PDGFRalpha

PDGF receptor alpha (PDGFR-α) is a receptor tyrosine kinase encoded by the PDGFRA gene. It is expressed in various mesenchymal cell types and mediates cellular responses to platelet-derived growth factor (PDGF) ligands. PDGFR-α signaling regulates processes such as cell proliferation, survival, migration, and differentiation, and it participates in development, wound healing, and angiogenesis.

The receptor has an extracellular segment with five immunoglobulin-like domains, a single transmembrane region, and an intracellular tyrosine kinase domain. Ligand binding induces receptor dimerization (homodimer or with PDGFR-β) and autophosphorylation on tyrosine residues, creating docking sites for SH2-domain proteins. This activates downstream signaling pathways, including PI3K-Akt, Ras-MAPK, and PLCγ, leading to diverse cellular outcomes.

Ligands for PDGFR-α include PDGF-A and PDGF-B homodimers and heterodimers; PDGF-C and PDGF-D can also activate PDGFR-α in certain contexts after proteolytic processing. The receptor plays a critical role in development and tissue repair, influencing the formation of the vasculature and the maturation of neural and mesenchymal tissues.

Clinical significance and therapeutics: Somatic mutations in PDGFRA, particularly in gastrointestinal stromal tumors (GIST), can cause constitutive receptor activation. Some mutations confer sensitivity or resistance to tyrosine kinase inhibitors. PDGFRA amplification or overexpression has been observed in various cancers.

Targeted treatments include inhibitors such as imatinib and sunitinib, used in PDGFRA-mutant GISTs, and avapritinib for specific PDGFRA mutations, including D842V. Resistance and adverse effects can occur, and ongoing research seeks more selective and durable therapies. The PDGFRA gene is located on chromosome 4q12.