Journal article
Neuropilin-1 directs PDGFR alpha-entry into lung fibroblasts and signaling from very early endosomes
American journal of physiology. Lung cellular and molecular physiology, Vol.320(2), pp.L179-L192
02/01/2021
DOI: 10.1152/ajplung.00149.2020
PMID: 33174445
Abstract
Platelet-derived growth factor receptor-alpha (PDGFR alpha) is absolutely required for the development of secondary pulmonary alveolar septa. Our earlier observations indicated that PDGFR alpha 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 PDGFR alpha in LF obtained from mice, some bearing a targeted deletion of Nrp1 in myofibroblasts. Using the proximity ligation assay, we observed that PDGFR alpha 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 PDGFR alpha 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 PDGFR alpha, and limited accumulation of inositol-3 phosphates in APPL1-containing endosomes after exposure to PDGFA. PDGFR alpha co-immunoprecipitated with APPL1, indicating that PDGFR alpha 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 PDGFR alpha into APPL1 containing VEE and that APPL1 enhances PDGFR alpha signaling. Therefore, Nrp1 promotes endosomal signaling by PDGFR alpha offering a potential mechanism to explain our prior observation that Nrp1 supports the formation of alveolar ducts and alveoli during secondary septation in mice.
Details
- Title: Subtitle
- Neuropilin-1 directs PDGFR alpha-entry into lung fibroblasts and signaling from very early endosomes
- Creators
- Stephen E. McGowan - Roy J. and Lucille A. Carver College of MedicineDiann M. McCoy - Roy J. and Lucille A. Carver College of Medicine
- Resource Type
- Journal article
- Publication Details
- American journal of physiology. Lung cellular and molecular physiology, Vol.320(2), pp.L179-L192
- Publisher
- Amer Physiological Soc
- DOI
- 10.1152/ajplung.00149.2020
- PMID
- 33174445
- ISSN
- 1040-0605
- eISSN
- 1522-1504
- Number of pages
- 14
- Grant note
- Department of Veterans Affairs Research Service; US Department of Veterans Affairs
- Language
- English
- Date published
- 02/01/2021
- Academic Unit
- Pulmonary, Critical Care, and Occupational Medicine; International Programs; Internal Medicine
- Record Identifier
- 9984360151902771
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