Abstract
Regulated assembly and disassembly, or turnover, of integrin-mediated cell–extracellular matrix (ECM) adhesions is essential for dynamic cell movements and long-term tissue maintenance. For example, in Drosophila, misregulation of integrin turnover disrupts muscle–tendon attachment at myotendinous junctions (MTJs). We demonstrate that mechanical force, which modulates integrin activity, also regulates integrin and intracellular adhesion complex (IAC) turnover in vivo. Using conditional mutants to alter the tensile force on MTJs, we found that the proportion of IAC components undergoing turnover inversely correlated with the force applied on MTJs. This effect was disrupted by point mutations in β-integrin that interfere with ECM-induced conformational changes and activation of β-integrin or integrin-mediated cytoplasmic signalling. These mutants also disrupted integrin dynamics at MTJs during larval development. Together, these data suggest that specific β-integrin-mediated signals regulate adhesion turnover in response to tension during tissue formation. We propose that integrin–ECM adhesive stability is continuously controlled by force in vivo through integrin-dependent auto-regulatory feedback mechanisms so that tissues can quickly adapt to and withstand mechanical stresses.
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Acknowledgements
We thank T. Littleton (MIT, USA) and F. Schöck (McGill University, Canada) for flies, and D. Moerman and members of the laboratory for helpful discussions and comments on the manuscript. S.J.E. holds an NSERC Alexander Graham Bell Canada Graduate Scholarship. D.C. is financially supported through an NSERC discovery grant. G.T. is financially supported through NSERC discovery grant 356502 and Canadian Institutes of Health Research operating grant 89835. G.T. is a CIHR New Investigator and Michael Smith Foundation for Health Research Scholar.
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G.T. conceived, designed and supervised the project and participated in data analysis. M.P. carried out most of the genetics crosses, FRAP experiments and data analysis. S.J.E. performed genetic crosses, FRAP experiments and analysed data. L.Y. optimized the conditions and protocols for using the Brkd and para mutants. M.K. performed the force transducer experiments. A.M. and S.C. performed FRAP experiments and analysed data. A.M. carried out the stainings on larval flat preparations. M.P., S.J.E., A.M. and S.C. recorded movies for analysis. R.D and D.C. performed the mathematical modeling and data analysis. G.T., M.P., R.D. and S.J.E. wrote and revised the manuscript.
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Pines, M., Das, R., Ellis, S. et al. Mechanical force regulates integrin turnover in Drosophila in vivo. Nat Cell Biol 14, 935–943 (2012). https://doi.org/10.1038/ncb2555
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DOI: https://doi.org/10.1038/ncb2555
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