Platelet-derived growth factor (PDGF) receptor activation in cell transformation and human malignancy

1992 ◽  
Vol 27 (5-6) ◽  
pp. 523-532 ◽  
Author(s):  
Timothy P. Fleming ◽  
Toshimitsu Matsui ◽  
Stuart A. Aaronson
Keyword(s):  
Growth Factor ◽  
Cell Transformation ◽  
Receptor Activation ◽  
Platelet Derived Growth Factor ◽  
Pdgf Receptor ◽  
Human Malignancy

scholarly journals The Bovine Papillomavirus E5 Protein Requires a Juxtamembrane Negative Charge for Activation of the Platelet-Derived Growth Factor β Receptor and Transformation of C127 Cells

1999 ◽  
Vol 73 (4) ◽  
pp. 3264-3272 ◽  
Author(s):  
Ophir Klein ◽  
Deena Kegler-Ebo ◽  
Jennifer Su ◽  
Steven Smith ◽  
Daniel DiMaio
Keyword(s):  
Growth Factor ◽  
Glutamic Acid ◽  
Aspartic Acid ◽  
Negative Charge ◽  
Cell Transformation ◽  
Receptor Activation ◽  
Platelet Derived Growth Factor ◽  
Bovine Papillomavirus ◽  
E5 Protein ◽  
Β Receptor

ABSTRACT The bovine papillomavirus E5 gene encodes a 44-amino-acid, homodimeric transmembrane protein that is the smallest known transforming protein. The E5 protein transforms cultured fibroblasts by forming a stable complex with the endogenous platelet-derived growth factor (PDGF) β receptor through transmembrane and juxtamembrane interactions, leading to sustained receptor activation. Aspartic acid 33 in the extracellular juxtamembrane region of the E5 protein is important for cell transformation and interaction with the PDGF β receptor. A. N. Meyer et al. (Proc. Natl. Acad. Sci USA 91:4634–4638, 1994) speculated that this residue interacted with lysine 499 on the receptor. We constructed E5 mutants containing all possible substitutions at position 33, as well as several double mutants containing substitutions at aspartic acid 33 and at glutamic acid 36, and we examined the ability of these mutants to transform C127 mouse fibroblasts and to bind to and induce activation of the PDGF β receptor. There was an excellent correlation between the transformation activities of the various mutants and their ability to bind to and activate the PDGF β receptor. Analysis of the mutants demonstrated that a juxtamembrane negative charge on the E5 protein was required for cell transformation and for productive interaction with the PDGF β receptor and indicated that aspartic acid 33 was more important for these activities than was glutamic acid 36. These results are consistent with the existence of an essential juxtamembrane salt bridge between lysine 499 on the PDGF β receptor and an acidic residue in the C terminus of the E5 protein and lend support to our proposed model for the complex between the E5 dimer and the PDGF β receptor.

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

1998 ◽  
Vol 72 (11) ◽  
pp. 8921-8932 ◽  
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.

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

1991 ◽  
Vol 266 (30) ◽  
pp. 20232-20237 ◽  
Author(s):  
M.A. Heidaran ◽  
J.H. Pierce ◽  
J.C. Yu ◽  
D. Lombardi ◽  
J.E. Artrip ◽  
...  
Keyword(s):  
Growth Factor ◽  
Receptor Activation ◽  
Platelet Derived Growth Factor ◽  
Pdgf Receptor ◽  
Beta Receptor ◽  
Alpha Beta

scholarly journals Involvement of a phosphotyrosine protein phosphatase in the suppression of platelet-derived growth factor receptor autophosphorylation in ras-transformed cells

1993 ◽  
Vol 293 (1) ◽  
pp. 215-221 ◽  
Author(s):  
L Tomáska ◽  
R J Resnick
Keyword(s):  
Growth Factor ◽  
Phosphatase Activity ◽  
Receptor Tyrosine Kinase ◽  
Protein Phosphatase ◽  
Kinase Activity ◽  
Platelet Derived Growth Factor ◽  
Transformed Cells ◽  
Pdgf Receptor ◽  
Tyrosine Kinase Activity ◽  
Phosphotyrosine Protein Phosphatase

