scholarly journals Down-regulation of cellular platelet-derived growth factor receptors induced by an activated neu receptor tyrosine kinase.

1991 ◽  
Vol 2 (8) ◽  
pp. 651-661 ◽  
Author(s):  
L Lehtola ◽  
M Nistér ◽  
E Hölttä ◽  
B Westermark ◽  
K Alitalo
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Receptor Expression ◽  
Platelet Derived Growth Factor ◽  
Target Cells ◽  
Mrna Levels ◽  
Pdgf Receptor ◽  
Down Regulation ◽  
Beta Receptors ◽  
Neu Oncogene

The functional integration of growth factor signaling occurs at several levels in target cells. One of the most proximal mechanisms is receptor transmodulation, by which one activated receptor can regulate the expression of other receptors in the same cells. Well-established transregulatory loops involve platelet-derived growth factor (PDGF) down-regulation of epidermal growth factor (EGF) receptors and beta-type transforming growth factors modulation of PDGF receptors. We have studied the relationship between neu tyrosine kinase activation and the expression of the PDGF receptors in transfected NIH/3T3 cells. Expression of the neu oncogene, but not of the neu proto-oncogene, was associated with a decrease of PDGF alpha- and beta-receptors on the cell surface, as measured by [125-I]PDGF-AA and -BB binding. These results were corroborated by metabolic labeling and immunoprecipitation of the PDGF beta-receptors. PDGF alpha- and beta-receptor mRNAs were strongly decreased in the neu oncogene-transformed cells in comparison with control cells expressing the neu proto-oncogene. Down-regulation of the PDGF receptors and their mRNAs was also observed after EGF treatment of cells expressing a chimeric EGF receptor/neu receptor, where the neu tyrosine kinase is activated by EGF binding. These results show that the neu tyrosine kinase can down-modulate PDGF receptor expression, and the effect is mediated via decreased PDGF receptor mRNA levels.

scholarly journals Insulin Inhibits Platelet-derived Growth Factor-induced Cell Proliferation

2005 ◽  
Vol 16 (1) ◽  
pp. 73-83 ◽  
Author(s):  
P. Cirri ◽  
M. L. Taddei ◽  
P. Chiarugi ◽  
F. Buricchi ◽  
A. Caselli ◽  
...  
Keyword(s):  
Growth Factor ◽  
Temporal Integration ◽  
C2c12 Cell ◽  
Protein Tyrosine Phosphatases ◽  
C2c12 Cells ◽  
Platelet Derived Growth Factor ◽  
Pdgf Receptor ◽  
Down Regulation ◽  
Receptor Phosphorylation ◽  
Nih 3T3

Cellular behavior can be considered to be the result of a very complex spatial and temporal integration of intracellular and extracellular signals. These signals arise from serum-soluble factors as well as from cell–substrate or cell–cell interactions. The current approach in mitogenesis studies is generally to analyze the effect of a single growth factor on serum-starved cells. In this context, a metabolic hormone such as insulin is found to be a mitogenic agent in many cellular types. In the present study, we have considered the effect of insulin stimulation in platelet-derived growth factor (PDGF)-activated NIH-3T3 and C2C12 cells. Our results show that insulin is able to inhibit strongly both NIH-3T3 and C2C12 cell growth induced by PDGF, one of the most powerful mitotic agents for these cell types. This inhibitory effect of insulin is due primarily to a premature down-regulation of the PDGF receptor. Thus, when NIH-3T3 or C2C12 cells are stimulated with both PDGF and insulin, we observe a decrease in PDGF receptor phosphorylation with respect to cells treated with PDGF alone. In particular, we find that costimulation with insulin leads to a reduced production of H2O2 with respect to cell stimulation with PDGF alone. The relative low concentration of H2O2 in PDGF/insulin-costimulated cell leads to a limited down-regulation of protein tyrosine phosphatases, and, consequently, to a reduced PDGF receptor phosphorylation efficiency. The latter is very likely to be responsible for the insulin-dependent inhibition of PDGF-receptor mitogenic signaling.

scholarly journals Role of tyrosine kinase and membrane-spanning domains in signal transduction by the platelet-derived growth factor receptor.

