Journal
JOURNAL OF CELL SCIENCE
Volume 127, Issue 12, Pages 2683-2696Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.141820
Keywords
Intermediate filament; Lamin A; Phosphorylation; Sequestration; Signaling
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Funding
- Academy of Finland
- Sigrid Juselius Foundation
- Finnish Cancer Foundations
- Center of Excellence grant from the Endowment of the Abo Akademi University
- National Institutes of Health grants [GM106023, CA03176]
- Progeria Research Foundation grant
- National Cancer Institute
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Nuclear lamins form the major structural elements that comprise the nuclear lamina. Loss of nuclear structural integrity has been implicated as a key factor in the lamin A/C gene mutations that cause laminopathies, whereas the normal regulation of lamin A assembly and organization in interphase cells is still undefined. We assumed phosphorylation to be a major determinant, identifying 20 prime interphase phosphorylation sites, of which eight were high-turnover sites. We examined the roles of these latter sites by site-directed mutagenesis, followed by detailed microscopic analysis including fluorescence recovery after photobleaching, fluorescence correlation spectroscopy and nuclear extraction techniques. The results reveal three phosphorylation regions, each with dominant sites, together controlling lamin A structure and dynamics. Interestingly, two of these interphase sites are hyper-phosphorylated in mitotic cells and one of these sites is within the sequence that is missing in progerin of the Hutchinson-Gilford progeria syndrome. We present a model where different phosphorylation combinations yield markedly different effects on the assembly, subunit turnover and the mobility of lamin A between, and within, the lamina, the nucleoplasm and the cytoplasm of interphase cells.
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