with the intermediate filament (IF) system. Overexpression of nesprin-3 results in a dramatic recruitment of plectin to the nuclear perimeter, which is where these two molecules are colocalized with both keratin-6 and -14. Importantly, plectin binds to the integrin alpha6beta4 at the cell surface and to nesprin-3 at the ONM in keratinocytes, suggesting that there is a continuous connection between the nucleus and the extracellular matrix through the IF cytoskeleton.

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Model depicting how the nesprins can link the nucleus to the actin and IF cytoskeletal systems. Nesprin-3 at the ONM and the integrin β4 subunit at the cell surface are shown bound to the NH2-terminal plectin ABD. COOH-terminal plectin plakin repeats are free to make associations with IFs, thus linking the nucleus to the hemidesmosomes at the cell surface. In an analogous way, nesprin-1/2 and talin, bound to the cytoplasmic tail of β integrins, interact with the actin filaments, which link the nucleus to FCs (black, IF cytoskeleton; green, MT system; red, F-actin). MTOC, MT organizing center.
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fig7: Model depicting how the nesprins can link the nucleus to the actin and IF cytoskeletal systems. Nesprin-3 at the ONM and the integrin β4 subunit at the cell surface are shown bound to the NH2-terminal plectin ABD. COOH-terminal plectin plakin repeats are free to make associations with IFs, thus linking the nucleus to the hemidesmosomes at the cell surface. In an analogous way, nesprin-1/2 and talin, bound to the cytoplasmic tail of β integrins, interact with the actin filaments, which link the nucleus to FCs (black, IF cytoskeleton; green, MT system; red, F-actin). MTOC, MT organizing center.

Mentions: Our finding that in keratinocytes nesprin-3α can compete with the integrin β4 subunit for binding to plectin suggests that these two molecules are connected to the same IF system. Indeed, immunofluorescence studies showed that the keratin-14 IF system is colocalized with both plectin at the NE and plectin in hemidesmosomes (Geerts et al., 1999). This implies that plectin can be the link in a continuous protein scaffold from the extracellular matrix to the nucleus via the IF cytoskeleton (Fig. 7), analogous to the manner in which nesprin-1/2 can link the nucleus to FCs at the plasma membrane via actin filaments (Fig. 7). This notion is consistent with the cellular tensegrity model, which describes the cell as a prestressed structure whereby forces can be transferred from the extracellular environment through the different cytoskeletons into the nucleus (Ingber, 2003a,b). This model integrates and explains many observations in cell biology, such as nuclear architecture, but importantly it can explain how external forces may affect events in the nucleus such as chromatin organization (Maniotis et al., 1997). The nesprins are the prime candidates for mediating these processes because they have been shown to interact with INM proteins associated with the nuclear lamins (Gruenbaum et al., 2005). The lamins are known to bind chromatin and have even been suggested to play a role in regulating transcription by RNA polymerase II and DNA replication (Spann et al., 1997, 2002). If force can indeed directly alter gene expression, the need for cytoplasmic signaling events would be circumvented, allowing for a more instantaneous regulation of transcriptional events during cell migration or situations of applied force. Although these ideas are intriguing, clearly more studies are necessary to determine the extent to which the nesprins can mediate the transfer of force into the nucleus.


Nesprin-3, a novel outer nuclear membrane protein, associates with the cytoskeletal linker protein plectin.

Wilhelmsen K, Litjens SH, Kuikman I, Tshimbalanga N, Janssen H, van den Bout I, Raymond K, Sonnenberg A - J. Cell Biol. (2005)