1988 ◽  
Vol 8 (12) ◽  
pp. 5126-5131 ◽  
Author(s):  
J A Escobedo ◽  
P J Barr ◽  
L T Williams
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Kinase Activity ◽  
Growth Factor Receptor ◽  
Platelet Derived Growth Factor ◽  
Tyrosine Kinase Activity ◽  
Down Regulation ◽  
Atp Binding Site ◽  
Membrane Spanning ◽  
Membrane Spanning Domains

Three types of mutations were introduced into the platelet-derived growth factor (PDGF) receptor to cause a loss of PDGF-stimulated tyrosine kinase activity: (i) a point mutation of the ATP-binding site, (ii) a deletion of the carboxyl-terminal region, and (iii) replacement of the membrane-spanning sequences by analogous transmembrane sequences of other receptors. Transfectants expressing mutated receptors bind, 125I-labeled PDGF with a high affinity but had no PDGF-sensitive tyrosine kinase activity, phosphatidylinositol turnover, increase in the intracellular calcium concentration, change in cellular pH, or stimulation of DNA synthesis. However, PDGF-induced receptor down regulation was normal in the mutant cells. These results indicate that the transmembrane sequence has a specific signal-transducing function other than merely serving as a membrane anchor and that the receptor kinase activity is necessary for most responses to PDGF but is not required for receptor down regulation.

scholarly journals Repression of platelet-derived growth factor beta-receptor expression by mitogenic growth factors and transforming oncogenes in murine 3T3 fibroblasts.

1995 ◽  
Vol 15 (3) ◽  
pp. 1244-1253 ◽  
Author(s):  
C Vaziri ◽  
D V Faller
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Cell Surface ◽  
Growth Arrest ◽  
Serum Deprivation ◽  
Receptor Expression ◽  
Platelet Derived Growth Factor ◽  
Mrna Levels ◽  
Beta Receptor ◽  
3T3 Fibroblasts

Platelet-derived growth factor BB (PDGF-BB) is an important extracellular factor for regulating the G0-S phase transition of murine BALB/c-3T3 fibroblasts. We have investigated the expression of the PDGF beta receptor (PDGF beta R) in these cells. We show that the state of growth arrest in G0, resulting from serum deprivation, is associated with increased expression of the PDGF beta R. When the growth-arrested fibroblasts are stimulated to reenter the cell cycle by the mitogenic action of serum or certain specific combinations of growth factors, PDGF beta R mRNA levels and cell surface PDGF-BB-binding sites are markedly downregualted. Oncogene-transformed 3T3 cell lines, which fail to undergo growth arrest following prolonged serum deprivation, express constitutively low levels of the PDGF beta R mRNA and possess greatly reduced numbers of cell surface PDGF receptors, as determined by PDGF-BB binding and Western blotting (immunoblotting). Nuclear runoff assays indicate the mechanism of repression of PDGF beta R expression to be, at least in large part, transcriptional. These data indicate that expression of the PDGF beta R is regulated in a growth state-dependent manner in fibroblasts and suggest that this may provide a means by which cells can modulate their responsiveness to the actions of PDGF.

scholarly journals Tyrosine Kinase Receptor Expression in Canine Liposarcoma

2016 ◽  
Vol 54 (2) ◽  
pp. 212-217 ◽  
Author(s):  
G. Avallone ◽  
V. Pellegrino ◽  
P. Roccabianca ◽  
E. Lepri ◽  
L. Crippa ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Fibroblast Growth Factor ◽  
Growth Factor Receptor ◽  
Mitotic Count ◽  
Receptor Expression ◽  
Platelet Derived Growth Factor ◽  
Proliferation Index ◽  
Tyrosine Kinase Receptor ◽  
Fibroblast Growth

