LIMK2 is required for membrane cytoskeleton reorganization of contracting airway smooth muscle |
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| Institution: | 1. Department of Health Sciences, Center on Autoimmune and Allergic Diseases (CAAD), UPO, University of Eastern Piedmont, A. Avogadro, Novara 28100, Italy;2. Consorzio Interuniversitario di Biotecnologie (CIB), Trieste 34149, Italy;3. Laboratory of Human Genetics of Neurological Disorders, Institute of Experimental Neurology, Division of Neurosciences, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy;4. National Research Council of Italy, Institute for Biomedical Technologies, Segrate, Milan 20090, Italy;5. Department of Genetic Medicine and Development (GEDEV), Faculty of Medicine, University of Geneva Medical School, Geneva 1211, Switzerland;6. Department of Informatics, Systems and Communications (DISCo), University of Milano-Bicocca, Milan 20126, Italy;7. MS Centre, SCDU Neurology, AOU Maggiore della Carità, Novara 28100, Italy;8. Department of Translational Medicine, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Novara, Avogadro University, Novara 28100, Italy;9. Neuroscience Institute Cavalieri Ottolenghi, Orbassano, Turin 10043, Italy;10. Neurobiology Unit, Neurology - CReSM (Regional Referring Center of Multiple Sclerosis), AOU San Luigi Gonzaga, Orbassano, Turin 10043, Italy;11. Department of Neuroscience ‘Rita Levi Montalcini’, University of Turin, Turin 10126, Italy;12. Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona 37134, Italy;13. UO Neurologia Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia 71013, Italy;14. Centro Recupero e Rieducazione Funzionale “Mons L Novarese”, Moncrivello (VC) 13040, Italy;15. Department of Neurology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy;p. Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy;q. Vita-Salute San Raffaele University, Milan 20138, Italy;r. Neurophysiology Unit, IRCCS San Raffaele Scientific Institute, Milan 20138, Italy;s. Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Milan 20122, Italy;t. Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurology Unit and MS Center, Milan 20122, Italy;1. National Key Laboratory of Crop Genetic Improvement, National Center of Plant Gene Research (Wuhan), Huazhong Agricultural University, Wuhan 430070, China;2. Jiangsu Kingearth Seed Co., Ltd., Yangzhou 225012, China;1. Institute of Entomology, College of Life Sciences, Nankai University, Tianjin 300071, China;2. Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;3. Environment and Plant Protection Institute, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China;4. Guangxi Key Laboratory of Beibu Gulf Marine Biodiversity Conservation, College of Marine Sciences, Beibu Gulf University, Qinzhou 535011, China;5. Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;6. Berry Genomics Corporation, Beijing 102206, China;1. The State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China;2. Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China |
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| Abstract: | Airway smooth muscle(ASM) has developed a mechanical adaption mechanism by which it transduces force and responds to environmental forces, which is essential for periodic breathing. Cytoskeletal reorganization has been implicated in this process, but the regulatory mechanism remains to be determined.We here observe that ASM abundantly expresses cytoskeleton regulators Limk1 and Limk2, and their expression levels are further upregulated in chronic obstructive pulmonary disease(COPD) animals. By establishing mouse lines with deletions of Limk1 or Limk2, we analyse the length-sensitive contraction, F/Gactin dynamics, and F-actin pool of mutant ASM cells. As LIMK1 phosphorylation does not respond to the contractile stimulation, LIMK1-deficient ASM develops normal maximal force, while LIMK2 or LIMK1/LIMK2 deficient ASMs show approximately 30% inhibition. LIMK2 deletion causes a significant decrease in cofilin phosphorylation along with a reduced F/G-actin ratio. As LIMK2 functions independently of cross-bridge movement, this observation indicates that LIMK2 is necessary for F-actin dynamics and hence force transduction. Moreover, LIMK2-deficient ASMs display abolishes stretching-induced suppression of 5-hydroxytryptamine(5-HT) but not acetylcholine-evoks force, which is due to the differential contraction mechanisms adopted by the agonists. We propose that LIMK2-mediated cofilin phosphorylation is required for membrane cytoskeleton reorganization that is necessary for ASM mechanical adaption including the 5-HT-evoked length-sensitive effect. |
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| Keywords: | Smooth muscle LIM kinases Cofilin Cytoskeleton Length sensitive effect |
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