Role of alpha beta receptor heterodimer formation in beta platelet-derived growth factor (PDGF) receptor activation by PDGF-AB.

Platelet-derived growth factor (PDGF) is a major mitogen for connective tissue cells and certain other cell types. It is a dimeric molecule consisting of disulfide-bonded, structurally similar A- and B-polypeptide chains, which combine to homo- and heterodimers. The PDGF isoforms exert their cellular effects by binding to and activating two structurally related protein tyrosine kinase receptors, denoted the α-receptor and the β-receptor. Activation of PDGF receptors leads to stimulation of cell growth, but also to changes in cell shape and motility; PDGF induces reorganization of the actin filament system and stimulates chemotaxis, i.e., a directed cell movement toward a gradient of PDGF. In vivo, PDGF has important roles during the embryonic development as well as during wound healing. Moreover, overactivity of PDGF has been implicated in several pathological conditions. The sis oncogene of simian sarcoma virus (SSV) is related to the B-chain of PDGF, and SSV transformation involves autocrine stimulation by a PDGF-like molecule. Similarly, overproduction of PDGF may be involved in autocrine and paracrine growth stimulation of human tumors. Overactivity of PDGF has, in addition, been implicated in nonmalignant conditions characterized by an increased cell proliferation, such as atherosclerosis and fibrotic conditions. This review discusses structural and functional properties of PDGF and PDGF receptors, the mechanism whereby PDGF exerts its cellular effects, and the role of PDGF in normal and diseased tissues.

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Platelet-derived growth factor receptor can mediate tumorigenic transformation by the bovine papillomavirus E5 protein.

Molecular and Cellular Biology ◽

10.1128/mcb.13.7.4137 ◽

1993 ◽

Vol 13 (7) ◽

pp. 4137-4145 ◽

Cited By ~ 42

Author(s):

L A Nilson ◽

D DiMaio

Keyword(s):

Growth Factor ◽

Growth Factor Receptor ◽

Platelet Derived Growth Factor ◽

Stable Complex ◽

Epithelial Cell Line ◽

Bovine Papillomavirus ◽

Pdgf Receptor ◽

Beta Receptor ◽

E5 Protein ◽

Tumorigenic Transformation

We showed previously that the beta receptor for platelet-derived growth factor (PDGF) is constitutively activated in fibroblasts transformed by the 44-amino-acid bovine papillomavirus type 1 (BPV) E5 protein and that the E5 protein and the PDGF receptor exist in a stable complex in E5-transformed fibroblasts. On the basis of these results, we proposed that activation of the PDGF receptor by the BPV E5 protein generates a sustained proliferative signal, resulting in fibroblast transformation. In this study, we used a gene transfer approach to provide functional evidence that the PDGF receptor can mediate transformation by the E5 protein. We show that normal mouse mammary gland (NMuMG) cells, a murine mammary epithelial cell line that does not express PDGF receptors, are not susceptible to transformation by the E5 protein. Coexpression of the PDGF beta receptor and E5 genes in these cells results in markedly increased tyrosine phosphorylation of an immature PDGF receptor species and the formation of a stable complex between the E5 protein and this immature PDGF receptor form. Importantly, introduction of the PDGF receptor gene into NMuMG cells renders them highly susceptible to E5-mediated tumorigenic transformation. In contrast, the E5 protein does not induce transformation via the endogenous epidermal growth factor receptor pathway in these cells. These results demonstrate that the PDGF receptor, a cellular protein with a well-characterized role in the positive control of cell proliferation, can mediate transformation by a DNA virus transforming protein.

