|Figure 1. Receptor-ligand interactions of the PDGF family members. [Note: figure adapted from Li, X. & U. Eriksson (2003) Cytokine Growth Factor Rev. 14:91.]|
The four PDGF isoforms (A, B, C, and D) are characterized by a highly conserved eight-cysteine domain termed the PDGF/VEGF homology domain. The PDGF isoforms exist as disulfide-linked homo- and heterodimers and differentially bind homo- and heterodimer combinations of two receptor tyrosine kinases, PDGF Rα and PDGF Rß (Figure 1).
Widely expressed in fibroblasts, osteoblasts, platelets, macrophages, smooth muscle cells, endothelial cells, and Langerhans cells, PDGF-AA activity is ubiquitous, but dependent on cell expression of PDGF Rα. PDGF-AA plays key roles in protein synthesis, chemotaxis inhibition, embryonic neuron fiber development, and bronchial lung development.
PDGF-AB demonstrates mitogenic activity for vascular smooth muscle cells as well as stimulating angiogenesis in the heart. Parallel to PDGF-AA and PDGF-BB expression, PDGF-AB is important in a wide variety of cellular processes of the immune, nervous, and cardiovascular systems.
Mainly expressed in endothelial cells, PDGF-BB participates in angiogenesis and arterialization of early organ, respiratory, and neuronal development. PDGF-BB is also observed in platelets, neurons, macrophages, and fetal fibroblasts. PDGF-BB, via PDGF Rß, is involved in cellular proliferation and transforming growth factor-like activities.
PDGF-CC and -DD form a novel subgroup of the PDGF family distinguished by structural differences that include an N-terminal CUB domain. Widely expressed in multiple embryonic and adult cell, tissue, and organ types, PDGF-CC appears to be important for angiogenesis, cardiovasculature development, and tumorigenesis.
The fairly restricted expression pattern of PDGF-DD, compared to other family members, suggests a highly specific function yet to be elucidated. PDGF-DD is co-expressed at lower levels with other family members in the heart, lung, kidney, and musculature and it has been implicated in cardiovasculature development, tumorigenesis, and tissue regeneration.
PDGF Ra and PDGF Rß contain five immunoglobulin-like extracellular domains and an intracellular split tyrosine kinase domain. PDGF receptors are independently regulated in fibroblasts, osteoblasts, chondroblasts, smooth muscle, glia, and endothelium. The PDGF receptors function as homo- and/or heterodimers depending on the cell type. Upon receptor ligation, autophosphorylation initiates a variety of signal transduction cascades.