Nuclear envelope functions in signaling and disease
Luiza Bengtsson, Simon Dokel, Uli Rockenbauch, Petra Knaus
Nuclear envelope defines the border of the nucleus. It consists of the double nuclear membrane (inner and outer), the pore membrane (sites where the inner and outer nuclear membranes join to form pores), the nuclear pore complexes (protein complexes gating the entry and exit from the nucleus), the integral membrane proteins and a meshwork of intermediate filaments called lamins. The integral membrane proteins of the inner nuclear membrane, their soluble isoforms and the lamins are collectively called the nuclear lamina.
The nuclear lamina extends from the nuclear periphery into the nucleus. Lamina gives nucleus structural stability and defines its shape. Importantly, the interactions between lamins, specific INM proteins and/or their soluble isoforms and chromatin components have active roles in the spatial organization of nuclear functions. Lamina is thought to provide scaffolds for proteins required for DNA replication, gene expression, chromosome attachment, signaling and nuclear positioning.
The importance of nuclear envelope in the regulation of cellular processes has been highlighted by the occurrence of laminopathies – a group of diverse diseases caused by mutations in lamina proteins. For example, different missense mutations in A-type lamins can cause muscular dystrophy, dilated cardiomyopathy, lipodystrophy, restrictive dermopathy, mandibuloacral dysplasia as well as progeria syndrome (accelerated aging). Several diseases originate in mutations in inner nuclear membrane proteins, such as emerin (muscular dystrophy), MAN1 (bone disorders), lamin B receptor (chondrodystrophies) and lap2a (cardiomyopathy). The list of laminopathic diseases is growing almost daily. The exact molecular mechanism leading to disease is not yet known. Based on the gathered biochemical and cell biological data, it is now thought that laminopathic mutations disturb protein-protein interactions that are important for structural stability of the nucleus and the tissue-specific gene expression.
We are interested in elucidating the mechanism of regulation of cellular signal transduction by the proteins of the nuclear lamina. We are studying TGF?/BMP-signaling, as both A-type lamins and MAN1 have recently been identified as novel regulators of TGFß/BMP signaling and most of the laminopathies affect cells of mesenchymal origin. Our model system is the murine myoblast C2C12 cellline. We use a variety of molecular, biochemical and cell biological approaches to study the protein-protein interactions that govern the events at the nuclear periphery. Our goal is to understand the molecular mechanism leading to laminopathies.
PUBLICATIONS
Bengtsson L.
What MAN1 does to the Smads: TGFß/BMP signaling and the nuclear envelope.
FEBS Journal 2007 in press
Bengtsson L and Wilson KL.
BAF phosphorylation on Ser-4 regulates emerin binding to lamin A in vitro and emerin localization in vivo.
Mol Biol Cell 2006 17(3):1154-63 Epub 2005 Dec 21
Hodzic DM, Yeater DB, Bengtsson L, Otto H, Stahl PD.
Sun2 is a novel mammalian inner nuclear membrane protein.
J Biol Chem. 2004 279(24): 25805-12.
Bengtsson L and Wilson KL.
Multiple and surprising new functions for emerin, a nuclear membrane protein.
Curr Opin Cell Biol. 2004 16(1): 73-9.
Dreger M*, Bengtsson L*, Schoneberg T, Otto H and Hucho F.
*equal contribution
Nuclear envelope proteomics: novel integral membrane proteins of the inner nuclear membrane.
Proc Natl Acad Sci U S A 2001 98: 11943-8
Otto H, Dreger M, Bengtsson L, Hucho F.
Identification of tyrosine-phosphorylated proteins associated with the nuclear envelope.
Eur J Biochem 2001 268: 420-8
