PDGFRalpha/beta heterodimer activation negatively affects downstream ERK1/2 signaling and cellular proliferation

ABSTRACT: The platelet-derived growth factor receptor (PDGFR) family of receptor tyrosine kinases consists of two receptors, PDGFRalpha and PDGFRbeta, 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 PDGFRalpha/beta heterodimers are rapidly internalized into early endosomes. We showed that PDGFRalpha/beta 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 PDGFRalpha/beta heterodimers and demonstrated that knockdown of MYO1D leads to retention of PDGFRalpha/beta 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.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung, Cell Culture

DISEASE(S): Lung Squamous Cell Carcinoma

SUBMITTER: Katherine Fantauzzo  

LAB HEAD: Katherine Fantauzzo

PROVIDER: PXD048421 | Pride | 2025-04-25

REPOSITORIES: Pride