Tyrosine kinase activity of purified recombinant cytoplasmic domain of platelet-derived growth factor β-receptor (β-PDGFR) and discovery of a novel inhibitor of receptor tyrosine kinases

1999 ◽  
Vol 57 (1) ◽  
pp. 57-64 ◽  
Author(s):  
Guido J.R. Zaman ◽  
Paul M.F. Vink ◽  
Antoon A. van den Doelen ◽  
Gerrit H. Veeneman ◽  
Henri J.M. Theunissen
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Receptor Tyrosine Kinases ◽  
Cytoplasmic Domain ◽  
Platelet Derived Growth Factor ◽  
Tyrosine Kinase Activity ◽  
Β Receptor

scholarly journals Platelet-derived growth factor induces phosphorylation of multiple JAK family kinases and STAT proteins.

1996 ◽  
Vol 16 (4) ◽  
pp. 1759-1769 ◽  
Author(s):  
M L Vignais ◽  
H B Sadowski ◽  
D Watling ◽  
N C Rogers ◽  
M Gilman
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Human Fibroblasts ◽  
Platelet Derived Growth Factor ◽  
Interferon Signaling ◽  
Tyrosine Kinase Activity ◽  
Protein Tyrosine ◽  
Stat Proteins

Receptors for interferons and other cytokines signal through the action of associated protein tyrosine kinases of the JAK family and latent cytoplasmic transcription factors of the STAT family. Genetic and biochemical analysis of interferon signaling indicates that activation of STATs by interferons requires two distinct JAK family kinases. Loss of either of the required JAKs prevents activation of the other JAK and extinguishes STAT activation. These observations suggest that JAKs provide interferon receptors with a critical catalytic signaling function and that at least two JAKs must be incorporated into an active receptor complex. JAK and STAT proteins are also activated by ligands such as platelet-derived growth factor (PDGF), which act through receptors that possess intrinsic protein tyrosine kinase activity, raising questions about the role of JAKs in signal transduction by this class of receptors. Here, we show that all three of the ubiquitously expressed JAKs--JAK1, JAK2, and Tyk2--become phosphorylated on tyrosine in both mouse BALB/c 3T3 cells and human fibroblasts engineered to express the PDGF-beta receptor. All three proteins are also associated with the activated receptor. Through the use of cell lines each lacking an individual JAK, we find that in contrast to interferon signaling, PDGF-induced JAK phosphorylation and activation of STAT1 and STAT3 is independent of the presence of any other single JAK but does require receptor tyrosine kinase activity. These results suggests that the mechanism of JAK activation and JAK function in signaling differs between receptor tyrosine kinases and interferon receptors.

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 Platelet-derived growth factor induces multisite phosphorylation of pp60c-src and increases its protein-tyrosine kinase activity.

1988 ◽  
Vol 8 (8) ◽  
pp. 3345-3356 ◽  
Author(s):  
K L Gould ◽  
T Hunter
Keyword(s):  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Kinase Activity ◽  
Platelet Derived Growth Factor ◽  
Tyrosine Kinase Activity ◽  
Kinase C ◽  
Protein Tyrosine Kinase Activity

We have shown previously that pp60c-src is a substrate for protein kinase C in vivo and that the target of protein kinase C phosphorylation in mammalian pp60c-src is serine 12. We now demonstrate that in addition to tumor promoters, all activators of phosphatidylinositol turnover that we have tested in fibroblasts (platelet-derived growth factor, fibroblast growth factor, serum, vasopressin, sodium orthovanadate, and prostaglandin F2 alpha) lead to the phosphorylation of pp60c-src at serine 12. In addition to stimulating serine 12 phosphorylation in pp60c-src, platelet-derived growth factor treatment of quiescent fibroblasts induces phosphorylation of one or two additional serine residues and one tyrosine residue within the N-terminal 16 kilodaltons of the enzyme and activates its immune complex protein-tyrosine kinase activity.

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 Unlocking Doors without Keys: Activation of Src by Truncated C-terminal Intracellular Receptor Tyrosine Kinases Lacking Tyrosine Kinase Activity

Cells ◽  
2014 ◽  
Vol 3 (1) ◽  
pp. 92-111 ◽  
Author(s):  
Belén Mezquita ◽  
Pau Mezquita ◽  
Montserrat Pau ◽  
Jovita Mezquita ◽  
Cristóbal Mezquita
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Receptor Tyrosine Kinases ◽  
Tyrosine Kinase Activity ◽  
Intracellular Receptor

Platelet-derived growth factor induces multisite phosphorylation of pp60c-src and increases its protein-tyrosine kinase activity

1988 ◽  
Vol 8 (8) ◽  
pp. 3345-3356
Author(s):  
K L Gould ◽  
T Hunter
Keyword(s):  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Kinase Activity ◽  
Platelet Derived Growth Factor ◽  
Tyrosine Kinase Activity ◽  
Kinase C ◽  
Protein Tyrosine Kinase Activity

We have shown previously that pp60c-src is a substrate for protein kinase C in vivo and that the target of protein kinase C phosphorylation in mammalian pp60c-src is serine 12. We now demonstrate that in addition to tumor promoters, all activators of phosphatidylinositol turnover that we have tested in fibroblasts (platelet-derived growth factor, fibroblast growth factor, serum, vasopressin, sodium orthovanadate, and prostaglandin F2 alpha) lead to the phosphorylation of pp60c-src at serine 12. In addition to stimulating serine 12 phosphorylation in pp60c-src, platelet-derived growth factor treatment of quiescent fibroblasts induces phosphorylation of one or two additional serine residues and one tyrosine residue within the N-terminal 16 kilodaltons of the enzyme and activates its immune complex protein-tyrosine kinase activity.

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