Platelet-derived growth factor receptor alpha (PDGFRA) and related type III receptor tyrosine kinases (PDGFRA and type III RTKs)

Platelet-derived growth factor receptor alpha (PDGFRA) is a key member of the type III receptor tyrosine kinase (RTK) family, which also encompasses PDGFRB, KIT (CD117), FLT3, and CSF1R (UniProt P16234). These receptors are structurally defined by five extracellular immunoglobulin-like domains and an intracellular split tyrosine kinase domain interrupted by a kinase insert sequence (PMID: 20434948). They play pivotal roles in embryonic development and adult tissue maintenance by regulating cell proliferation, migration, and survival across various lineages. Dysregulation of these receptors, particularly through gain-of-function mutations, gene amplifications, or chromosomal translocations, is a primary driver in several malignancies, including gastrointestinal stromal tumors (GIST), acute myeloid leukemia (AML), and systemic mastocytosis (StatPearls: Gastrointestinal Stromal Tumors). Consequently, this family represents a major class of therapeutic targets for small-molecule tyrosine kinase inhibitors (TKIs) like imatinib and sunitinib. A significant clinical challenge remains the emergence of secondary resistance mutations, such as the PDGFRA D842V substitution, which has necessitated the development of specialized next-generation inhibitors like avapritinib (FDA: Ayvakit).

Other names

PDGFR-alphaCD140AKITCD117FLT3CD135CSF1RCD115PDGFRBCD140BType III RTK family

Small-molecule inhibition of the intracellular tyrosine kinase domain by competing with ATP for the binding pocket, thereby preventing autophosphorylation and the activation of downstream signaling cascades such as PI3K/AKT, MAPK/ERK, and STAT (PMID: 20434948, PMID: 19147405).