TY - JOUR
T1 - The Rho-guanine nucleotide exchange factor Solo decelerates collective cell migration by modulating the Rho-ROCK pathway and keratin networks
AU - Isozaki, Yusuke
AU - Sakai, Kouki
AU - Kohiro, Kenta
AU - Kagoshima, Katsuhiko
AU - Iwamura, Yuma
AU - Sato, Hironori
AU - Rindner, Daniel
AU - Fujiwara, Sachiko
AU - Yamashita, Kazunari
AU - Mizuno, Kensaku
AU - Ohashi, Kazumasa
N1 - Funding Information:
We thank Naoki Honzawa for technical assistance. This work was supported by the Japan Agency for Medical Research and Development (Grant no. JP18gm5810015h0003 to K.O.), https://www .amed.go.jp/en/index.html; the Japan Society for the Promotion of Science (JSPS) KAKENHI (Grants no. JP23112005 and no. JP16K07335 to K.O., Grants no. JP15K14469, no. JP16H00749, and no. JP18K19280 to K.M., and Grant no. JPT17K151180 to S.F.), http://www.jsps.go.jp/j-grantsinaid/; and JSPS (Fellowship no. JPA16J041330 to S.F.), http://www.jsps.go.jp/j-pd/.
Publisher Copyright:
© 2020 Isozaki et al.
PY - 2020/3
Y1 - 2020/3
N2 - Collective cell migration plays crucial roles in tissue remodeling, wound healing, and cancer cell invasion. However, its underlying mechanism remains unknown. Previously, we showed that the RhoA-targeting guanine nucleotide exchange factor Solo (ARHGEF40) is required for tensile force–induced RhoA activation and proper organization of keratin-8/keratin-18 (K8/K18) networks. Here, we demonstrate that Solo knockdown significantly increases the rate at which Madin-Darby canine kidney cells collectively migrate on collagen gels. However, it has no apparent effect on the migratory speed of solitary cultured cells. Therefore, Solo decelerates collective cell migration. Moreover, Solo localized to the anteroposterior regions of cell–cell contact sites in collectively migrating cells and was required for the local accumulation of K8/K18 filaments in the forward areas of the cells. Partial Rho-associated protein kinase (ROCK) inhibition or K18 or plakoglobin knockdown also increased collective cell migration velocity. These results suggest that Solo acts as a brake for collective cell migration by generating pullback force at cell–cell contact sites via the RhoA-ROCK pathway. It may also promote the formation of desmosomal cell–cell junctions related to K8/K18 filaments and plakoglobin.
AB - Collective cell migration plays crucial roles in tissue remodeling, wound healing, and cancer cell invasion. However, its underlying mechanism remains unknown. Previously, we showed that the RhoA-targeting guanine nucleotide exchange factor Solo (ARHGEF40) is required for tensile force–induced RhoA activation and proper organization of keratin-8/keratin-18 (K8/K18) networks. Here, we demonstrate that Solo knockdown significantly increases the rate at which Madin-Darby canine kidney cells collectively migrate on collagen gels. However, it has no apparent effect on the migratory speed of solitary cultured cells. Therefore, Solo decelerates collective cell migration. Moreover, Solo localized to the anteroposterior regions of cell–cell contact sites in collectively migrating cells and was required for the local accumulation of K8/K18 filaments in the forward areas of the cells. Partial Rho-associated protein kinase (ROCK) inhibition or K18 or plakoglobin knockdown also increased collective cell migration velocity. These results suggest that Solo acts as a brake for collective cell migration by generating pullback force at cell–cell contact sites via the RhoA-ROCK pathway. It may also promote the formation of desmosomal cell–cell junctions related to K8/K18 filaments and plakoglobin.
UR - http://www.scopus.com/inward/record.url?scp=85082881657&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85082881657&partnerID=8YFLogxK
U2 - 10.1091/MBC.E19-07-0357
DO - 10.1091/MBC.E19-07-0357
M3 - Article
C2 - 32049581
AN - SCOPUS:85082881657
VL - 31
SP - 741
EP - 752
JO - Molecular Biology of the Cell
JF - Molecular Biology of the Cell
SN - 1059-1524
IS - 8
ER -
