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Regulation of the TGF-β1 signaling in cystic fibrosis : the role of LMTK2

2020-03Tese de doutoramento Acesso aberto
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datacite.subject.fosCiências Naturais::Ciências Biológicaspt_PT
dc.contributor.advisorFarinha, Carlos Miguel
dc.contributor.advisorSwiatecka-Urban, Agnieszka
dc.contributor.authorCruz, Daniel Filipe Soares Pereira da
dc.date.accessioned2020-12-30T10:34:10Z
dc.date.available2023-04-04T00:30:42Z
dc.date.issued2020-03
dc.date.submitted2020-01
dc.description.abstractCystic fibrosis (CF), the most common autosomal recessive disease in Caucasians, is a multi-organ disease, affecting the epithelial tissues in the lungs, sweat glands, pancreas, intestine, liver and in the male reproductive tract. CF is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, which encodes a Cl- channel expressed at the apical membrane of epithelial cells. Besides the CFTR genotype, other factors influence the heterogeneity of CF lung disease, including environmental and socioeconomic factors and genetic modifiers. Understanding the genetic modifiers will help to unveil their role in disease progression and identify novel therapeutic targets. Transforming Growth Factor (TGF)-β1, besides being a gene modifier of CF lung disease in F508del homozygous patients, has been shown to interfere with the modulators-based functional rescue of F508del-CFTR. Lemur tyrosine kinase 2 (LMTK2), which mediates the inhibitory phosphorylation of CFTR and protein phosphatase 1 catalytic subunit (PP1c), has also been suggested to play a role in CF. This project aims to establish a relation between LMTK2 and the TGF-β1 signaling pathway and understand the role of the interaction in the CF airway. Here, we first observed that TGF-β1 increases LMTK2 abundance at the apical membrane of CFBE41o- cells by increasing Rab11-dependent LMTK2 recycling. Next, we unveiled for the first time that LMTK2 mediates activation of the TGF-β1 signaling pathway. Indeed, TGF-β1 induced the LMTK2-mediated inhibitory phosphorylation of PP1c-Thr320 to promote the activation of its canonical signaling pathway. At last, we increased the knowledge by identifying the LMTK2 networks of genes, proteins, and signaling pathways and elucidated novel molecular and cellular mechanisms of the LMTK2 function in human airway epithelial cells. Our studies may lead to novel therapeutic targets blocking abnormal TGF-β1 signaling, thereby improving the modulators-based functional rescue of CFTR bearing F508del, the most common CF-causing mutation.pt_PT
dc.identifier.tid101580517pt_PT
dc.identifier.urihttp://hdl.handle.net/10451/45586
dc.language.isoengpt_PT
dc.relationFCT/PD/00065/2012pt_PT
dc.relationLMTK2 signalling in cystic fibrosis: an interactomics approach
dc.subjectCystic Fibrosispt_PT
dc.subjectLMTK2pt_PT
dc.subjectTGF-B1pt_PT
dc.subjectPP1cpt_PT
dc.subjectsignaling pathwaypt_PT
dc.titleRegulation of the TGF-β1 signaling in cystic fibrosis : the role of LMTK2pt_PT
dc.typedoctoral thesis
dspace.entity.typePublication
oaire.awardNumberPD/BD/114384/2016
oaire.awardTitleLMTK2 signalling in cystic fibrosis: an interactomics approach
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/PD%2FBD%2F114384%2F2016/PT
oaire.fundingStreamOE
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typedoctoralThesispt_PT
relation.isProjectOfPublication4555af8c-4b38-40ca-a43a-8c31412427a9
relation.isProjectOfPublication.latestForDiscovery4555af8c-4b38-40ca-a43a-8c31412427a9
thesis.degree.nameTese de doutoramento, Biologia (Biologia de Sistemas), Universidade de Lisboa, Faculdade de Ciências, 2020pt_PT

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