Benzoquinoid ansamycins (herbimycin A and geldanamycin) interfere with the maturation of growth factor receptor tyrosine kinases.
Benzoquinoid ansamycins, such as herbimycin A (HA) and geldanamycin (GA), are antibiotics that exhibit anti-tumor effects. These compounds have been shown to result in the intracellular depletion of important growth signaling molecules. Recently, GA has been shown to bind tightly to Hsp90, thereby implicating Hsp90 as a possible chaperone for those signaling molecules adversely affected by the benzoquinoid ansamycins. Here we have investigated the effects of HA and GA on the synthesis, maturation and stability of different protein tyrosine kinases. Exposing cells to either compound blocked normal maturation of the epidermal growth factor (EGF) receptor, platelet-derived growth factor (PDGF) receptor, and pp60(v-src). We show that only the nascent forms of the EGF and PDGF receptors are degraded under these conditions. Once the newly synthesized receptors had been translocated into the endoplasmic reticulum membrane, addition of the drugs no longer affected their stability. For the cytoplasmic tyrosine kinase, pp60(v-src), both the nascent as well as the mature forms of the protein were degraded in cells treated with the drugs. We discuss these observations as they pertain to the possible role of Hsp90 as a substrate-specific molecular chaperone, perhaps involved in the maturation and/or stability of proteins important for growth control.
Sakagami
M
M
Department of Medicine and Physiology, University of California, San Francisco, California 94143, USA.
Morrison
P
P
Welch
W J
WJ
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D016227:Benzoquinones; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004795:Enzyme Stability / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones / Q000378:metabolism; D015688:Oncogene Protein pp60(v-src) / Q000037:antagonists & inhibitors / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011809:Quinones / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D017828:Rifabutin / Q000031:analogs & derivatives
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones; D011809:Quinones; D017828:Rifabutin; C020754:herbimycin; D066246:ErbB Receptors; C099852:PDGF receptor tyrosine kinase; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D015688:Oncogene Protein pp60(v-src); C001277:geldanamycin