Benzoquinoid ansamycins (herbimycin A and geldanamycin) interfere with thematuration of growth factor receptor tyrosine kinases

Benzoquinoid ansamycins, such as herbimycin A (HA) and geldanamycin (GA), a re antibiotics that exhibit anti-tumor effects. These compounds have been s hown to result in the intracellular depletion of important growth signaling molecules. Recently GA has been shown to bind tightly to Hsp90, thereby im plicating Hsp90 as a possible chaperone for those signaling molecules adver sely affected by the benzoquinoid ansamycins. Here we have investigated the effects of HA and GA on the synthesis, maturation and stability of differe nt protein tyrosine kinases. Exposing cells to either compound blocked norm al maturation of the epidermal growth factor (EGF) receptor, platelet-deriv ed growth factor (PDGF) receptor, and pp60(v-src). We show that only the na scent forms of the EGF and PDGF receptors are degraded under these conditio ns. Once the newly synthesized receptors had been translocated into the end oplasmic reticulum membrane, addition of the drugs no longer affected their stability. For the cytoplasmic tyrosine kinase, pp60(v-src), both the nasc ent as well as the mature forms of the protein were degraded in cells treat ed with the drugs. We discuss these observations as they pertain to the pos sible role of Hsp90 as a substrate-specific molecular chaperone, perhaps in volved in the maturation and/or stability of proteins important for growth control.