title: PDGF-D, a new protease-activated growth factor.
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.
authors.affiliation: CuraGen Corporation, 555 Long Wharf Drive, New Haven, Connecticut 06511, USA. wlaroche@curagen.com
authors.forename: W J
authors.initials: WJ
authors.lastname: LaRochelle
authors.forename: M
authors.initials: M
authors.lastname: Jeffers
authors.forename: W F
authors.initials: WF
authors.lastname: McDonald
authors.forename: R A
authors.initials: RA
authors.lastname: Chillakuru
authors.forename: N A
authors.initials: NA
authors.lastname: Giese
authors.forename: N A
authors.initials: NA
authors.lastname: Lokker
authors.forename: C
authors.initials: C
authors.lastname: Sullivan
authors.forename: F L
authors.initials: FL
authors.lastname: Boldog
authors.forename: M
authors.initials: M
authors.lastname: Yang
authors.forename: C
authors.initials: C
authors.lastname: Vernet
authors.forename: C E
authors.initials: CE
authors.lastname: Burgess
authors.forename: E
authors.initials: E
authors.lastname: Fernandes
authors.forename: L L
authors.initials: LL
authors.lastname: Deegler
authors.forename: B
authors.initials: B
authors.lastname: Rittman
authors.forename: J
authors.initials: J
authors.lastname: Shimkets
authors.forename: R A
authors.initials: RA
authors.lastname: Shimkets
authors.forename: J M
authors.initials: JM
authors.lastname: Rothberg
authors.forename: H S
authors.initials: HS
authors.lastname: Lichenstein
mesh_terms: D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001667:Binding, Competitive; D001973:Bromodeoxyuridine / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008222:Lymphokines; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000737:chemistry* / Q000502:physiology*; D016133:Polymerase Chain Reaction; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; D008222:Lymphokines; C427493:PDGFD protein, human; C498951:Pdgfd protein, mouse; D010982:Platelet-Derived Growth Factor; D011994:Recombinant Proteins; D014443:Tyrosine; D017479:Receptors, Platelet-Derived Growth Factor; D001973:Bromodeoxyuridine