P185(ERBB2) BINDS TO GRP94 IN-VIVO - DISSOCIATION OF THE P185(ERBB2) GRP94 HETEROCOMPLEX BY BENZOAUINONE ANSAMYCINS PRECEDES DEPLETION OF P185(ERBB2)/

Treatment of SKBr3 cells with benzoquinone ansamycins, such as geldana mycin (GA), depletes p185(erbB2), the receptor tyrosine kinase encoded by the erbB2 gene. In the same cells, a biologically active benzoquin one photoaffinity label specifically binds a protein of about 100 kDa, and the ability of various GA derivatives to reduce the intracellular level of p185(erbB2) correlates with their ability to compete with th e 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(erbB2) exists in a stable complex with GRP94. GA binding to GRP94 disrupts this complex, leading to degr adation of pre-existing p185(erbB2) protein, and resulting in an alter ed subcellular distribution of newly synthesized p185(erbB2).