Selective Inhibition of Platelet-Derived Growth Factor (PDGF) Receptor Autophosphorylation and PDGF-Mediated Cellular Events by a Quinoline Derivative

1997 ◽  
Vol 234 (2) ◽  
pp. 285-292 ◽  
Author(s):  
Mikio Yagi ◽  
Shinichiro Kato ◽  
Yoshiko Kobayashi ◽  
Kazuo Kubo ◽  
Shinichi Oyama ◽  
...  
Keyword(s):  
Growth Factor ◽  
Selective Inhibition ◽  
Quinoline Derivative ◽  
Platelet Derived Growth Factor ◽  
Pdgf Receptor ◽  
Cellular Events

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.

scholarly journals cDNA cloning and expression of a human platelet-derived growth factor (PDGF) receptor specific for B-chain-containing PDGF molecules.

1988 ◽  
Vol 8 (8) ◽  
pp. 3476-3486 ◽  
Author(s):  
L Claesson-Welsh ◽  
A Eriksson ◽  
A Morén ◽  
L Severinsson ◽  
B Ek ◽  
...  
Keyword(s):  
Amino Acid ◽  
Growth Factor ◽  
Cdna Cloning ◽  
Cho Cells ◽  
Chinese Hamster ◽  
Cloning And Expression ◽  
Platelet Derived Growth Factor ◽  
Amino Acid Sequence Similarity ◽  
Pdgf Receptor

The structure of the human receptor for platelet-derived growth factor (PDGF) has been deduced through cDNA cloning. A 5.45-kilobase-pair cDNA clone predicts a 1,106-amino-acid polypeptide, including the cleavable signal sequence. The overall amino acid sequence similarity with the murine PDGF receptor is 85%. After transcription of the cDNA and translation in vitro, a PDGF receptor antiserum was used to immunoprecipitate a product of predicted size, which also could be phosphorylated in vitro. Stable introduction of the cDNA into Chinese hamster ovary (CHO) cells led to the expression of a 190-kilodalton component, which was immunoprecipitated by the PDGF receptor antiserum; this most probably represents the mature PDGF receptor. Binding assays with different 125I-labeled dimeric forms of PDGF A and B chains showed that the PDGF receptor expressed in CHO cells bound PDGF-BB and, to a lesser extent, PDGF-AB, but not PDGF-AA.

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