PDGFR

PDGFR stands for platelet-derived growth factor receptor, a pair of transmembrane receptor tyrosine kinases consisting of PDGFR-α and PDGFR-β. They are activated by binding of PDGFs (PDGF-A, -B, -C, -D) and form homo- or heterodimers, which triggers trans-autophosphorylation and activation of downstream signaling.

The receptors have an extracellular ligand-binding domain with immunoglobulin-like loops, a single-pass transmembrane helix, and an intracellular tyrosine kinase domain. Ligand binding induces dimerization and kinase activation, creating docking sites for signaling proteins.

PDGF ligands form dimers; PDGF-AA binds PDGFR-α; PDGF-BB binds PDGFR-β; PDGF-CC binds PDGFR-α and PDGF-DD binds PDGFR-β. PDGF-AB can activate both receptors with varying affinity.

Activated PDGFRs stimulate signaling pathways including PI3K-Akt, Ras-MAPK, PLCγ, and STAT, promoting cell proliferation, survival, migration, and angiogenesis. In normal tissue, PDGFR signaling contributes to development, wound healing, and vascular stabilization, particularly through pericyte recruitment.

Pathologically, PDGFR signaling is implicated in cancers, gliomas, and fibrotic diseases. A hallmark in dermatofibrosarcoma protuberans is a COL1A1-PDGFRB fusion leading to constitutive PDGFRβ activation. Overexpression or autocrine/paracrine PDGF signaling also supports tumor stroma and fibrosis.

Therapeutically, PDGFR signaling is targeted by tyrosine kinase inhibitors such as imatinib, sunitinib, pazopanib, and sorafenib, which reduce receptor activity. Specific inhibitors and clinical trials are ongoing for DFSP, glioblastoma, and fibrotic diseases. Resistance can arise via receptor mutations or downstream pathway alterations.