PDGF Ra (platelet-derived growth factor receptor alpha) is a type I transmembrane glycoprotein in the class III subfamily of receptor tyrosine kinases (RTK) (1-4). PDGF Ra and PDGF Rb can form homo- or hetero-dimeric receptors when engaged by dimers of the PDGF family of growth factors, which include disulfide-linked homodimers of PDGF-A, B, C or D, or the heterodimer PDGF-AB that is mainly found in human platelets. While multiple in vitro ligand-receptor combinations have been identified, in vivo evidence indicates that PDGF Ra primarily binds PDGF-AA and PDGF-CC, while PDGF Rb primarily binds PDGF-BB and probably PDGF-DD. Like all class III RTKs, the extracellular domain (ECD) of human PDGF Ra (aa24-524) contains five immunoglobulin-like domains, while the intracellular region contains a split tyrosine kinase domain (aa593-954) (1-4). Within the ECD, human PDGF Ra shares 85%, 83%, 95%, 93%, and 88% aa sequence identity with mouse, rat, equine, canine and bovine PDGF Ra respectively. PDGF Ra autophosphorylates upon dimerization, activating signaling cascades in PI 3-kinase Ras-MAP kinase, and PLC-g pathways (1, 2). Signaling is down-regulated by SHP-2 phosphatase activity and by receptor endocytosis and lysosomal degradation. PDGF Ra is expressed at low levels in most mesenchymal cells, but is strongly expressed in oligodendrocyte, lung, skin and intestinal progenitor cells and induced by inflammation or growth in culture (1-4). During development, mesenchymal cells expressing PDGF Ra respond to local gradients of epithelially produced PDGF-AA or PDGF-CC during formation of the cranial and cardiac neural crest, retina, gonads, lung alveoli, intestinal villi, skin, hair follicles, skeleton, teeth, palate, and interstitial kidney mesenchyme (1, 5). Deletion of PDGF Ra in mice severely impairs mesenchymal derivatives in both embryo and extraembryonic tissues, and high or low PDGF Ra signaling in humans may result in spina bifida or cleft palate-type malformations. Postnatally, PDGF Ra is implicated in gliomas and fibrotic disorders of lung, heart and skin (scleroderma) (6-8).
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