The expression of tyrosine kinase receptors is attracting major interest in human and veterinary oncological pathology because of their role as targets for adjuvant therapies. Little is known about tyrosine kinase receptor (TKR) expression in canine liposarcoma (LP), a soft tissue sarcoma. The aim of this study was to evaluate the immunohistochemical expression of the TKRs fibroblast growth factor receptor 1 (FGFR1) and platelet-derived growth factor receptor–β (PDGFRβ); their ligands, fibroblast growth factor 2 (FGF2) and platelet-derived growth factor B (PDGFB); and c-kit in canine LP. Immunohistochemical labeling was categorized as high or low expression and compared with the mitotic count and MIB-1–based proliferation index. Fifty canine LPs were examined, classified, and graded. Fourteen cases were classified as well differentiated, 7 as myxoid, 25 as pleomorphic, and 4 as dedifferentiated. Seventeen cases were grade 1, 26 were grade 2, and 7 were grade 3. A high expression of FGF2, FGFR1, PDGFB, and PDGFRβ was identified in 62% (31/50), 68% (34/50), 81.6% (40/49), and 70.8% (34/48) of the cases, respectively. c-kit was expressed in 12.5% (6/48) of the cases. Mitotic count negatively correlated with FGF2 ( R = –0.41; P < .01), being lower in cases with high FGF2 expression, and positively correlated with PDGFRβ ( R = 0.33; P < .01), being higher in cases with high PDGFRβ expression. No other statistically significant correlations were identified. These results suggest that the PDGFRβ-mediated pathway may have a role in the progression of canine LP and may thus represent a promising target for adjuvant cancer therapies.

scholarly journals Src tyrosine kinase mediates platelet-derived growth factor BB-induced and redox-dependent migration in metanephric mesenchymal cells

2014 ◽  
Vol 306 (1) ◽  
pp. F85-F97 ◽  
Author(s):  
Brent Wagner ◽  
Yves Gorin
Keyword(s):  
Cell Migration ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Wound Closure ◽  
Platelet Derived Growth Factor ◽  
Ros Generation ◽  
Pdgf Receptor ◽  
Src Tyrosine Kinase ◽  
Akt Phosphorylation ◽  
And Migration

The adult kidney is derived from the interaction between the metanephric blastema and the ureteric bud. Platelet-derived growth factor (PDGF) receptor β is essential for the development of the mature glomerular tuft, as mice deficient for this receptor lack mesangial cells. This study investigated the role of Src tyrosine kinase in PDGF-mediated reactive oxygen species (ROS) generation and migration of metanephric mesenchymal cells (MMCs). Cultured embryonic MMCs from wild-type and PDGF receptor-deficient embryos were established. Migration was determined via wound-healing assay. Unlike PDGF AA, PDGF BB-induced greater migration in MMCs with respect to control. This was abrogated by neutralizing an antibody to PDGF BB. Phosphatidylinositol 3-kinase (PI3K) inhibitors suppressed PDGF BB-induced migration. Conversely, mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) inhibitors had no effect. Src inhibitors inhibited PDGF-induced cell migration, PI3K activity, and Akt phosphorylation. Adenoviral dominant negative Src (AD DN Src) abrogated PDGF BB-induced Akt phosphorylation. Hydrogen peroxide stimulated cell migration. PDGF BB-induced wound closure was inhibited by the antioxidants N-acetyl-l-cysteine, tiron, and the flavoprotein inhibitor diphenyleneiodonium. These cells express the NADPH oxidase homolog Nox4. Inhibiting Nox4 with antisense oligonucleotides or small interfering RNA (siRNA) suppressed PDGF-induced wound closure. Inhibition of Src with siRNA reduced PDGF BB-induced ROS generation as assessed by 2′,7′-dichlorodihydrofluorescein diacetate fluorescence. Furthermore, PDGF BB-stimulated ROS generation and migration were similarly suppressed by Ad DN Src. In MMCs, PDGF BB-induced migration is mediated by PI3K and Src in a redox-dependent manner involving Nox4. Src may be upstream to PI3K and Nox4.

