期刊
CELLULAR AND MOLECULAR LIFE SCIENCES
卷 80, 期 4, 页码 -出版社
SPRINGER BASEL AG
DOI: 10.1007/s00018-023-04735-6
关键词
Pkdcc; Lung organogenesis; Collagen; Skull; Proteomics
Vertebrate lonesome kinase (VLK) is a secreted tyrosine kinase that phosphorylates various secretory pathway-resident and extracellular matrix proteins. However, its specific functions in vivo are still largely unknown. In this study, mice lacking the VLK gene in mesenchymal cells were generated, leading to lung abnormalities and respiratory failure in most homozygous mice. Proteomics analysis revealed differential abundance of extracellular matrix proteins in the lungs of these mice, suggesting that mesenchyme-derived VLK regulates lung development through modulation of matrix dynamics and alveolar epithelial cell differentiation.
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.
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