Tyrphostins inhibit the epidermal growth factor receptor-mediated breakdown of phosphoinositides.
In response to epidermal growth factor (EGF) and the Ca2+ ionophore A23187, the total phosphatidylinositides (IPT) increased in A431 human epidermoid carcinoma cells 1.8- and 2.0-fold and in the EGF-dependent A431/Clone 15-2 cells 3.0- and 8.0-fold, respectively, over basal levels. Both responses were inhibited by the antiproliferative agents tyrphostins, but the EGF-induced increase in IPT was inhibited to a much greater extent than that induced by the ionophore. Tyrphostins which are potent EGF-receptor kinase inhibitors were also potent in blocking the EGF-induced production of phosphoinositides. The less potent tyrphostins were found to inhibit the EGF-dependent IPT formation more weakly. These results support the notion that phospholipase C is activated through its phosphorylation by the EGF receptor.
Posner
I
I
Department of Biological Chemistry, Hebrew University of Jerusalem, Israel.
Gazit
A
A
Gilon
C
C
Levitzki
A
A
D000001:Calcimycin / Q000494:pharmacology; D002396:Catechols / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology*; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D013329:Structure-Activity Relationship
D002396:Catechols; D007295:Inositol Phosphates; D009570:Nitriles; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols; D000001:Calcimycin; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases