ABSTRACT
Platelet-derived growth factor (PDGF) has been directly implicated in developmental and physiological processes, as well as in human cancer, fibrotic diseases and arteriosclerosis. The PDGF family currently consists of at least three gene products, PDGF-A, PDGF-B and PDGF-C, which selectively signal through two PDGF receptors (PDGFRs) to regulate diverse cellular functions. After two decades of searching, PDGF-A and B were the only ligands identified for PDGFRs. Recently, however, database mining has resulted in the discovery of a third member of the PDGF family, PDGF-C, a functional analogue of PDGF-A that requires proteolytic activation. PDGF-A and PDGF-C selectively activate PDGFR-alpha, whereas PDGF-B activates both PDGFR-alpha and PDGFR-beta. Here we identify and characterize a new member of the PDGF family, PDGF D, which also requires proteolytic activation. Recombinant, purified PDGF-D induces DNA synthesis and growth in cells expressing PDGFRs. In cells expressing individual PDGFRs, PDGF-D binds to and activates PDGFR-beta but not PDGFR-alpha. However, in cells expressing both PDGFRs, PDGF-D activates both receptors. This indicates that PDGFR-alpha activation may result from PDGFR-alpha/beta heterodimerization.
Subject(s)
Lymphokines , Platelet-Derived Growth Factor/chemistry , Platelet-Derived Growth Factor/physiology , 3T3 Cells , Amino Acid Sequence , Animals , Base Sequence , Binding, Competitive , Bromodeoxyuridine/metabolism , DNA, Complementary/metabolism , Dimerization , Dose-Response Relationship, Drug , Enzyme Activation , Enzyme-Linked Immunosorbent Assay , Fibroblasts/metabolism , Humans , Mice , Molecular Sequence Data , Phosphorylation , Polymerase Chain Reaction , Receptors, Platelet-Derived Growth Factor/metabolism , Recombinant Proteins/metabolism , Sequence Homology, Amino Acid , Signal Transduction , Tissue Distribution , Tumor Cells, Cultured , Tyrosine/metabolismABSTRACT
The fibroblast growth factor (FGF) family of signaling molecules has been implicated in normal developmental and physiological processes, as well as in human malignancy. Using a homology-based genomic DNA mining process, we identified a human gene encoding a novel member of the FGF family, that we designate FGF-20. The FGF-20 cDNA was isolated, and its sequence confirmed the gene prediction. FGF-20 is expressed in normal brain, particularly the cerebellum, and in some cancer cell lines. Recombinant FGF-20 protein induces DNA synthesis in a variety of cell types and is recognized by multiple FGF receptors. Ectopic expression of FGF-20 in NIH 3T3 cells renders the cells transformed in vitro and tumorigenic in nude mice. These results underscore the utility of mining genomic DNA databases and reveal FGF-20 to be a novel oncogene that may play a role in human cancer.
