Mesenchyme-derived vertebrate lonesome kinase controls lung organogenesis by altering the matrisome.
Salome M BrütschElizabeta MadzharovaSophia PantasisTill WüstemannSelina GurriHeiko SteenbockAmiq GazdharGisela KuhnPeter AngelSaverio BellusciJürgen BrinckmannUlrich Auf dem KellerSabine WernerMattia R BordoliPublished in: Cellular and molecular life sciences : CMLS (2023)
Vertebrate lonesome kinase (VLK) is the only known secreted tyrosine kinase and responsible for the phosphorylation of a broad range of secretory pathway-resident and extracellular matrix proteins. However, its cell-type specific functions in vivo are still largely unknown. Therefore, we generated mice lacking the VLK gene (protein kinase domain containing, cytoplasmic (Pkdcc)) in mesenchymal cells. Most of the homozygous mice died shortly after birth, most likely as a consequence of their lung abnormalities and consequent respiratory failure. E18.5 embryonic lungs showed a reduction of alveolar type II cells, smaller bronchi, and an increased lung tissue density. Global mass spectrometry-based quantitative proteomics identified 97 proteins with significantly and at least 1.5-fold differential abundance between genotypes. Twenty-five of these had been assigned to the extracellular region and 15 to the mouse matrisome. Specifically, fibromodulin and matrilin-4, which are involved in extracellular matrix organization, were significantly more abundant in lungs from Pkdcc knockout embryos. These results support a role for mesenchyme-derived VLK in lung development through regulation of matrix dynamics and the resulting modulation of alveolar epithelial cell differentiation.
Keyphrases
- extracellular matrix
- tyrosine kinase
- protein kinase
- mass spectrometry
- induced apoptosis
- respiratory failure
- epidermal growth factor receptor
- cell cycle arrest
- stem cells
- high resolution
- mechanical ventilation
- type diabetes
- extracorporeal membrane oxygenation
- endoplasmic reticulum stress
- patient safety
- bone marrow
- cell death
- pregnant women
- genome wide
- oxidative stress
- microbial community
- adipose tissue
- transcription factor
- copy number
- wild type
- pi k akt
- gestational age
- antibiotic resistance genes
- genome wide analysis
- anaerobic digestion
- preterm birth
- label free