mTORC1 loss impairs epidermal adhesion via TGF-b/Rho kinase activation

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dc.contributor.author Georgess, Dan
dc.contributor.author Asrani, Kaushal
dc.contributor.author Sood, Akshay
dc.contributor.author Torres, Alba
dc.contributor.author Phatak, Pornima
dc.contributor.author Kaur, Harmisar
dc.date.accessioned 2019-04-04T12:05:44Z
dc.date.available 2019-04-04T12:05:44Z
dc.date.copyright 2017 en_US
dc.date.issued 2019-04-04
dc.identifier.issn 1558-8238 en_US
dc.identifier.uri http://hdl.handle.net/10725/10343
dc.description.abstract Despite its central position in oncogenic intracellular signaling networks, the role of mTORC1 in epithelial development has not been studied extensively in vivo. Here, we have used the epidermis as a model system to elucidate the cellular effects and signaling feedback sequelae of mTORC1 loss of function in epithelial tissue. In mice with conditional epidermal loss of the mTORC1 components Rheb or Rptor, mTORC1 loss of function unexpectedly resulted in a profound skin barrier defect with epidermal abrasions, blistering, and early postnatal lethality, due to a thinned epidermis with decreased desmosomal protein expression and incomplete biochemical differentiation. In mice with mTORC1 loss of function, we found that Rho kinase (ROCK) signaling was constitutively activated, resulting in increased cytoskeletal tension and impaired cell-cell adhesion. Inhibition or silencing of ROCK1 was sufficient to rescue keratinocyte adhesion and biochemical differentiation in these mice. mTORC1 loss of function also resulted in marked feedback upregulation of upstream TGF-β signaling, triggering ROCK activity and its downstream effects on desmosomal gene expression. These findings elucidate a role for mTORC1 in the regulation of epithelial barrier formation, cytoskeletal tension, and cell adhesion, underscoring the complexity of signaling feedback following mTORC1 inhibition. en_US
dc.language.iso en en_US
dc.title mTORC1 loss impairs epidermal adhesion via TGF-b/Rho kinase activation en_US
dc.type Article en_US
dc.description.version Published en_US
dc.author.school SAS en_US
dc.author.idnumber 201900498 en_US
dc.author.department Natural Sciences en_US
dc.description.embargo N/A en_US
dc.relation.journal Journal of Clinical Investigation en_US
dc.journal.volume 127 en_US
dc.journal.issue 11 en_US
dc.article.pages 4001-4017 en_US
dc.identifier.doi https://doi.org/10.1172/JCI92893 en_US
dc.identifier.ctation Asrani, K., Sood, A., Torres, A., Georgess, D., Phatak, P., Kaur, H., ... & Xiao, B. (2017). mTORC1 loss impairs epidermal adhesion via TGF-β/Rho kinase activation. The Journal of clinical investigation, 127(11), 4001-4017. en_US
dc.author.email dan.georgess@lau.edu.lb en_US
dc.identifier.tou http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php en_US
dc.identifier.url https://www.jci.org/articles/view/92893 en_US
dc.author.affiliation Lebanese American University en_US

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