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. 2018 Oct 30;9:1533. doi: 10.3389/fphys.2018.01533

Figure 1.

Figure 1

Schematic model of the nuclear envelope proteins and their potential roles in EDMD physiopathology. Nuclear lamins form a meshwork underneath the INM connected with the cytoplasm. It interacts with TM proteins of the nuclear envelope, i.e., emerin, LBR, LAP2, SUN1/2, and MAN1, and with several transcription factors such as Rb. Through the LINC complex, A-type lamins interact with actin microfilaments, microtubules, and cytoplasmic intermediate filaments, connecting the nuclear lamina to the extracellular matrix. MAPK pathways are important transduction cascades initiated by extracellular mitogens, growth factors and cytokines at the cell surface and finalized to the nucleus to control gene expression, regulating cell proliferation and differentiation, survival and apoptosis. LMNA mutations causing EDMD have been related to the activation of ERK, JNK, and p38α cascades, leading to the posterior activation of CTGF/CCN2 via TGF-ß/Smad signaling pathway and cofilin-1, the latter leading to actin depolymerization. After serum or mechanical stimulation, RhoA promotes cytoplasmic actin polymerization, causing the release of MKL1 from cytoplasmic G-actin. MKL1 translocates into the nucleus and together with SRF induces gene expression. In addition, emerin facilitates polymerization of nuclear actin, reducing the nuclear export of MKL1 to the cytoplasm. In EDMD cells, emerin mislocalizes and is unable to modulate nuclear actin polymerization. G-actin binds to MKL1 and it is exported from the nucleus, impairing gene expression. YAP and TAZ are key transcription factors for cell proliferation. YAP/TAZ activation causes their nuclear accumulation, promoting cell proliferation, and inhibiting differentiation. Nuclear localization of YAP/TAZ is increased in patient myoblasts with LMNA mutations. Green arrows indicate reported pathways and red arrows indicate altered EDMD reported pathways. BAF, barrier-to-autointegration factor; ECM, Extracellular matrix; EDMD, Emery-Dreifuss muscular dystrophy; ERK, extracellular signal-regulated kinase; F-actin, actin filament; G-actin, globular actin; Grb2, growth factor receptor-bound protein 2; INM, inner nuclear membrane; Kif5B, kinesin family member 5B; LAP, lamin associated protein; LBR, lamin B receptor; MAPK, mitogen-activated protein kinase; MKL1, megakaryoblastic leukemia 1; NPC, nuclear pore complex; ONM, outer nuclear membrane; Raf, proto-oncogen serine/threonine-protein kinase; Rb, retinoblastoma protein; RhoA, ras homolog family member A; Sos, son of sevenless homolog 1; SRF, serum response factor; TGF-ß, transforming growth factor ß; YAP, yes-associated protein 1; TAZ, transcriptional coactivator with PDZ-binding motif.