期刊
MOLECULAR BIOLOGY OF THE CELL
卷 18, 期 10, 页码 3860-3872出版社
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E07-01-0075
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- NCI NIH HHS [R01 CA133346] Funding Source: Medline
- NIMH NIH HHS [MH77306, R21 MH077306] Funding Source: Medline
- NINDS NIH HHS [NS39754, NS45477, R01 NS039475, F31 NS045477] Funding Source: Medline
in migrating cells, actin polymerization promotes protrusion of the leading edge, whereas actomyosin contractility powers net cell body translocation. Although they promote F-actin-dependent protrusions of the cell periphery upon adhesion to fibronectin (FN), Ab1 family kinases inhibit cell migration on FN. We provide evidence here that the Ab1-related gene (Arg/Ab12) kinase inhibits fibroblast migration by attenuating actomyosin contractility and regulating focal adhesion dynamics. arg(-/-) fibroblasts migrate at faster average speeds than wild-type (wt) cells, whereas Arg re-expression in these cells slows migration. Surprisingly, the faster migrating arg(-/-) fibroblasts have more prominent F-actin stress fibers and focal adhesions and exhibit increased actomyosin contractility relative to wt cells. Interestingly, Arg requires distinct functional domains to inhibit focal adhesions and actomyosin contractility. The kinase domain-containing Arg N-terminal half can act through the RhoA inhibitor p190RhoGAP to attenuate stress fiber formation and cell contractility. However, Arg requires both its kinase activity and its cytoskeleton-binding C-terminal half to fully inhibit focal adhesions. Although focal adhesions do not turn over efficiently in the trailing edge of arg(-/-) cells, the increased contractility of arg(-/-) cells tears the adhesions from the substrate, allowing for the faster migration observed in these cells. Together, our data strongly suggest that Arg inhibits cell migration by restricting actomyosin contractility and regulating its coupling to the substrate through focal adhesions.
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