首页|PDGFR dimer-specific activation, trafficking and downstream signaling dynamics
PDGFR dimer-specific activation, trafficking and downstream signaling dynamics
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NSTL
Company Biologists Ltd
Signaling through the platelet-derived growth factor receptors (PDGFRs) plays a critical role in multiple cellular processes during development. The two PDGFRs, PDGFR alpha and PDGFRp, 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 PDGFRp receptors homodimerize more quickly than PDGFRa receptors in response to PDGF ligand, with increased levels of autophosphorylation. Furthermore, we demonstrate that PDGFRa homodimers are trafficked and degraded more quickly, whereas PDGFRp homodimers are more likely to be recycled back to the cell membrane. We show that PDGFRp 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.This article has an associated First Person interview with the first author of the paper.
NSTL
Company Biologists Ltd
