Inhibition of PDGF-induced phosphoinositide-turnover by glucopiericidin A.
In the search for a substance which would specifically block a particular step in the signal transduction cascade, we identified glucopiericidin A produced by Streptomyces sp. as an inhibitor of phosphoinositide (PI)-turnover in phospholipase-Cgamma1 (PLC-gamma1) overexpressing NIH 3T3 fibroblasts (NIH 3T3gamma1). Glucopiericidin A inhibited the formation of inositol phosphate (IPt) in platelet-derived growth factor (PDGF)-stimulated NIH 3T3gamma1 cells with an IC50 of 5.0 microM. In vitro enzyme assay showed the compound had no inhibitory effect on PLC-gamma1 even at 100 microM concentration. Glucopiericidin A reduced PDGF-induced tyrosine phosphorylations of proteins, including PDGF receptor and PLC-gamma1, in the cells. In contrast, glucopiericidin A showed only a slight inhibitory effect on epidermal growth factor (EGF)-induced IPt production and protein tyrosine phosphorylations in A431 cells. These results suggest that glucopiericidin A inhibits PDGF-induced activation of PLC-gamma1 by reducing the tyrosine kinase activity of the PDGF receptor and it more potently inhibits PI-turnover induced by PDGF than by EGF.
Ahn
S C
SC
Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong, Taejon, Korea.
Kim
B Y
BY
Park
C S
CS
Lee
H S
HS
Suh
P G
PG
Ryu
S H
SH
Rho
H M
HM
Rhee
J S
JS
Mheen
T I
TI
Ahn
J S
JS
D016475:3T3 Cells / Q000187:drug effects / Q000378:metabolism; D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007527:Isoenzymes / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D010716:Phosphatidylinositols / Q000378:metabolism*; D051966:Phospholipase C gamma; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011233:Precipitin Tests; D017479:Receptors, Platelet-Derived Growth Factor / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D007527:Isoenzymes; D010716:Phosphatidylinositols; D010982:Platelet-Derived Growth Factor; C052314:glucopiericidin A; D014443:Tyrosine; D004815:Epidermal Growth Factor; D017479:Receptors, Platelet-Derived Growth Factor; D010738:Type C Phospholipases; D051966:Phospholipase C gamma