Chapter 60 - Signaling by the Platelet-Derived Growth Factor Receptor Family

Abstract

PDGF is a family of disulfide-bonded dimeric proteins, made up of A, B, C, or D chains. There are five dimeric combinations that include PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD. The two PDGF receptors have distinct functions. While the PDGF β-receptor is involved in pericyte recruitment to capillaries, development of smooth muscle cells in vessels, and development of mesangial cells in the kidney, the PDGF α-receptors are required for formation of alveolar smooth muscle cells, hair follicle development, proper villus formation in the gut, and oligodendrocyte development. In the adult organism, PDGF signaling contributes to wound healing through stimulation of fibroblasts, smooth muscle cells, and different inflammatory cells. PDGF β-receptors are also involved in regulation of the interstitial fluid pressure, and can thus control transport of fluids from the vessels to surrounding tissues. PDGFs mediate their biological function through binding to two types of PDGF receptors, which belong to the type III family of receptor tyrosine kinases (RTKs, also including the M-CSF receptor, c-Kit, and Flt3). They both share a similar layout, in that they possess an extracellular domain of five immunoglobulin-like (Ig-like) domains, a transmembrane domain, a juxtamembrane domain, a split kinase domain interrupted by a stretch of amino acids denoted the kinase insert, and a carboxyterminal tail. The four different PDGF chains show differences in binding specificity to the two PDGF receptors. PDGF-A and PDGF-C bind exclusively to PDGF α-receptors, while PDGF-B binds to both PDGF α-receptors and PDGF β-receptors. PDGF-D is a PDGF β-receptor agonist, but is able to induce PDGF α-β heterodimers.