Targeting the AXL Receptor in Combating Smoking-related Pulmonary Fibrosis
| Autor: | Ji Min Li, Wen Hsin Chang, Ssu-Wei Hsu, Shenwen Gu, David C. Yang, Ching-Hsien Chen, Szu Jung Chen |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Cell Survival Pulmonary Fibrosis Clinical Biochemistry Receptor tyrosine kinase 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Proto-Oncogene Proteins Pulmonary fibrosis Animals Humans Medicine MARCKS Myristoylated Alanine-Rich C Kinase Substrate Fibroblast Receptor Lung Molecular Biology Original Research biology business.industry GAS6 Smoking Receptor Protein-Tyrosine Kinases Cell Biology Fibroblasts medicine.disease Axl Receptor Tyrosine Kinase Phenotype Up-Regulation Mice Inbred C57BL Disease Models Animal 030104 developmental biology medicine.anatomical_structure 030228 respiratory system biology.protein Cancer research business Signal Transduction |
| Zdroj: | Am J Respir Cell Mol Biol |
| ISSN: | 1535-4989 1044-1549 |
| DOI: | 10.1165/rcmb.2020-0303oc |
| Popis: | Tobacco smoking is a well-known risk factor for both fibrogenesis and fibrotic progression; however, the mechanisms behind these processes remain enigmatic. RTKs (receptor tyrosine kinases) have recently been reported to drive profibrotic phenotypes in fibroblasts during pulmonary fibrosis (PF). Using a phospho-RTK array screen, we identified the RTK AXL as a top upregulated RTK in response to smoke. Both expression and signaling activity of AXL were indeed elevated in lung fibroblasts exposed to tobacco smoke, whereas no significant change to the levels of a canonical AXL ligand, Gas6 (growth arrest–specific 6), was seen upon smoke treatment. Notably, we found that smoke-exposed human lung fibroblasts exhibited highly proliferative and invasive activities and were capable of inducing fibrotic lung lesions in mice. Conversely, genetic suppression of AXL in smoke-exposed fibroblasts cells led to suppression of AXL downstream pathways and aggressive phenotypes. We further demonstrated that AXL interacted with MARCKS (myristoylated alanine-rich C kinase substrate) and cooperated with MARCKS in regulating downstream signaling activity and fibroblast invasiveness. Pharmacological inhibition of AXL with AXL-specific inhibitor R428 showed selectivity for smoke-exposed fibroblasts. In all, our data suggest that AXL is a potential marker for smoke-associated PF and that targeting of the AXL pathway is a potential therapeutic strategy in treating tobacco smoking–related PF. |
| Databáze: | OpenAIRE |
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