| الوصف: |
Cystic 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. |
