Platelet-derived growth factor receptor alpha

PDGFRA, i.e. platelet-derived growth factor receptor A, also termed PDGFRα, i.e. platelet-derived growth factor receptor α, is a receptor located on the surface of a wide range of cell types. This receptor binds to certain isoforms of platelet-derived growth factors (PDGFs) and thereby becomes active in stimulating cell signaling pathways that elicit responses such as cellular growth and differentiation. The receptor is critical for the development of certain tissues and organs during embryogenesis and for the maintenance of these tissues and organs, particularly hematologic tissues, throughout life. Mutations in the gene which codes for PDGFRA, i.e. the PDGFRA gene, are associated with an array of clinically significant neoplasms.

This gene encodes a typical receptor tyrosine kinase, which is a transmembrane protein consisting of an extracellular ligand binding domain, a transmembrane domain and an intracellular tyrosine kinase domain. The molecular mass of the mature, glycosylated PDGFRα protein is approximately 170 kDA. cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family.

Activation of PDGFRα requires de-repression of the receptor's kinase activity. The ligand for PDGFRα (PDGF) accomplishes this in the course of assembling a PDGFRα dimer. Four of the five PDGF isoforms activate PDGFRα (PDGF-A, PDGF-B, PDGF-AB and PDGF-C). The activated receptor phosphorylates itself and other proteins, and thereby engages intracellular signaling pathways that trigger cellular responses such as migration and proliferation. There are also PDGF-independent modes of de-repressing the PDGFRα's kinase activity and hence activating it. For instance, forcing PDGFRα into close proximity of each other by overexpression or with antibodies directed against the extracellular domain. Alternatively, mutations in the kinase domain that stabilize a kinase active conformation result in constitutive activation. Finally, growth factors outside of the PDGFR family (non-PDGFs) activate PDGFRα indirectly [1]. Non-PDGFs bind to their own receptors that trigger intracellular events that de-repress the kinase activity of PDGFRα monomers. The intracellular events by which non-PDGFs indirectly activate PDGFRα include elevation of reactive oxygen species that activate Src family kinases, which phosphorylate PDGFRα. The mode of activation determines the duration that PDGFRα remains active. The PDGF-mediated mode, which dimerized PDGFRα, accelerates internalization and degradation of activated PDGFRα such that the half-life of PDGF-activated PDGFRα is approximately 5 min [2, 3]. Enduring activation of PDGFRα (half-life greater than 120 min) occurs when PDGFRα monomers are activated [4].

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