p185 super(erbB2) binds to GRP94 in vivo. Dissociation of the p185 super(erbB2)/GRP94 heterocomplex by benzoquinone ansamycins precedes depletion of p185 super(erbB2)

Treatment of SKBr3 cells with benzoquinone ansamycins, such as geldanamycin (GA), depletes p185 super(erbB2), the receptor tyrosine kinase encoded by the erbB2 gene. In the same cells, a biologically active benzoquinone photoaffinity label specifically binds a protein of about 100 kDa, and the ability of various GA derivatives to reduce the intracellular level of p185 super(erbB2) correlates with their ability to compete with the photoaffinity label for binding to this protein. In this report, we present evidence that the similar to 100-kDa ansamycin-binding protein is GRP94. Membrane-associated p185 super(erbB2) exists in a stable complex with GRP94. GA binding to GRP94 disrupts this complex, leading to degradation of pre-existing p185 super(erbB2) protein, and resulting in an altered subcellular distribution of newly synthesized p185 super(erbB2).