Disease relevance of Pdgfa

• Pdgfc(-/-) Pdgfa(-/-) embryos developed a cleft face, subepidermal blistering, deficiency of renal cortex mesenchyme, spina bifida and skeletal and vascular defects [1].
• Dominant-negative mutations of PDGF and other growth factors which, like PDGF, function as dimers may prove useful for creating animals models of growth factor deficiency disease states and for revealing the function of growth factors during early embryonic development [2].
• Because of its expression pattern and its potent effects on mesenchymal cells, platelet-derived growth factor (PDGF) has been implicated as an important factor in epithelial-mesenchymal cell interactions during normal lung development and in the pathogenesis of fibrotic lung disease [3].
• These were used, together with a mouse PDGF receptor beta subunit cDNA clone, to monitor gene expression in early postimplantation mouse embryos and in F9 embryonal carcinoma cells [4].
• In this study, the expression of interleukin (IL)-1 alpha and beta, platelet-derived growth factor (PDGF) A and B, and insulin-like growth factor (IGF) I in BAL cells, which may be involved in fibroblast proliferation, was investigated in murine bleomycin (BLM)-induced pulmonary fibrosis [5].

High impact information on Pdgfa

• Mutations in these genes lead to a high frequency of phenotypes that affect the same cell types and processes as those controlled by the PDGF pathway [6].
• PDGF signaling specificity is mediated through multiple immediate early genes [6].
• Identification and validation of PDGF transcriptional targets by microarray-coupled gene-trap mutagenesis [7].
• However, targetted inactivation of the Pdgfb gene or the Pdgf receptor beta (Pdgfrb) gene, by homologous recombination, does not prevent the development of apparently normal large arteries and connective tissue [8].
• The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase [9].

Chemical compound and disease context of Pdgfa

• To test this hypothesis, we used the small molecule inhibitors SU5416 (an inhibitor for Vegf receptor) and SU6668 (an inhibitor for Vegf, Fgf and Pdgf receptors) alone and in combination with fractionated irradiation to treat C3H mice bearing SCC VII carcinomas [10].
• These data suggest that PDGF plays a role in the progression of nephritis and that the beneficial effect of MPSL correlates with its ability to decrease the abnormally high PDGF mRNA levels seen in lupus nephritis [11].
• Western blot analysis of cytoplasmic extracts from Rauscher murine erythroleukemia cells and phenylhydrazine-treated mouse splenic erythroid cells revealed the presence of several PDGF-like proteins [12].
• Fibroblasts transformed with simian sarcoma virus constitutively produce a growth factor that stimulates the endogenous tyrosine kinase of PDGF receptors in an autocrine manner [13].
• These results expand the profile of STI571 and suggest that in addition to chronic myelogenous leukemia, STI571 may have clinical potential in the treatment of diseases that involve abnormal activation of c-Kit or PDGF receptor tyrosine kinases [14].

Biological context of Pdgfa

• Based on the established role of the platelet-derived growth factor (PDGF) family of ligands and receptors in migration, proliferation, and differentiation of cells in various organ systems, we have investigated the role of PDGF in testis organogenesis [15].
• Several lines of evidence now exist to suggest an interaction between the platelet-derived growth factor (PDGF) growth-stimulatory signal transduction pathway and the beta interferon (IFN-beta) growth-inhibitory signal transduction pathway [16].
• It appears that PDGF modulates a program of gene expression with the accumulation of some transcripts, typified by MEP, being dependent upon the translation of others [17].
• Moreover, compared to wild-type cells, cellular proliferation stimulated by serum or platelet-derived growth factor (PDGF) was enhanced and accelerated in STAT1(-/-) HSCs, which was partially mediated via elevated PDGF receptor beta expression on such cells [18].
• Down-regulation of PKC by prolonged treatment with 4 beta-phorbol 12-myristate 13-acetate also abolished EGF- and PDGF-stimulated phosphatidylbutanol formation [19].

Anatomical context of Pdgfa

• Platelet-derived growth factor (PDGF) stimulates density-arrested BALB/c-3T3 cells to synthesize MEP, a lysosomal protein [17].
• To investigate the significance of these observations, we have examined the role of PDGF signaling in the developing somite [20].
• Platelet-derived growth factor (PDGF) B and A homodimers transform murine fibroblasts depending on the genetic background of the cell [21].
• We now have established conditions in which subconfluent, logarithmically growing NIH 3T3 cells are efficiently transformed by exogenous PDGF B but not PDGF A [21].
• The Cdc42(-/-) cells were defective in filopodia formation stimulated by bradykinin and in dorsal membrane ruffling stimulated by PDGF, whereas the Cdc42GAP(-/-) cells displayed spontaneous filopodia [22].