Role of tyrosine kinase and membrane-spanning domains in signal transduction by the platelet-derived growth factor receptor

1988 ◽  
Vol 8 (12) ◽  
pp. 5126-5131
Author(s):  
J A Escobedo ◽  
P J Barr ◽  
L T Williams
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Kinase Activity ◽  
Growth Factor Receptor ◽  
Platelet Derived Growth Factor ◽  
Tyrosine Kinase Activity ◽  
Down Regulation ◽  
Atp Binding Site ◽  
Membrane Spanning ◽  
Membrane Spanning Domains

Three types of mutations were introduced into the platelet-derived growth factor (PDGF) receptor to cause a loss of PDGF-stimulated tyrosine kinase activity: (i) a point mutation of the ATP-binding site, (ii) a deletion of the carboxyl-terminal region, and (iii) replacement of the membrane-spanning sequences by analogous transmembrane sequences of other receptors. Transfectants expressing mutated receptors bind, 125I-labeled PDGF with a high affinity but had no PDGF-sensitive tyrosine kinase activity, phosphatidylinositol turnover, increase in the intracellular calcium concentration, change in cellular pH, or stimulation of DNA synthesis. However, PDGF-induced receptor down regulation was normal in the mutant cells. These results indicate that the transmembrane sequence has a specific signal-transducing function other than merely serving as a membrane anchor and that the receptor kinase activity is necessary for most responses to PDGF but is not required for receptor down regulation.

scholarly journals Induction of platelet-derived growth factor receptor expression in smooth muscle cells and fibroblasts upon tissue culturing.

1988 ◽  
Vol 107 (5) ◽  
pp. 1947-1957 ◽  
Author(s):  
L Terracio ◽  
L Rönnstrand ◽  
A Tingström ◽  
K Rubin ◽  
L Claesson-Welsh ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Smooth Muscle Cells ◽  
Human Skin ◽  
Muscle Cells ◽  
Receptor Expression ◽  
Platelet Derived Growth Factor ◽  
Pdgf Receptor ◽  
Myometrial Cells

The expression of platelet-derived growth factor (PDGF) receptors in porcine uterus and human skin in situ, was compared with that of cultured primary cells isolated from the same tissues. PDGF receptor expression was examined by monoclonal antibodies specific for the B type PDGF receptor and by RNA/RNA in situ hybridization with a probe constructed from a cDNA clone encoding the B type PDGF receptor. In porcine uterus tissue both mRNA and the protein product for the PDGF receptor were detected in the endometrium; the myometrium, in contrast, contained much lower amounts. Moreover, freshly isolated myometrial cells were devoid of PDGF receptors. However, after 1 d in culture receptors appeared, and after 2 wk of culturing essentially all of the myometrial cells stained positively with the anti-PDGF receptor antibodies and contained PDGF receptor mRNA. Similarly, B type PDGF receptors were not detected in normal human skin, but fibroblast-like cells from explant cultures of human skin possessed PDGF receptors. When determined by immunoblotting, porcine uterus myometrial membranes contained approximately 20% of the PDGF receptor antigen compared with the amount found in endometrial membranes. In addition, PDGF stimulated the phosphorylation of a 175-kD component, most likely representing autophosphorylation of the B type PDGF receptor in endometrial membranes, whereas only a marginal phosphorylation was seen in myometrial membranes. Taken together, these results demonstrate that PDGF receptor expression varies in normal tissues and that fibroblasts and smooth muscle cells do not uniformly express the receptor in situ. Furthermore, fibroblasts and smooth muscle cells that are released from tissues are induced to express PDGF receptors in response to cell culturing. The data suggest that, in addition to the availability of the ligand, PDGF-mediated cell growth in vivo is dependent on factors regulating expression of the receptor.

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