Defects in cell spreading and ERK1/2 activation in fibroblasts with lamin A/C mutations.
In-frame mutations in nuclear lamin A/C lead to a multitude of tissue-specific degenerative diseases known as the 'laminopathies'. Previous studies have demonstrated that lamin A/C-null mouse fibroblasts have defects in cell polarisation, suggesting a role for lamin A/C in nucleo-cytoskeletal-cell surface cross-talk. However, this has not been examined in patient fibroblasts expressing modified forms of lamin A/C. Here, we analysed skin fibroblasts from 3 patients with Emery-Dreifuss muscular dystrophy and from 1 with dilated cardiomyopathy. The emerin-lamin A/C interaction was impaired in each mutant cell line. Mutant cells exhibited enhanced cell proliferation, collagen-dependent adhesion, larger numbers of filopodia and smaller cell spread size, compared with control cells. Furthermore, cell migration, speed and polarization were elevated. Mutant cells also showed an enhanced ability to contract collagen gels at early time points, compared with control cells. Phosphotyrosine measurements during cell spreading indicated an initial temporal lag in ERK1/2 activation in our mutant cells, followed by hyper-activation of ERK1/2 at 2 h post cell attachment. Deregulated ERK1/2 activation is linked with cardiomyopathy, cell spreading and proliferation defects. We conclude that a functional emerin-lamin A/C complex is required for cell spreading and proliferation, possibly acting through ERK1/2 signalling.
Emerson
Lindsay J
LJ
The Randall Division of Cell and Molecular Biophysics, King's College, New Hunts House, Guy's Campus, London, SE1 1UL, UK.
Holt
Mark R
MR
Wheeler
Matthew A
MA
Wehnert
Manfred
M
Parsons
Maddy
M
Ellis
Juliet A
JA
D000293:Adolescent; D000328:Adult; D000818:Animals; D002448:Cell Adhesion; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D004789:Enzyme Activation; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D006801:Humans; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; C092710:emerin; C440308:lamin C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3