全周 (9AM - 6PM)

我们和你在一起

Extra info thumb
PLATELET-DERIVED GROWTH FACTOR D; PDGFD

PLATELET-DERIVED GROWTH FACTOR D; PDGFD

Alternative titles; symbolsSPINAL CORD-DERIVED GROWTH FACTOR B; SCDGFBIRIS-EXPRESSED GROWTH FACTOR; IEGFHGNC Approved Gene Symbol: PDGFDCytogenetic location: 11q...

Alternative titles; symbols

  • SPINAL CORD-DERIVED GROWTH FACTOR B; SCDGFB
  • IRIS-EXPRESSED GROWTH FACTOR; IEGF

HGNC Approved Gene Symbol: PDGFD

Cytogenetic location: 11q22.3 Genomic coordinates (GRCh38): 11:103,907,188-104,164,146 (from NCBI)

▼ Description
Members of the PDGF family, such as PDGFD, are disulfide-bonded dimeric proteins involved in developmental and physiologic processes, as well as in cancer, fibrotic diseases, and arteriosclerosis (LaRochelle et al., 2001).

▼ Cloning and Expression
Bergsten et al. (2001), LaRochelle et al. (2001), and Hamada et al. (2001) independently cloned PDGFD. The deduced 370-amino acid protein contains an N-terminal hydrophobic signal sequence, followed by a CUB domain, a hinge region, and a C-terminal PDGF/VEGF (192240) homology domain. PDGFD has a site for signal peptidase cleavage between residues 22 and 23 and an N-glycosylation site in its core PDGF domain. It shares 43% amino acid identity with PDGFC (608452). Hamada et al. (2001) also isolated a PDGFD splice variant that encodes a protein lacking 6 amino acids just prior to the CUB domain.

Using Northern blot analysis, Bergsten et al. (2001) detected a 4.0-kb PDGFD transcript highly expressed in heart, pancreas, and ovary, with lower expression in placenta, liver, kidney, prostate, testis, small intestine, spleen, and colon. No expression was detected in brain, lung, and skeletal muscle. Bergsten et al. (2001) calculated that the mature secreted 348-amino acid PDGFD protein has a molecular mass of 40.3 kD. However, in vitro-translated PDGFD migrated by SDS-PAGE at an apparent molecular mass of 90 kD, suggesting PDGFD, like other PDGFs, forms a disulfide-linked homodimer. Immunohistochemical analysis of day-14.5 mouse embryos detected intense Pdgfd staining in developing heart, lung, and kidney, as well as in some muscle derivatives.

Using real-time quantitative PCR, LaRochelle et al. (2001) determined that PDGFD expression was high in adrenal gland and moderate in pancreas, adipose tissue, heart, stomach, bladder, trachea, mammary gland, ovary, and testis. PDGFD was secreted into the culture medium by transfected human embryonic kidney cells. Under nonreducing conditions, the dimeric protein had an apparent molecular mass of 84 kD. Under reducing conditions, the monomer had an apparent molecular mass of 35 kD.

Using immunohistochemical analysis, Changsirikulchai et al. (2002) examined expression of PDGFD in fetal and adult human kidney. In developing kidney, PDGFD was first expressed by epithelial cells of comma- and S-shaped structures of the developing nephron, and most consistently in the visceral epithelial cells in the later stages of glomerular differentiation. In normal adult kidney, PDGFD was expressed by visceral epithelial cells. There was persistent expression in arterial smooth muscle cells, as well as in some neointimal smooth muscle cells of arteriosclerotic vessels, and in smooth muscle cells of vasa rectae in the medulla. PDGFD was expressed at the basolateral membrane of some injured tubules in areas of chronic tubulointerstitial injury routinely encountered in aging kidneys. Western blot analysis detected PDGFD as a single protein of about 50 kD.

Ray et al. (2005) found that expression of PDGFD in mammalian eye was tissue specific. In the anterior segment, it was localized to iris and ciliary body, whereas in retina, it was restricted to the outer plexiform layer.

▼ Gene Function
Bergsten et al. (2001) found that PDGFD bound PDGFR-beta (PDGFRB; 173410) following activation by limited proteolysis. It did not interact with PDGFR-alpha (PDGFRA; 173490) or several VEGF receptors (see FLT1; 165070), and it did not bind PDGFRB prior to its proteolytic activation. Activated PDGFD stimulated tyrosine phosphorylation of PDGFRB in a dose-dependent manner in vitro and in human foreskin fibroblasts. PDGFRA was only marginally phosphorylated by PDGFD. Bergsten et al. (2001) concluded that PDGFD is a PDGFRB-specific agonist and that proteolytic processing, which releases the core domains of PDGFD dimers from the N-terminal CUB domains, is necessary to unmask the receptor-binding site within the core domain.

LaRochelle et al. (2001) found that recombinant PDGFD induced DNA synthesis and supported the growth of several mammalian cell lines that expressed only PDGFRB, but not those that expressed only PDGFRA. However, in cell expressing both PDGFRB and PDGFRA, PDGFD activated both receptors. In these cells, PDGFD induced formation of PDGFRA-PDGFRB heterodimers, resulting in tyrosine phosphorylation and activation of PDGFRA.

Hamada et al. (2001) demonstrated that both variants of human PDGFD were secreted into the medium of transfected Chinese hamster ovary cells. The culture supernatant containing either variant stimulated proliferation of mouse embryonic fibroblasts.

By overexpressing human PDGFD in skin and muscle of transgenic mice, Uutela et al. (2004) determined that PDGFD recruited macrophages and elevated interstitial fluid pressure. Wound healing in transgenic mice was characterized by increased cell density and enhanced recruitment of macrophages. Macrophage recruitment was also the characteristic response when PDGFD was expressed in skeletal muscle or ear. Combined expression of PDGFD with VEGFE led to increased pericyte/smooth muscle cell coating of VEGFE-induced vessels and inhibition of the vascular leakiness that accompanied VEGFE-induced angiogenesis.

Rabbit lens-derived cells secrete Pdgfd to their culture medium. Ray et al. (2005) found that this conditioned medium stimulated cell proliferation in rat lens explants and in mouse fibroblasts. In organ culture of rat eye anterior segments, antibodies directed against Pdgfd inhibited lens epithelial cell proliferation.

Lui et al. (2014) analyzed differential gene coexpression relationships between mouse and human and demonstrated that the growth factor PDGFD is specifically expressed by radial glia in human, but not mouse, corticogenesis. Lui et al. (2014) also showed that the expression domain of PDGFRB is evolutionarily divergent, with high expression in the germinal region of dorsal human neocortex but not in the mouse. Pharmacologic inhibition of PDGFD-PDGFRB signaling in slice culture prevents normal cell cycle progression of neocortical radial glia in human, but not mouse. Conversely, injection of recombinant PDGFD or ectopic expression of constitutively active PDGFRB in developing mouse neocortex increases the proportion of radial glia and their subventricular dispersion. The authors concluded that their findings highlighted the requirement of PDGFD-PDGFRB signaling for human neocortical development and suggested that local production of growth factors by radial glia supports the expanded germinal region and progenitor heterogeneity of species with large brains.

▼ Gene Structure
LaRochelle et al. (2001) determined that the PDGFD gene contains 7 exons.

▼ Mapping
By genomic sequence analysis and radiation hybrid analysis, LaRochelle et al. (2001) mapped the PDGFD gene to chromosome 11q22.3.

Tags: 11q22.3