Abstract
BackgroundCellular contractility, essential for cell movement and proliferation, is regulated by microtubules, RhoA and actomyosin. The RhoA dependent kinase ROCK ensures the phosphorylation of the regulatory Myosin II Light Chain (MLC) Ser19, thereby activating actomyosin contractions. Microtubules are upstream inhibitors of contractility and their depolymerization or depletion cause cells to contract by activating RhoA. How microtubule dynamics regulates RhoA remains, a major missing link in understanding contractility.Principal FindingsWe observed that contractility is inhibited by microtubules not only, as previously reported, in adherent cells, but also in non-adhering interphase and mitotic cells. Strikingly we observed that contractility requires ubiquitin mediated proteolysis by a Cullin-RING ubiquitin ligase. Inhibition of proteolysis, ubiquitination and neddylation all led to complete cessation of contractility and considerably reduced MLC Ser19 phosphorylation.ConclusionsOur results imply that cells express a contractility inhibitor that is degraded by ubiquitin mediated proteolysis, either constitutively or in response to microtubule depolymerization. This degradation seems to depend on a Cullin-RING ubiquitin ligase and is required for cellular contractions.
Highlights
Cellular contractility and the ability of cells to change their shape are prerequisites for many biological phenomena such as cytokinesis, movement, differentiation and substrate adherence
Our results imply that cells express a contractility inhibitor that is degraded by ubiquitin mediated proteolysis, either constitutively or in response to microtubule depolymerization
This degradation seems to depend on a Cullin-RING ubiquitin ligase and is required for cellular contractions
Summary
Cellular contractility and the ability of cells to change their shape are prerequisites for many biological phenomena such as cytokinesis, movement, differentiation and substrate adherence These changes in cell shape are achieved by modulation of the cytoskeleton, most importantly the actin cytoskeleton, through forces generated by the actomyosin network. Cell contractility is typically achieved by localized activation of Myosin II Light Chain (MLC) by its phosphorylation on Ser. Cell contractility is typically achieved by localized activation of Myosin II Light Chain (MLC) by its phosphorylation on Ser19 This phosphorylation, which causes contractions of the actin network by Myosin II is regulated by various MLC kinases and Myosin phosphatase (MYP). The RhoA dependent kinase ROCK ensures the phosphorylation of the regulatory Myosin II Light Chain (MLC) Ser, thereby activating actomyosin contractions. How microtubule dynamics regulates RhoA remains, a major missing link in understanding contractility
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