Role of A-type lamins in signaling, transcription, and chromatin organization

Abstract

A-type lamins (lamins A and C), encoded by the LMNA gene, are major protein constituents of the mammalian nuclear lamina, a complex structure that acts as a scaffold for protein complexes that regulate nuclear structure and functions. Interest in these proteins has increased in recent years with the discovery that LMNA mutations cause a variety of human diseases termed laminopathies, including progeroid syndromes and disorders that primarily affect striated muscle, adipose, bone, and neuronal tissues. In this review, we discuss recent research supporting the concept that lamin A/C and associated nuclear envelope proteins regulate gene expression in health and disease through interplay with signal transduction pathways, transcription factors, and chromatin-associated proteins.

Figure 1.

Control of Wnt–β-catenin and TGF-β signaling by A-type lamins and associated proteins. (A, left) In the absence of Wnt, cytoplasmic β-catenin (β-cat) undergoes proteasomal degradation, and TCF-dependent transcription is repressed. (right) Upon Wnt binding to its receptors (e.g., frizzled), β-catenin accumulates in the cytoplasm, translocates to the nucleus, and induces TCF-dependent transcription. Emerin exports nuclear β-catenin to the cytoplasm, thereby inhibiting TCF-dependent transcription. GSK3β, glycogen synthase kinase 3β. (B, left) In the absence of TGF-β, hypophosphorylated R-Smads accumulate in the cytoplasm. (right) Binding of TGF-β to its receptors leads to R-Smad phosphorylation and the formation and nuclear import of R-Smad–Smad4 complexes, which induce target gene expression in conjunction with other transcription factors (TF). MAN1 might sequester active R-Smads at the NE, preventing them from oligomerizing with co-Smads. A-type lamins interact with activated PP2A, which can dephosphorylate R-Smads and ppRb.

Figure 2.

Control of Notch signaling by lamin A/C and progerin. (left) In the absence of Notch ligands, transcription of target genes is repressed. (right) Notch activation by neighboring cells leads to proteolytic release of the NICD, which translocates to the nucleus, where it activates target genes upon binding to coactivators and the release of corepressors (Co-R) from the promoter. Stem cells from HGPS patients express progerin. Notch signaling is elevated in these cells, and there is an up-regulation in the expression of Notch target genes, coincident with reduced amounts of the repressor NcoR and increased availability of the coactivator SKIP in the nuclear interior. Mam, Mastermind; DSL, Delta/Serrate/LAG-2 family of proteins.

Figure 3.

Fast regulation of AP-1 activity through interaction of lamin A/C, ERK1/2, and c-Fos at the NE. (left) Quiescent cells contain low levels of c-Fos, which is predominantly hypophosphorylated and sequestered at the NE through its interaction with A-type lamins. (right) Upon mitogen stimulation, phosphorylated (active) ERKs 1 and 2 interact with A-type lamins and phosphorylate c-Fos, releasing it from the NE. The released c-Fos can heterodimerize in the nucleoplasm with other AP-1 family members (e.g., c-Jun), allowing the activation of AP-1 target genes before de novo c-Fos synthesis.

Figure 4.

Interactions of A-type lamins and NE-associated proteins with DNA, chromatin complexes, and related transcription factors. (A) Schematic illustration of the mammalian NE showing proteins involved in the organization and regulation of chromatin and gene expression. (B) Network of NE-associated chromatin complexes. The thick lines indicate direct interactions with lamin A/C. CRX, cone-rod homeobox.