Neuropilin-1 directs PDGFRα-entry into lung fibroblasts and signaling from very early endosomes
| Autor: | Stephen E. McGowan, Diann M. McCoy |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Physiology Endosome Endosomes Biology Receptor Platelet-Derived Growth Factor beta Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine Growth factor receptor Physiology (medical) Neuropilin 1 medicine Animals Lung Adaptor Proteins Signal Transducing Mice Knockout Cell Biology Fibroblasts Neuropilin-1 Cell biology 030104 developmental biology medicine.anatomical_structure Proto-Oncogene Proteins c-akt Myofibroblast 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology. 320:L179-L192 |
| ISSN: | 1522-1504 1040-0605 |
| Popis: | Platelet-derived growth factor receptor-α (PDGFRα) is absolutely required for the development of secondary pulmonary alveolar septa. Our earlier observations indicated that PDGFRα resides intracellularly as well as on the plasma membrane of murine lung fibroblasts (LF). We have examined how neuropilin-1 (Nrp1), a surface receptor without kinase activity, regulates the intracellular trafficking of PDGFRα in LF obtained from mice, some bearing a targeted deletion of Nrp1 in myofibroblasts. Using the proximity ligation assay, we observed that PDGFRα and Nrp1 colocalized in both early antigen-1 (EEA1) containing sorting endosomes and with adaptor protein containing a pleckstrin homology domain and a phosphotyrosine-binding domain-1 (APPL1) in very early endosomes (VEE). These findings were confirmed using live-cell imaging, which demonstrated that recently internalized PDGFRα was observed in Rab5-containing vesicles residing within 100 nm of the plasma membrane. Nrp1 deletion reduced the phosphorylation of Akt (protein kinase B), the major downstream target of PDGFRα, and limited accumulation of inositol-3 phosphates in APPL1-containing endosomes after exposure to PDGFA. PDGFRα co-immunoprecipitated with APPL1, indicating that PDGFRα enters VEE. Targeted deletion of Nrp1 or APPL1-depletion in control LF reduced the activity of an Akt1 biosensor following stimulation with PDGFA. Our findings demonstrate that Nrp1 enhances the entry of PDGFRα into APPL1 containing VEE and that APPL1 enhances PDGFRα signaling. Therefore, Nrp1 promotes endosomal signaling by PDGFRα offering a potential mechanism to explain our prior observation that Nrp1 supports the formation of alveolar ducts and alveoli during secondary septation in mice. |
| Databáze: | OpenAIRE |
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