Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 27, Issue 6, Pages 954-966Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E15-06-0417
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [23112005, 25440076, 24370051, 26102505]
- Mitsubishi Foundation
- Uehara Memorial Foundation
- Grants-in-Aid for Scientific Research [25440076, 14J03455, 16K07335, 26102505] Funding Source: KAKEN
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Mechanical force-induced cytoskeletal reorganization is essential for cell and tissue remodeling and homeostasis; however, the underlying cellular mechanisms remain elusive. Solo (ARHGEF40) is a RhoA-targeting guanine nucleotide exchange factor (GEF) involved in cyclical stretch-induced human endothelial cell reorientation and convergent extension cell movement in zebrafish gastrula. In this study, we show that Solo binds to keratin-8/keratin-18 (K8/K18) intermediate filaments through multiple sites. Solo overexpression promotes the formation of thick actin stress fibers and keratin bundles, whereas knockdown of Solo, expression of a GEF-inactive mutant of Solo, or inhibition of ROCK suppresses stress fiber formation and leads to disorganized keratin networks, indicating that the Solo-RhoA-ROCK pathway serves to precisely organize keratin networks, as well as to promote stress fibers. Of importance, knockdown of Solo or K18 or overexpression of GEF-inactive or deletion mutants of Solo suppresses tensile force-induced stress fiber reinforcement. Furthermore, knockdown of Solo or K18 suppresses tensile force-induced RhoA activation. These results strongly suggest that the interplay between Solo and K8/K18 filaments plays a crucial role in tensile force-induced RhoA activation and consequent actin cytoskeletal reinforcement.
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