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Platelet-derived growth factor (PDGF)-AB-mediated phosphorylation of PDGF β receptors

Biochemical Journal ◽

10.1042/bj2970379 ◽

1994 ◽

Vol 297 (2) ◽

pp. 379-384 ◽

Cited By ~ 6

Author(s):

S R Coats ◽

H D Love ◽

W J Pledger

Keyword(s):

Growth Factor ◽

Platelet Derived Growth Factor ◽

Receptor Dimerization ◽

Beta Receptor ◽

3T3 Fibroblasts ◽

Beta Receptors ◽

Alpha Receptors ◽

Alpha Beta ◽

Subsequent Activation ◽

Receptor Dimers

Platelet-derived growth factor (PDGF) stimulates the proliferation of Balb/c-3T3 fibroblasts through binding and subsequent activation of PDGF receptors. Activation of the PDGF receptors has been proposed to involve receptor dimerization. PDGF-AB has been shown to bind PDGF alpha and beta receptor subunits to form PDGF alpha beta and alpha alpha receptor dimers. In this paper we demonstrate that, following the down-regulation of PDGF alpha receptors, the binding of PDGF-AB to beta receptors occurred at 37 degrees C but not at 4 degrees C. PDGF-AB stimulated the phosphorylation of PDGF beta receptor monomers in cells depleted of PDGF alpha receptors by prior exposure to PDGF-AA.

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Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis

Journal of Experimental Medicine ◽

10.1084/jem.20041393 ◽

2005 ◽

Vol 201 (6) ◽

pp. 925-935 ◽

Cited By ~ 247

Author(s):

Amir Abdollahi ◽

Minglun Li ◽

Gong Ping ◽

Christian Plathow ◽

Sophie Domhan ◽

...

Keyword(s):

Growth Factor ◽

Pulmonary Fibrosis ◽

Lung Fibrosis ◽

Kinase Inhibitors ◽

Platelet Derived Growth Factor ◽

Growth Factor Signaling ◽

Pdgf Receptor ◽

Pdgf Signaling ◽

Radiation Induced

Pulmonary fibrosis is the consequence of a variety of diseases with no satisfying treatment option. Therapy-induced fibrosis also limits the efficacy of chemotherapy and radiotherapy in numerous cancers. Here, we studied the potential of platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitors (RTKIs) to attenuate radiation-induced pulmonary fibrosis. Thoraces of C57BL/6 mice were irradiated (20 Gy), and mice were treated with three distinct PDGF RTKIs (SU9518, SU11657, or Imatinib). Irradiation was found to induce severe lung fibrosis resulting in dramatically reduced mouse survival. Treatment with PDGF RTKIs markedly attenuated the development of pulmonary fibrosis in excellent correlation with clinical, histological, and computed tomography results. Importantly, RTKIs also prolonged the life span of irradiated mice. We found that radiation up-regulated expression of PDGF (A–D) isoforms leading to phosphorylation of PDGF receptor, which was strongly inhibited by RTKIs. Our findings suggest a pivotal role of PDGF signaling in the pathogenesis of pulmonary fibrosis and indicate that inhibition of fibrogenesis, rather than inflammation, is critical to antifibrotic treatment. This study points the way to a potential new approach for treating idiopathic or therapy-related forms of lung fibrosis.

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A Novel Monoclonal Antibody Dependent on Domain 5 of the Platelet-Derived Growth Factor Beta Receptor Inhibits Ligand Binding and Receptor Activation

Growth Factors ◽

10.3109/08977199308991571 ◽

1993 ◽

Vol 8 (4) ◽

pp. 253-265 ◽

Cited By ~ 8

Author(s):

Vanitha Ramakrishnan ◽

Maria-Amelia Escobedo ◽

Larry J Fretto ◽

Joseph J Seroogy ◽

James E Tomlinson ◽

...

Keyword(s):

Monoclonal Antibody ◽

Growth Factor ◽

Ligand Binding ◽

Receptor Activation ◽

Platelet Derived Growth Factor ◽

Beta Receptor ◽

Growth Factor Beta

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Platelet-derived growth factor (PDGF) alpha receptor activation modulates the calcium mobilizing activity of the PDGF beta receptor in Balb/c3T3 fibroblasts.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)49781-0 ◽

1992 ◽

Vol 267 (17) ◽

pp. 11888-11897

Author(s):

P.A. Diliberto ◽

G.W. Gordon ◽

C.L. Yu ◽

H.S. Earp ◽

B Herman

Keyword(s):

Growth Factor ◽

Receptor Activation ◽

Platelet Derived Growth Factor ◽

Beta Receptor

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Role of Glutamine 17 of the Bovine Papillomavirus E5 Protein in Platelet-Derived Growth Factor β Receptor Activation and Cell Transformation

Journal of Virology ◽

10.1128/jvi.72.11.8921-8932.1998 ◽

1998 ◽

Vol 72 (11) ◽

pp. 8921-8932 ◽

Cited By ~ 43

Author(s):

Ophir Klein ◽

Glenda W. Polack ◽

Toral Surti ◽

Deena Kegler-Ebo ◽

Steven O. Smith ◽

...

