TGF-β1 Augments the Apical Membrane Abundance of Lemur Tyrosine Kinase 2 to Inhibit CFTR-Mediated Chloride Transport in Human Bronchial Epithelia

Cruz, Daniel Filipe; Mitash, Nilay; Farinha, Carlos M.; Swiatecka‐Urban, Agnieszka

doi:10.3389/fcell.2020.00058

Cited by 9 publications

(9 citation statements)

References 69 publications

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“…Cruz has explained the mechanism by which TGF-β inhibits CFTR in the bronchial epithelial cells. TGF-β, after interacting with the TGF-beta receptor, stimulates intracellular trafficking of lemur tyrosine kinase 2 (LMTK2) via Rab11, which causes LMTK2 to be recycled and shifted to the cell membrane where LMTK2 phosphorylates serine-737 of CFTR and inhibits CFTR activity [ 69 ]. Kabir et al have reported the effect of TGF-β on the expression of CFTR.…”

Section: Reactive Oxygen Species Non-dependent Pathwaysmentioning

confidence: 99%

Role of pirfenidone in TGF-β pathways and other inflammatory pathways in acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a theoretical perspective

2021

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Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes pulmonary injury or multiple-organ injury by various pathological pathways. Transforming growth factor-beta (TGF-β) is a key factor that is released during SARS-CoV-2 infection. TGF-β, by internalization of the epithelial sodium channel (ENaC), suppresses the anti-oxidant system, downregulates the cystic fibrosis transmembrane conductance regulator (CFTR), and activates the plasminogen activator inhibitor 1 (PAI-1) and nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-kB). These changes cause inflammation and lung injury along with coagulopathy. Moreover, reactive oxygen species play a significant role in lung injury, which levels up during SARS-CoV-2 infection. Drug Suggestion Pirfenidone is an anti-fibrotic drug with an anti-oxidant activity that can prevent lung injury during SARS-CoV-2 infection by blocking the maturation process of transforming growth factor-beta (TGF-β) and enhancing the protective role of peroxisome proliferator-activated receptors (PPARs). Pirfenidone is a safe drug for patients with hypertension or diabetes and its side effect tolerated well. Conclusion The drug as a theoretical perspective may be an effective and safe choice for suppressing the inflammatory response during COVID-19. The recommendation would be a combination of pirfenidone and N -acetylcysteine to achieve maximum benefit during SARS-CoV-2 treatment.

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Section: Reactive Oxygen Species Non-dependent Pathwaysmentioning

confidence: 99%

Role of pirfenidone in TGF-β pathways and other inflammatory pathways in acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a theoretical perspective

2021

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“…LMTK2 protein abundance was decreased by 85% in cells transfected with siLMTK2, compared to siCTRL ( Figure 1 ). Previous studies have demonstrated that TGF-β1 stimulation does not affect total protein abundance of LMTK2 ( 14 ).…”

Section: Resultsmentioning

confidence: 96%

“…LMTK2 is an integral membrane protein associated with endosomal membranes ( 7 , 14 ). Endocytic trafficking of membrane proteins can affect the intracellular signal transduction, including effects on the activity of various nuclear transcription factors.…”

Section: Discussionmentioning

confidence: 99%

“…Proteins were separated by SDS-PAGE using 7.5% pre-cast gels (Bio-Rad). LMTK2 was detected by western blotting (WB) with Western Lightning Chemiluminescence Reagent Plus (PerkinElmer LAS Inc., Boston, MA, USA), using previously validated polyclonal anti-LMTK2 antibody (#SAB4500900, Sigma-Aldrich, St. Louis, MO, USA) ( 14 ). Monoclonal anti-Ezrin (Cat.…”

Section: Methodsmentioning

confidence: 99%

“…Smad2 is a transcription factor that mediates the canonical TGF-β1 signaling that regulates variety of cellular processes ( 13 ). Second, TGF-β1 recruited LMTK2 to the plasma membrane by a Rab11-dependent mechanism in human bronchial epithelial CFBE41o- cells ( 14 ), facilitating the LMTK2-mediated CFTR phosphorylation. These studies are clinically relevant because elevated TGF-β1 levels, observed in many CF patients, compromise the functional rescue of F508del-CFTR by current generation CFTR modulators ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

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Differential Gene Expression Analysis Reveals Global LMTK2 Regulatory Network and Its Role in TGF-β1 Signaling

Cruz

Mitash

et al. 2021

Front. Oncol.

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Lemur tyrosine kinase 2 (LMTK2) is a transmembrane Ser/Thr kinase whose role has been increasingly recognized; however, when compared to other kinases, understanding of the LMTK2 networks and biological functions is still limited. Recent data have shown that transforming growth factor (TGF)-β1 plays a role in modulating LMTK2 function by controlling its endocytic trafficking in human bronchial epithelial cells. Here, we aimed to unveil the LMTK2 regulatory network and elucidate how it affects cellular functions and disease pathways in either TGF-β1 dependent or independent manner. To understand how the LMTK2 and TGF-β1 pathways interconnect, we knocked down (KD) LMTK2 using small(si)RNA-mediated silencing in human bronchial epithelial CFBE41o- cells, treated cells with TGF-β1 or vehicle control, and performed differential gene expression analysis by RNA sequencing (RNAseq). In vehicle-treated cells, LMTK2 KD affected expression of 2,506 genes while it affected 4,162 genes after TGF-β1 stimulation. Bioinformatics analysis shows that LMTK2 is involved in diverse cellular functions and disease pathways, such as cell death and survival, cellular development, and cancer susceptibility. In summary, our study increases current knowledge about the LMTK2 network and its intersection with the TGF-β1 signaling pathway. These findings will serve as basis for future exploration of the predicted LMTK2 interactions and signaling pathways.

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Fundamental and translational research in Cystic Fibrosis – why we still need it

Farinha

Brodsky

Pedemonte

2023

Journal of Cystic Fibrosis

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TGF-β1 Augments the Apical Membrane Abundance of Lemur Tyrosine Kinase 2 to Inhibit CFTR-Mediated Chloride Transport in Human Bronchial Epithelia

Cited by 9 publications

References 69 publications

Role of pirfenidone in TGF-β pathways and other inflammatory pathways in acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a theoretical perspective

Role of pirfenidone in TGF-β pathways and other inflammatory pathways in acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a theoretical perspective

Differential Gene Expression Analysis Reveals Global LMTK2 Regulatory Network and Its Role in TGF-β1 Signaling

Fundamental and translational research in Cystic Fibrosis – why we still need it

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