JCI - Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy

Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy

Antoine Muchir, Paul Pavlidis, Valérie Decostre, Alan J. Herron, Takuro Arimura, Gisèle Bonne, Howard J. Worman

Published in Volume 117, Issue 5

J Clin Invest. 2007; 117(5):1282–1293 doi:10.1172/JCI29042

Abstract | Full text | PDF | Supplemental material

Options: View larger image (or click on image)

Figure 9

Model of how abnormalities of A-type lamins in the nuclear lamina may lead to cardiomyopathy.

Abnormalities of A-type lamins in the nuclear lamina activate MAPK cascades, possibly via heterotrimeric G-protein receptors or by inducing stress responses by unknown mechanisms (?). This leads to activation of G-proteins (RAS and RAC), protein kinase (RAF), and subsequent enhanced phosphorylation of ERK and JNK1/2, resulting in nuclear translocation. In the nucleus, pERK1/2 and pJNK activate transcription factors such as Elk1, bcl-2, JunD, c-Jun, and Elk4, leading to increased synthesis of these proteins. Increased amounts and activities of transcription factors activated by pJNK and pERK1/2 alter expression of other genes, some encoding components of muscle fibers and sarcomeres. Aberrant expression of these proteins leads to development of cardiomyopathy.