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Deregulation of focal adhesion formation and cytoskeletal tension due to loss of A-type lamins

Tobias Corne UGent, Tom Sieprath UGent, Jonathan Vandenbussche, Danahe Mohammed, Mariska te Lindert, Kris Gevaert UGent, Sylvain Gabriele, Katarina Wolf and Winnok De Vos UGent (2017) CELL ADHESION & MIGRATION. 11(5-6). p.447-463
abstract
The nuclear lamina mechanically integrates the nucleus with the cytoskeleton and extracellular environment and regulates gene expression. These functions are exerted through direct and indirect interactions with the lamina's major constituent proteins, the A-type lamins, which are encoded by the LMNA gene. Using quantitative stable isotope labeling-based shotgun proteomics we have analyzed the proteome of human dermal fibroblasts in which we have depleted A-type lamins by means of a sustained siRNA-mediated LMNA knockdown. Gene ontology analysis revealed that the largest fraction of differentially produced proteins was involved in actin cytoskeleton organization, in particular proteins involved in focal adhesion dynamics, such as actin-related protein 2 and 3 (ACTR2/3), subunits of the ARP2/3 complex, and fascin actin-bundling protein 1 (FSCN1). Functional validation using quantitative immunofluorescence showed a significant reduction in the size of focal adhesion points in A-type lamin depleted cells, which correlated with a reduction in early cell adhesion capacity and an increased cell motility. At the same time, loss of A-type lamins led to more pronounced stress fibers and higher traction forces. This phenotype could not be mimicked or reversed by experimental modulation of the STAT3-IL6 pathway, but it was partly recapitulated by chemical inhibition of the ARP2/3 complex. Thus, our data suggest that the loss of A-type lamins perturbs the balance between focal adhesions and cytoskeletal tension. This imbalance may contribute to mechanosensing defects observed in certain laminopathies.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
cytoskeleton, focal adhesion, LMNA, nuclear lamina, proteomics, SILAC, stress fibers, wound healing, GILFORD PROGERIA SYNDROME, CANCER-CELL-MIGRATION, EMBRYONIC STEM-CELLS, ARP2/3 COMPLEX, MITOCHONDRIAL DYSFUNCTION, GENE-EXPRESSION, NUCLEAR LAMINS, DAP KINASE, PROTEIN, A/C
journal title
CELL ADHESION & MIGRATION
Cell Adhes. Migr.
volume
11
issue
5-6
pages
447 - 463
Web of Science type
Article
Web of Science id
000423046400003
ISSN
1933-6918
1933-6926
DOI
10.1080/19336918.2016.1247144
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
8506868
handle
http://hdl.handle.net/1854/LU-8506868
date created
2017-02-02 10:09:00
date last changed
2018-02-21 11:34:55
@article{8506868,
  abstract     = {The nuclear lamina mechanically integrates the nucleus with the cytoskeleton and extracellular environment and regulates gene expression. These functions are exerted through direct and indirect interactions with the lamina's major constituent proteins, the A-type lamins, which are encoded by the LMNA gene. Using quantitative stable isotope labeling-based shotgun proteomics we have analyzed the proteome of human dermal fibroblasts in which we have depleted A-type lamins by means of a sustained siRNA-mediated LMNA knockdown. Gene ontology analysis revealed that the largest fraction of differentially produced proteins was involved in actin cytoskeleton organization, in particular proteins involved in focal adhesion dynamics, such as actin-related protein 2 and 3 (ACTR2/3), subunits of the ARP2/3 complex, and fascin actin-bundling protein 1 (FSCN1). Functional validation using quantitative immunofluorescence showed a significant reduction in the size of focal adhesion points in A-type lamin depleted cells, which correlated with a reduction in early cell adhesion capacity and an increased cell motility. At the same time, loss of A-type lamins led to more pronounced stress fibers and higher traction forces. This phenotype could not be mimicked or reversed by experimental modulation of the STAT3-IL6 pathway, but it was partly recapitulated by chemical inhibition of the ARP2/3 complex. Thus, our data suggest that the loss of A-type lamins perturbs the balance between focal adhesions and cytoskeletal tension. This imbalance may contribute to mechanosensing defects observed in certain laminopathies.},
  author       = {Corne, Tobias and Sieprath, Tom and Vandenbussche, Jonathan and Mohammed, Danahe and te Lindert, Mariska and Gevaert, Kris and Gabriele, Sylvain and Wolf, Katarina and De Vos, Winnok},
  issn         = {1933-6918},
  journal      = {CELL ADHESION \& MIGRATION},
  keyword      = {cytoskeleton,focal adhesion,LMNA,nuclear lamina,proteomics,SILAC,stress fibers,wound healing,GILFORD PROGERIA SYNDROME,CANCER-CELL-MIGRATION,EMBRYONIC STEM-CELLS,ARP2/3 COMPLEX,MITOCHONDRIAL DYSFUNCTION,GENE-EXPRESSION,NUCLEAR LAMINS,DAP KINASE,PROTEIN,A/C},
  language     = {eng},
  number       = {5-6},
  pages        = {447--463},
  title        = {Deregulation of focal adhesion formation and cytoskeletal tension due to loss of A-type lamins},
  url          = {http://dx.doi.org/10.1080/19336918.2016.1247144},
  volume       = {11},
  year         = {2017},
}

Chicago
Corne, Tobias, Tom Sieprath, Jonathan Vandenbussche, Danahe Mohammed, Mariska te Lindert, Kris Gevaert, Sylvain Gabriele, Katarina Wolf, and Winnok De Vos. 2017. “Deregulation of Focal Adhesion Formation and Cytoskeletal Tension Due to Loss of A-type Lamins.” Cell Adhesion & Migration 11 (5-6): 447–463.
APA
Corne, T., Sieprath, T., Vandenbussche, J., Mohammed, D., te Lindert, M., Gevaert, K., Gabriele, S., et al. (2017). Deregulation of focal adhesion formation and cytoskeletal tension due to loss of A-type lamins. CELL ADHESION & MIGRATION, 11(5-6), 447–463.
Vancouver
1.
Corne T, Sieprath T, Vandenbussche J, Mohammed D, te Lindert M, Gevaert K, et al. Deregulation of focal adhesion formation and cytoskeletal tension due to loss of A-type lamins. CELL ADHESION & MIGRATION. 2017;11(5-6):447–63.
MLA
Corne, Tobias, Tom Sieprath, Jonathan Vandenbussche, et al. “Deregulation of Focal Adhesion Formation and Cytoskeletal Tension Due to Loss of A-type Lamins.” CELL ADHESION & MIGRATION 11.5-6 (2017): 447–463. Print.