Solo, a RhoA-targeting guanine nucleotide exchange factor, is critical for hemidesmosome formation and acinar development in epithelial cells.
Cell-substrate adhesions are essential for various physiological processes, including embryonic development and maintenance of organ functions. Hemidesmosomes (HDs) are multiprotein complexes that attach epithelial cells to the basement membrane. Formation and remodeling of HDs are dependent on the...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2018-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5909619?pdf=render |
| _version_ | 1818938570328506368 |
|---|---|
| author | Sachiko Fujiwara Tsubasa S Matsui Kazumasa Ohashi Shinji Deguchi Kensaku Mizuno |
| author_facet | Sachiko Fujiwara Tsubasa S Matsui Kazumasa Ohashi Shinji Deguchi Kensaku Mizuno |
| author_sort | Sachiko Fujiwara |
| collection | DOAJ |
| description | Cell-substrate adhesions are essential for various physiological processes, including embryonic development and maintenance of organ functions. Hemidesmosomes (HDs) are multiprotein complexes that attach epithelial cells to the basement membrane. Formation and remodeling of HDs are dependent on the surrounding mechanical environment; however, the upstream signaling mechanisms are not well understood. We recently reported that Solo (also known as ARHGEF40), a guanine nucleotide exchange factor targeting RhoA, binds to keratin8/18 (K8/K18) intermediate filaments, and that their interaction is important for force-induced actin and keratin cytoskeletal reorganization. In this study, we show that Solo co-precipitates with an HD protein, β4-integrin. Co-precipitation assays revealed that the central region (amino acids 330-1057) of Solo binds to the C-terminal region (1451-1752) of β4-integrin. Knockdown of Solo significantly suppressed HD formation in MCF10A mammary epithelial cells. Similarly, knockdown of K18 or treatment with Y-27632, a specific inhibitor of Rho-associated kinase (ROCK), suppressed HD formation. As Solo knockdown or Y-27632 treatment is known to disorganize K8/K18 filaments, these results suggest that Solo is involved in HD formation by regulating K8/K18 filament organization via the RhoA-ROCK signaling pathway. We also showed that knockdown of Solo impairs acinar formation in MCF10A cells cultured in 3D Matrigel. In addition, Solo accumulated at the site of traction force generation in 2D-cultured MCF10A cells. Taken together, these results suggest that Solo plays a crucial role in HD formation and acinar development in epithelial cells by regulating mechanical force-induced RhoA activation and keratin filament organization. |
| first_indexed | 2024-12-20T06:09:57Z |
| format | Article |
| id | doaj.art-9b1d211179304c74a50bcdeb9e841d5b |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T06:09:57Z |
| publishDate | 2018-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-9b1d211179304c74a50bcdeb9e841d5b2022-12-21T19:50:42ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01134e019512410.1371/journal.pone.0195124Solo, a RhoA-targeting guanine nucleotide exchange factor, is critical for hemidesmosome formation and acinar development in epithelial cells.Sachiko FujiwaraTsubasa S MatsuiKazumasa OhashiShinji DeguchiKensaku MizunoCell-substrate adhesions are essential for various physiological processes, including embryonic development and maintenance of organ functions. Hemidesmosomes (HDs) are multiprotein complexes that attach epithelial cells to the basement membrane. Formation and remodeling of HDs are dependent on the surrounding mechanical environment; however, the upstream signaling mechanisms are not well understood. We recently reported that Solo (also known as ARHGEF40), a guanine nucleotide exchange factor targeting RhoA, binds to keratin8/18 (K8/K18) intermediate filaments, and that their interaction is important for force-induced actin and keratin cytoskeletal reorganization. In this study, we show that Solo co-precipitates with an HD protein, β4-integrin. Co-precipitation assays revealed that the central region (amino acids 330-1057) of Solo binds to the C-terminal region (1451-1752) of β4-integrin. Knockdown of Solo significantly suppressed HD formation in MCF10A mammary epithelial cells. Similarly, knockdown of K18 or treatment with Y-27632, a specific inhibitor of Rho-associated kinase (ROCK), suppressed HD formation. As Solo knockdown or Y-27632 treatment is known to disorganize K8/K18 filaments, these results suggest that Solo is involved in HD formation by regulating K8/K18 filament organization via the RhoA-ROCK signaling pathway. We also showed that knockdown of Solo impairs acinar formation in MCF10A cells cultured in 3D Matrigel. In addition, Solo accumulated at the site of traction force generation in 2D-cultured MCF10A cells. Taken together, these results suggest that Solo plays a crucial role in HD formation and acinar development in epithelial cells by regulating mechanical force-induced RhoA activation and keratin filament organization.http://europepmc.org/articles/PMC5909619?pdf=render |
| spellingShingle | Sachiko Fujiwara Tsubasa S Matsui Kazumasa Ohashi Shinji Deguchi Kensaku Mizuno Solo, a RhoA-targeting guanine nucleotide exchange factor, is critical for hemidesmosome formation and acinar development in epithelial cells. PLoS ONE |
| title | Solo, a RhoA-targeting guanine nucleotide exchange factor, is critical for hemidesmosome formation and acinar development in epithelial cells. |
| title_full | Solo, a RhoA-targeting guanine nucleotide exchange factor, is critical for hemidesmosome formation and acinar development in epithelial cells. |
| title_fullStr | Solo, a RhoA-targeting guanine nucleotide exchange factor, is critical for hemidesmosome formation and acinar development in epithelial cells. |
| title_full_unstemmed | Solo, a RhoA-targeting guanine nucleotide exchange factor, is critical for hemidesmosome formation and acinar development in epithelial cells. |
| title_short | Solo, a RhoA-targeting guanine nucleotide exchange factor, is critical for hemidesmosome formation and acinar development in epithelial cells. |
| title_sort | solo a rhoa targeting guanine nucleotide exchange factor is critical for hemidesmosome formation and acinar development in epithelial cells |
| url | http://europepmc.org/articles/PMC5909619?pdf=render |
| work_keys_str_mv | AT sachikofujiwara soloarhoatargetingguaninenucleotideexchangefactoriscriticalforhemidesmosomeformationandacinardevelopmentinepithelialcells AT tsubasasmatsui soloarhoatargetingguaninenucleotideexchangefactoriscriticalforhemidesmosomeformationandacinardevelopmentinepithelialcells AT kazumasaohashi soloarhoatargetingguaninenucleotideexchangefactoriscriticalforhemidesmosomeformationandacinardevelopmentinepithelialcells AT shinjideguchi soloarhoatargetingguaninenucleotideexchangefactoriscriticalforhemidesmosomeformationandacinardevelopmentinepithelialcells AT kensakumizuno soloarhoatargetingguaninenucleotideexchangefactoriscriticalforhemidesmosomeformationandacinardevelopmentinepithelialcells |