Fig. 3.

Schematic diagram illustrating how A-type lamins in association with other INM proteins modulate different signalling pathways that participate in either adult stem cell maintenance (TGF-β pathway) or growth-related stress responses (Ras/MAPK pathway). In the TGF-β pathway, TGF-β ligands in the extracellular space bind to dimerized TGF-β serine/threonine kinase receptors (type I and type II R) found on the plasma membrane. Ligand-receptor binding results in the phosphorylation of the receptor Smads 2/3, which disassociate from the receptor and form a heteromeric complex with the co-mediator Smad 4 in the cytoplasm, which can then translocate across the nuclear membrane. A-type lamins alone or together with the INM protein MAN1 bind to the Smad complex in the nucleus and inhibit their activation of transcription factors (TF) and target genes. In the Ras/MAPK pathway, growth factors in the extracellular matrix bind to heterotrimeric G protein-coupled receptors (GPCR) or receptor tyrosine kinases (not shown) on the plasma membrane. This leads to the activation of the G protein Ras (in a complex with Grb2 and SOS proteins) through GDP/GTP exchange, which is then free to bind to serine/threonine protein kinase Raf and/or G protein Rac (not shown). In the cytosol, downstream kinase cascade from Raf includes phosphorylation of protein kinase MEK 1/2, which leads to activation and enhanced phosphorylation of ERK 1/2 dimers and their subsequent translocation across the nuclear membrane. A-type lamins alone or together with some unknown INM proteins may bind to phosphorylated ERK 1/2 and inhibit their activation of transcription factors (TF) and gene expression. Grb, growth factor receptor-bound protein; SOS, son-of-sevenless; GDP/GTP, guanosine di/triphosphate; MEK, mitogen- or extracellular signal-related kinase.