The nature of the suppression of platelet-derived growth factor (PDGF) receptor autophosphorylation in ras-transformed NIH 3T3 fibroblasts was investigated. The PDGF receptor from ras-transformed cells that had been purified by wheatgerm-lectin affinity chromatography displayed normal PDGF-induced autophosphorylation, indicating that the receptor is not irreversibly modified. Various phosphotyrosine-protein-phosphatase inhibitors did not reverse the inhibition of PDGF-receptor kinase in crude membrane preparations from ras-transformed cells. However, treatment of intact ras-transformed cells both with 2 mM sodium orthovanadate and with 20 microM phenylarsine oxide restored PDGF-receptor tyrosine-kinase activity to a level similar to that observed in normal cells. Direct measurement of the phosphatase activities in crude cellular fractions revealed a 2.5-fold higher membrane-associated phosphotyrosine-protein-phosphatase activity in ras-transformed cells, whereas phosphoserine-protein-phosphatase activity remained unchanged between the cell lines. These data suggest that the suppression of the PDGF-receptor tyrosine-kinase activity in ras-transformed cells is mediated via an inhibitory component, distinct from the receptor, that may be positively regulated by the dephosphorylation of tyrosine residue(s).

A small v-sis/platelet-derived growth factor (PDGF) B-protein domain in which subtle conformational changes abrogate PDGF receptor interaction and transforming activity

1990 ◽  
Vol 10 (10) ◽  
pp. 5496-5501
Author(s):  
N Giese ◽  
W J LaRochelle ◽  
M May-Siroff ◽  
K C Robbins ◽  
S A Aaronson
Keyword(s):  
Monoclonal Antibody ◽  
Growth Factor ◽  
Conformational Changes ◽  
Protein Domain ◽  
Platelet Derived Growth Factor ◽  
Receptor Interaction ◽  
Pdgf Receptor ◽  
Amino Acid Residues ◽  
Disulfide Linkages ◽  
Transforming Activity

Deletion scanning mutagenesis within the transforming region of the v-sis oncogene was used to dissect structure-function relationships. Mutations affecting codons within a domain encoding amino acids 136 through 148 had no effect upon homodimer formation or recognition by antisera which detect determinants dependent upon native intrachain disulfide linkages, yet the same mutations completely abolished transforming activity. A platelet-derived growth factor B (PDGF B) monoclonal antibody that prevents its interaction with PDGF receptors recognized v-sis, delta 142 (deletion of codon 142), and delta 148 but not delta 136, delta 137, or delta 139 mutants. These findings mapped the epitope recognized by this monoclonal antibody to include amino acid residues 136 to 139. Furthermore, mutations in the codon 136 to 148 domain caused markedly impaired ability to induce PDGF receptor tyrosine phosphorylation. Thus, subtle conformational alterations in this small domain critically affect PDGF receptor recognition and/or functional activation.

Platelet-derived growth factor (PDGF)-dependent association of phospholipase C-gamma with the PDGF receptor signaling complex

1990 ◽  
Vol 10 (5) ◽  
pp. 2359-2366
Author(s):  
D K Morrison ◽  
D R Kaplan ◽  
S G Rhee ◽  
L T Williams
Keyword(s):  
Growth Factor ◽  
Tyrosine Phosphorylation ◽  
Serine Phosphorylation ◽  
Platelet Derived Growth Factor ◽  
Pdgf Receptor ◽  
Wild Type ◽  
Receptor Proteins ◽  
Signaling Complex

We investigated the interaction of phospholipase C-gamma (PLC-gamma) with wild-type and mutant forms of the platelet-derived growth factor (PDGF) beta-receptor both in vivo and in vitro. After PDGF treatment of CHO cell lines expressing wild-type or either of two mutant (delta Ki and Y825F) PDGF receptors, PLC-gamma became tyrosine phosphorylated and associated with the receptor proteins. The receptor association and tyrosine phosphorylation of PLC-gamma correlated with the ability of these receptors to mediate ligand-induced phosphatidylinositol turnover. However, both the delta Ki and Y825F mutant receptors were deficient in transmitting mitogenic signals, suggesting that the PDGF-induced tyrosine phosphorylation and receptor association of PLC-gamma are not sufficient to account for the growth-stimulatory activity of PDGF. Wild-type and delta Ki mutant PDGF receptor proteins expressed with recombinant baculovirus vectors also associated in vitro with mammalian PLC-gamma. However, baculovirus-expressed c-fms, v-fms, c-src, and Raf-1 proteins failed to associate with PLC-gamma under similar conditions. Phosphatase treatment of the baculovirus-expressed PDGF receptor greatly decreased its association with PLC-gamma. This requirement for receptor phosphorylation was also observed in vivo, where PLC-gamma could not associate with a mutant PDGF receptor (K602A) defective in autophosphorylation. PLC-gamma also coimmunoprecipitated with two other putative receptor substrates, the serine-threonine kinase Raf-1 and the 85-kilodalton phosphatidylinositol-3' kinase, presumably through its association with the ligand-activated receptor. Furthermore, baculovirus-expressed Raf-1 phosphorylated purified PLC-gamma in vitro at sites which showed increased serine phosphorylation in vivo in response to PDGF. These results suggest that PDGF directly influences PLC activity by inducing the association of PLC-gamma with a receptor signaling complex, resulting in increased tyrosine and serine phosphorylation of PLC-gamma.

