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PDGFRα/β heterodimer activation negatively affects downstream ERK1/2 signaling and cellular proliferation
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PDGFRα/β heterodimer activation negatively affects downstream ERK1/2 signaling and cellular proliferation
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Journal Article
PDGFRα/β heterodimer activation negatively affects downstream ERK1/2 signaling and cellular proliferation
2025
Overview
The platelet-derived growth factor receptor (PDGFR) family of receptor tyrosine kinases consists of two receptors, PDGFRα and PDGFRβ, that homodimerize and heterodimerize upon ligand binding. Here, we tested the hypothesis that differential internalization and trafficking dynamics of the various PDGFR dimers underlie differences in downstream intracellular signaling and cellular behavior. Using a bimolecular fluorescence complementation approach, we demonstrated that PDGFRα/β heterodimers are rapidly internalized into early endosomes. We showed that PDGFRα/β heterodimer activation does not induce downstream phosphorylation of ERK1/2 and significantly inhibits cell proliferation. Further, we identified MYO1D as a protein that preferentially binds PDGFRα/β heterodimers and demonstrated that knockdown of MYO1D leads to retention of PDGFRα/β heterodimers at the plasma membrane, increased phosphorylation of ERK1/2 and increased cell proliferation. Collectively, our findings impart valuable insight into the molecular mechanisms by which specificity is introduced downstream of PDGFR activation to differentially propagate signaling and generate distinct cellular responses.
Here they show that heterodimerization of the receptor tyrosine kinases PDGFRa and PDGFRb negatively affects downstream ERK1/2 signaling and cellular proliferation, due in part to rapid internalization mediated by binding to the unconventional myosin protein MYO1D.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 96
/ 96/1
/ 96/106
/ 96/31
/ 96/35
/ 96/63
/ 96/95
/ Animals
/ Binding
/ Extracellular signal-regulated kinase
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Mitogen-Activated Protein Kinase 1 - metabolism
/ Mitogen-Activated Protein Kinase 3 - metabolism
/ Myosin
/ Platelet-derived growth factor
/ Platelet-derived growth factor receptors
/ Proteins
/ Receptor, Platelet-Derived Growth Factor alpha - genetics
/ Receptor, Platelet-Derived Growth Factor alpha - metabolism
/ Receptor, Platelet-Derived Growth Factor beta - genetics
/ Receptor, Platelet-Derived Growth Factor beta - metabolism
/ Science
/ Tyrosine
