Signaling through the platelet-derived growth factor receptors (PDGFRs) plays a critical role in multiple cellular processes during development. The two PDGFRs, PDGFR and PDGFR, dimerize to form homodimers and/or heterodimers. Here, we overcome previous limitations in studying PDGFR dimer-specific dynamics by generating cell lines stably expressing C-terminal fusions of each PDGFR with bimolecular fluorescence complementation (BiFC) fragments corresponding to the N-terminal or C-terminal regions of the Venus fluorescent protein. We find that PDGFR receptors homodimerize more quickly than PDGFR receptors in response to PDGF ligand, with increased levels of autophosphorylation. Further, we demonstrate that PDGFR homodimers are trafficked and degraded more quickly, while PDGFR homodimers are more likely to be recycled back to the cell membrane. We show that PDGFR homodimer activation results in a greater amplitude of phospho-ERK1/2 and phospho-AKT signaling, as well as increased proliferation and migration. Finally, we demonstrate that inhibition of clathrin-mediated endocytosis leads to changes in cellular trafficking and downstream signaling, particularly for PDGFRa homodimers. Collectively, our findings provide significant insight into how biological specificity is introduced to generate unique responses downstream of PDGFR engagement.
PDGFR dimer-specific activation, trafficking and downstream signaling dynamics
- Award Group:
- Funder(s): National Institutes of Health
- Award Id(s): R01DE027689
- Funder(s):
Currently Viewing Accepted Manuscript - Newer Version Available
Madison A. Rogers, Maria B. Campaña, Robert Long, Katherine A. Fantauzzo; PDGFR dimer-specific activation, trafficking and downstream signaling dynamics. J Cell Sci 2022; jcs.259686. doi: https://doi.org/10.1242/jcs.259686
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