Associations of Pdgfa with chemical compounds

• The block to signaling was not due to a defect in inositol phosphate metabolism, as PDGF treatment induced normal calcium mobilization and phosphotidylinositol-3-kinase activation in these cells [16].
• Autophosphorylation of the platelet-derived growth factor (PDGF) receptor on tyrosine, which is dependent upon and occurs immediately after ligand binding, has been linked to the activation of second messenger pathways thought to be necessary for the induction of gene expression, DNA synthesis, and mitogenesis [23].
• Platelet-derived growth factor (PDGF) receptor-alpha activates c-Jun NH2-terminal kinase-1 and antagonizes PDGF receptor-beta -induced phenotypic transformation [24].
• Insulin potentiated the effects of IGF-1, EGF, and PDGF on DNA synthesis in cells expressing the wild type insulin receptor, but this potentiation was inhibited in the presence of the FTase inhibitor, alpha-hydroxyfarnesylphosphonic acid [25].
• The effects of PDGF, EGF, and bFGF were completely abolished by pretreatment with actinomycin D, an inhibitor of RNA synthesis, suggesting a transcriptional mechanism [26].

Physical interactions of Pdgfa

• The exposure of density-arrested Balb/c 3T3 cells to BCP crystals had no effect on high affinity epidermal growth factor receptor binding under conditions in which PDGF and TPA reduced epidermal growth factor binding [27].
• Autophosphorylation of PDGF receptors upon ligand stimulation provides binding sites for Src homology 2 domains of intracellular signaling molecules, which thereby become activated [13].
• An electrophoretic mobility shift assay demonstrated that Egr-1 bound to the proximal promoter of the Mn-SOD gene in response to PDGF [28].
• Preincubation of cells with cycloheximide did not affect EGF binding or the ability of PDGF to stimulate inositol phosphate formation [29].
• The loss of PDGF-binding sites caused by TGF-beta is time- and concentration-dependent and reflects a change in the pattern of expression of receptor subunits; the number of alpha-subunits decreases, and the number of beta-subunits increases [30].

Enzymatic interactions of Pdgfa

• The EGF receptor is phosphorylated at tyrosine residues although we have not yet established if this represents direct phosphorylation by the PDGF receptor kinase or is mediated by activation of other cell membrane-associated tyrosine kinases [31].

Regulatory relationships of Pdgfa

• PDGF-C is a new protease-activated ligand for the PDGF alpha-receptor [32].
• PDGF-A chain homodimer PDGF AA activates alpha-PDGFR only, and its role for cell migration is still debatable [33].
• In addition, Src family kinases activate STAT signaling and are required for PDGF-induced mitogenesis in normal cells [34].
• In normal NIH 3T3 cells, disruption of Stat3 signaling with dominant-negative Stat3beta protein inhibits PDGF-induced mitogenesis in a manner that is reversed by ectopic c-Myc expression [34].
• The recruitment of the polyamine-depleted, serum-deprived cells into the cell division cycle does not require PDGF and can be induced by addition of EGF and insulin plus putrescine [35].

Other interactions of Pdgfa

• Neither PDGF A nor PDGF B transform normal rat kidney (NRK) cells under identical conditions of culture [21].
• Fibroblast growth factor-2 (FGF-2) and platelet-derived growth factor AB (PDGF AB) promote adult SVZ-derived oligodendrogenesis in vivo [36].
• Postnatally, PDGF A- and B-ligand and PDGFR alpha- and beta-subunit were confined in the epithelium [37].
• Radiation induces the production of VEGF, FGF and PDGF in many tumor cells [10].
• Further, TGF beta delays EGF or PDGF-induced 5-phase entry in C3H 10T1/2 mouse fibroblasts [38].

Analytical, diagnostic and therapeutic context of Pdgfa

• This block to signal transduction was not due to loss or inactivation of PDGF receptors, as immunoprecipitation of PDGF receptors with antiphosphotyrosine antibodies showed them to be present at equal levels in the BALB/c-3T3 and IRB cells and to be autophosphorylated normally in response to PDGF [16].
• To further understand their implications for ovarian tumorigenesis, we studied FORKO ovaries and hormonal regulation of the PDGF family members in normal mice, by using RT-PCR, Q-PCR, immunohistochemistry and western blotting [39].
• Cellular localization of the PDGF ligand and receptor protein molecules by immunohistochemistry detected significant immunostaining for all of these proteins in both the uterus and vagina of control animals [40].
• Analysis of cell-specific RNA expression by in situ hybridization reveals prominent induction of transcripts for the PDGF chains and receptor subunits in the uterine and vaginal epithelium after estrogen treatment, although enhanced expression of mRNA is also noted in the stroma, particularly for the PDGF receptor subunit genes [40].
• The identity of PDGF and PDGFR proteins were further confirmed by immunoblotting [37].

References