Keyword(s):

Amino Acids ◽

Growth Factor ◽

Cell Transformation ◽

Receptor Activation ◽

Platelet Derived Growth Factor ◽

Stable Complex ◽

Bovine Papillomavirus ◽

E5 Protein ◽

Β Receptor

ABSTRACT The bovine papillomavirus E5 protein is a small, homodimeric transmembrane protein that forms a stable complex with the cellular platelet-derived growth factor (PDGF) β receptor through transmembrane and juxtamembrane interactions, resulting in receptor activation and cell transformation. Glutamine 17 in the transmembrane domain of the 44-amino-acid E5 protein is critical for complex formation and receptor activation, and we previously proposed that glutamine 17 forms a hydrogen bond with threonine 513 of the PDGF β receptor. We have constructed and analyzed mutant E5 proteins containing all possible amino acids at position 17 and examined the ability of these proteins to transform C127 fibroblasts, which express endogenous PDGF β receptor. Although several position 17 mutants were able to transform cells, mutants containing amino acids with side groups that were unable to participate in hydrogen bonding interactions did not form a stable complex with the PDGF β receptor or transform cells, in agreement with the proposed interaction between position 17 of the E5 protein and threonine 513 of the receptor. The nature of the residue at position 17 also affected the ability of the E5 proteins to dimerize. Overall, there was an excellent correlation between the ability of the various E5 mutant proteins to bind the PDGF β receptor, lead to receptor tyrosine phosphorylation, and transform cells. Similar results were obtained in Ba/F3 hematopoietic cells expressing exogenous PDGF β receptor. In addition, treatment of E5-transformed cells with a specific inhibitor of the PDGF receptor tyrosine kinase reversed the transformed phenotype. These results confirm the central importance of the PDGF β receptor in mediating E5 transformation and highlight the critical role of the residue at position 17 of the E5 protein in the productive interaction with the PDGF β receptor. On the basis of molecular modeling analysis and the known chemical properties of the amino acids, we suggest a structural basis for the role of the residue at position 17 in E5 dimerization and in complex formation between the E5 protein and the PDGF β receptor.

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PDGF signalling is required for gastrulation of Xenopus laevis

Development ◽

10.1242/dev.121.9.3099 ◽

1995 ◽

Vol 121 (9) ◽

pp. 3099-3110 ◽

Cited By ~ 7

Author(s):

P. Ataliotis ◽

K. Symes ◽

M.M. Chou ◽

L. Ho ◽

M. Mercola

Keyword(s):

Growth Factor ◽

Marginal Zone ◽

Platelet Derived Growth Factor ◽

Pdgf Receptor ◽

Convergent Extension ◽

Mesodermal Cell ◽

Point Mutant ◽

Receptor Alpha

During Xenopus gastrulation, platelet-derived growth factor (PDGF) receptor-alpha is expressed in involuting marginal zone cells which migrate over ectodermal cells expressing PDGF-A. To investigate the role of PDGF signalling during this process, we have generated a novel point mutant of PDGF receptor-alpha analogous to the W37 mutation of c-kit. This molecule is a specific, potent, dominant inhibitor of PDGF signalling in vivo. Injection of RNA encoding this protein into Xenopus embryos prevents closure of the blastopore, leads to abnormal gastrulation and a loss of anterior structures. Convergent extension is not inhibited in these embryos, but rather, involuting mesodermal cells fail to adhere to the overlying ectoderm. PDGF may therefore be required for mesodermal cell-substratum interaction.

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