Messages from the voices within: regulation of signaling by proteins of the nuclear lamina

Abstract

The nuclear lamina (NL) is a protein scaffold lining the nuclear envelope that consists of nuclear lamins and associated transmembrane proteins. It helps to organize the nuclear envelope, chromosomes, and the cytoplasmic cytoskeleton. The NL also has an important role in regulation of signaling, as highlighted by the wide range of human diseases caused by mutations in the genes for NL proteins with associated signaling defects. This review will consider diverse mechanisms for signaling regulation by the NL that have been uncovered recently, including interaction with signaling effectors, modulation of actin assembly and compositional alteration of the NL. Cells with discrete NL mutations often show disruption of multiple signaling pathways, however, and for the most part the mechanistic basis for these complex phenotypes remains to be elucidated.

Figure 1

Model of nuclear envelope organization in mammalian cells. The diagram illustrates the direct connection of the ONM with the peripheral ER, and the lipid bilayer continuity between the ONM and INM at NPCs. Nuclear lamin filaments [13^••] are depicted as a green meshwork underlying the INM. Widely studied INM proteins are shown, with transmembrane segments and folded domains represented by cylinders spanning the lipid bilayer and external to it, respectively. The LEM domain, an ~45 amino acid segment near the N-terminus of LAP2β, emerin, MAN1 and Lem2, is designated as a short orange cylinder. The INM proteins represented have between 1–10 transmembrane segments, and all contain a nucleoplasmic region of at least 200 amino acids that is predicted to contain substantial intrinsic disorder (depicted as an extended thread). Torsin1A has a membrane-embedded segment but is not strictly a transmembrane protein. The luminal domains of LAP1 and TorsinA each have an AAA+ related fold that associates to form heterooligomers [35^•]. The LINC complex comprises SUN domain proteins spanning the INM associated with nesprins spanning the ONM [19,20]. The major SUN domain proteins of somatic cells (Sun1 and Sun2) each form a trimeric assembly via their luminal SUN domains. Nesprins, which occur as many splice isoforms, all contain a conserved ~30 amino acid luminal region that interacts with the SUN domain trimers. The cytoplasmic domains of nesprin-1 and nesprin-2 contain many tandem spectrin repeats (depicted as discs) and interact with actin filaments and microtubules by a variety of linker molecules (not shown). Nesprin-3 associates with intermediate filaments via the plectin linker [19,20]. Chromatin is associated with the INM by interaction with LBR and LEM domain proteins.