Platelet-derived growth factors (PDGFs) constitute a group of growth factors that play a significant role in blood vessel formation (angiogenesis), and the growth of blood vessels from already existing blood vessel tissue.
There are five different isoforms of PDGF, including PDGF-A, PDGF-B, PDGF-C, PDGF-D and an AB heterodimer PDGF-AB. Platelet-derived growth factor acts through a cell surface receptor, PDGFR, which is a receptor tyrosine kinase. Two types of PDGFRs have been identified: alpha type (PDGFRA) and beta type (PDGFRB) PDGFRs. The alpha type binds to PDGF-AA, PDGF-BB and PDGF-AB while the beta type PDGFR binds with high affinity to PDGF-BB and PDGF-AB. Upon activation by PDGF, PDGFR dimerise and activate signaling pathway involving gene expression, cell cycle and many other processes.
PDGF receptor alpha, also known as PDGFRA and CD140a, is a tyrosine-protein kinase that acts as a cell-surface receptor for PDGFA, PDGFB and PDGFC. PDGFRA plays an essential role in the regulation of embryonic development, cell proliferation, survival and chemotaxis. It promotes or inhibits cell proliferation and cell migration according to the context. CD140a plays an important role in the differentiation of bone marrow-derived mesenchymal stem cells. PDGF receptor alpha is also required for normal skeleton development and cephalic closure during embryonic development. PDGFRA plays a role in normal development of the mucosa lining the gastrointestinal tract, and for recruitment of mesenchymal cells and normal development of intestinal villi. Binding of its cognate ligands - homodimeric PDGFA, homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFC -leads to the activation of several signaling cascades; the response depends on the nature of the bound ligand and is modulated by the formation of heterodimers between PDGF receptor alpha and PDGF receptor beta. Meanwhile, PDGF receptor alpha phosphorylates PIK3R1, PLCG1, and PTPN11.
PDGFRA can phosphorylate PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, and thereby mediates activation of the AKT1 signaling pathway. Meanwhile, it also mediates activation of HRAS and of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1.
PDGFRA is involved in hypereosinophilic syndrome since a chromosomal aberration involving PDGFRA is found in some cases of this syndrome. Mutations that cause overexpression and/or constitutive activation of PDGFRA may be a cause of hypereosinophilic syndrome. Mutations causing PDGFRA constitutive activation also have been found in gastrointestinal stromal tumors lacking KIT mutations.
PDGF receptor beta, also known as PDGFRB and CD140b, is a tyrosine-protein kinase that acts as cell-surface receptor for homodimeric PDGFB and PDGFD and for heterodimers formed by PDGFA and PDGFB. PDGFRB plays an essential role in the regulation of embryonic development, cell proliferation, survival, differentiation, chemotaxis and migration. PDGFRB also is essential for blood vessel development. It is required for normal development of the cardiovascular system, for normal recruitment of pericytes (mesangial cells) in the kidney glomerulus, and for normal formation of a branched network of capillaries in kidney glomeruli. PDGF receptor beta promotes rearrangement of the actin cytoskeleton and the formation of membrane ruffles. It is required for normal recruitment of pericytes (mesangial cells) in the kidney glomerulus, and for normal formation of a branched network of capillaries in kidney glomeruli.
Fig 2. Ribbon image of two molecules of human PDGF receptor beta (yellow and magenta) in complex with dimeric PDGF-B (cyan and green).