scholarly journals Structural Role of Extracellular Domain 1 of α-Platelet-derived Growth Factor (PDGF) Receptor for PDGF-AA and PDGF-BB Binding

1995 ◽  
Vol 270 (46) ◽  
pp. 27595-27600 ◽  
Author(s):  
Daruka Mahadevan ◽  
Jin-Chen Yu ◽  
Jose W. Saldanha ◽  
Narmada Thanki ◽  
Peter McPhie ◽  
...  
Keyword(s):  
Growth Factor ◽  
Extracellular Domain ◽  
Platelet Derived Growth Factor ◽  
Pdgf Receptor ◽  
Structural Role

scholarly journals Characterization of a novel anti-peptide antibody that recognizes a specific conformation of the platelet-derived growth factor receptor.

1988 ◽  
Vol 8 (9) ◽  
pp. 3696-3702 ◽  
Author(s):  
S Bishayee ◽  
S Majumdar ◽  
C D Scher ◽  
S Khan
Keyword(s):  
Growth Factor ◽  
Growth Factor Receptor ◽  
Platelet Derived Growth Factor ◽  
Pdgf Receptor ◽  
Amino Acid Residues ◽  
Site Specific ◽  
Recognition Specificity ◽  
Peptide Antibody ◽  
Peptide Antibodies

Two site-specific anti-peptide antibodies (AbP1 and AbP2) were raised against the platelet-derived growth factor (PDGF) receptor. These two sites correspond to amino acid residues 977 through 988 (peptide 1) and 932 through 947 (peptide 2) of the murine PDGF receptor. Both antibodies recognized human and murine PDGF receptors in immunoprecipitation and immunoblotting analyses. None of the antibodies was directed to phosphotyrosine. One of the antibodies (AbP2) showed unusual antigen recognition specificity. This antibody specifically recognized the tyrosine-phosphorylated PDGF receptor and not the unphosphorylated native receptor, suggesting that recognition by this antibody requires a specific conformation that is induced by PDGF-stimulated autophosphorylation.

Abelson murine leukemia virus induces platelet-derived growth factor-independent fibroblast growth: correlation with kinase activity and dissociation from full morphologic transformation

1989 ◽  
Vol 9 (1) ◽  
pp. 278-287
Author(s):  
R W Rees-Jones ◽  
M Goldfarb ◽  
S P Goff
Keyword(s):  
Growth Factor ◽  
Murine Leukemia Virus ◽  
Kinase Activity ◽  
Cell Transformation ◽  
Leukemia Virus ◽  
Platelet Derived Growth Factor ◽  
Fibroblast Growth ◽  
Morphological Transformation ◽  
Abelson Murine Leukemia Virus ◽  
Murine Leukemia

Abelson murine leukemia virus (A-MuLV) encodes a single protein product, a tyrosine-specific protein kinase, whose activity is necessary for cell transformation by this retrovirus. Using a defined medium culture system, we demonstrate that transformation of NIH 3T3 fibroblasts by A-MuLV abrogates their normal requirement for platelet-derived growth factor (PDGF) for cell growth. Analysis of constructed insertional mutant viruses revealed an absolute correlation between A-MuLV-encoded tyrosine kinase activity and PDGF-independent fibroblast growth. Sequences of the provirus not required for kinase activity appeared unnecessary for abrogating the fibroblast requirement for PDGF. Conversely, sequences required for kinase activity appeared necessary, suggesting that induction of PDGF-independent fibroblast growth, like cell transformation, is a function of this tyrosine kinase. Fibroblasts transformed by a partially transformation-defective mutant demonstrated incomplete morphological transformation but were still independent of PDGF for growth. Thus, the processes of full morphological transformation and growth factor independence can be partially dissociated.

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