| First Author | McGowan SE | Year | 2020 |
| Journal | Am J Physiol Lung Cell Mol Physiol | PubMed ID | 33174445 |
| Mgi Jnum | J:301053 | Mgi Id | MGI:6501857 |
| Doi | 10.1152/ajplung.00149.2020 | Citation | McGowan SE, et al. (2020) Neuropilin-1 directs PDGFRalpha-entry into lung fibroblasts and signaling from very early endosomes. Am J Physiol Lung Cell Mol Physiol :L179-L192 |
| abstractText | Platelet-derived growth factor receptor alpha (PDGFRalpha) is absolutely required for the development of secondary pulmonary alveolar septa. Our earlier observations indicated that PDGFRalpha 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 PDGFRalpha in LF obtained from mice bearing a targeted deletion of Nrp1 in myofibroblasts. Using the proximity ligation assay we observed that PDGFRalpha and Nrp1 co-localized 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 PDGFRalpha was observed in Rab5-containing vesicles residing within 100 nm of the plasma membrane. Nrp1-deletion reduced the phosphorylation of Akt, (protein kinase B) a downstream target of PDGFRalpha, indicating that Nrp1 enhances PDGFRalpha-signaling. PDGFRalpha co-immunoprecipitated with APPL1 and APPL1-depletion reduced Akt phosphorylation after exposure to PDGF-A. Targeted deletion of Nrp1 or APPL1-depletion in control LF reduced the activity of an Akt1 biosensor following stimulation with PDGF-A. Our findings demonstrate that Nrp1 enhances the entry of PDGFRalpha into APPL1 containing VEE and that APPL1 enhances PDGFRalpha-signaling. Therefore, Nrp1 enhances endosomal signaling by PDGFRalpha offering a potential mechanism to explain our prior observation that Nrp1 supports the formation of alveolar ducts and alveoli during secondary septation in mice. |