Model depicting how the nesprins can link the nucleus to the actin and IF cytoskeletal systems. Nesprin-3 at the ONM and the integrin β4 subunit at the cell surface are shown bound to the NH2-terminal plectin ABD. COOH-terminal plectin plakin repeats are free to make associations with IFs, thus linking the nucleus to the hemidesmosomes at the cell surface. In an analogous way, nesprin-1/2 and talin, bound to the cytoplasmic tail of β integrins, interact with the actin filaments, which link the nucleus to FCs (black, IF cytoskeleton; green, MT system; red, F-actin). MTOC, MT organizing center.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171291&req=5

fig7: Model depicting how the nesprins can link the nucleus to the actin and IF cytoskeletal systems. Nesprin-3 at the ONM and the integrin β4 subunit at the cell surface are shown bound to the NH2-terminal plectin ABD. COOH-terminal plectin plakin repeats are free to make associations with IFs, thus linking the nucleus to the hemidesmosomes at the cell surface. In an analogous way, nesprin-1/2 and talin, bound to the cytoplasmic tail of β integrins, interact with the actin filaments, which link the nucleus to FCs (black, IF cytoskeleton; green, MT system; red, F-actin). MTOC, MT organizing center.
Mentions: Our finding that in keratinocytes nesprin-3α can compete with the integrin β4 subunit for binding to plectin suggests that these two molecules are connected to the same IF system. Indeed, immunofluorescence studies showed that the keratin-14 IF system is colocalized with both plectin at the NE and plectin in hemidesmosomes (Geerts et al., 1999). This implies that plectin can be the link in a continuous protein scaffold from the extracellular matrix to the nucleus via the IF cytoskeleton (Fig. 7), analogous to the manner in which nesprin-1/2 can link the nucleus to FCs at the plasma membrane via actin filaments (Fig. 7). This notion is consistent with the cellular tensegrity model, which describes the cell as a prestressed structure whereby forces can be transferred from the extracellular environment through the different cytoskeletons into the nucleus (Ingber, 2003a,b). This model integrates and explains many observations in cell biology, such as nuclear architecture, but importantly it can explain how external forces may affect events in the nucleus such as chromatin organization (Maniotis et al., 1997). The nesprins are the prime candidates for mediating these processes because they have been shown to interact with INM proteins associated with the nuclear lamins (Gruenbaum et al., 2005). The lamins are known to bind chromatin and have even been suggested to play a role in regulating transcription by RNA polymerase II and DNA replication (Spann et al., 1997, 2002). If force can indeed directly alter gene expression, the need for cytoplasmic signaling events would be circumvented, allowing for a more instantaneous regulation of transcriptional events during cell migration or situations of applied force. Although these ideas are intriguing, clearly more studies are necessary to determine the extent to which the nesprins can mediate the transfer of force into the nucleus.

Bottom Line: This is primarily the result of an incomplete knowledge of the proteins in the outer nuclear membrane (ONM) that are able to associate with the different cytoskeletal systems.Overexpression of nesprin-3 results in a dramatic recruitment of plectin to the nuclear perimeter, which is where these two molecules are colocalized with both keratin-6 and -14.Importantly, plectin binds to the integrin alpha6beta4 at the cell surface and to nesprin-3 at the ONM in keratinocytes, suggesting that there is a continuous connection between the nucleus and the extracellular matrix through the IF cytoskeleton.

View Article: PubMed Central - PubMed

Affiliation: Division of Cell Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.

ABSTRACT
Despite their importance in cell biology, the mechanisms that maintain the nucleus in its proper position in the cell are not well understood. This is primarily the result of an incomplete knowledge of the proteins in the outer nuclear membrane (ONM) that are able to associate with the different cytoskeletal systems. Two related ONM proteins, nuclear envelope spectrin repeat (nesprin)-1 and -2, are known to make direct connections with the actin cytoskeleton through their NH2-terminal actin-binding domain (ABD). We have now isolated a third member of the nesprin family that lacks an ABD and instead binds to the plakin family member plectin, which can associate with the intermediate filament (IF) system. Overexpression of nesprin-3 results in a dramatic recruitment of plectin to the nuclear perimeter, which is where these two molecules are colocalized with both keratin-6 and -14. Importantly, plectin binds to the integrin alpha6beta4 at the cell surface and to nesprin-3 at the ONM in keratinocytes, suggesting that there is a continuous connection between the nucleus and the extracellular matrix through the IF cytoskeleton.

Show MeSH