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Identification of ErbB-2 Kinase Domain Motifs Required for Geldanamycin-induced Degradation¹

Departments of Biochemistry [O. T., G. C.] and Medicine [G. C.], Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146

The ansamycin antibiotic geldanamycin (GA) induces the intracellular degradation of ErbB-2/neu. Degradation of ErbB-2 proceeds through cleavage(s) within the kinase domain, resulting in the formation of a 135 kDa ectodomain fragment and a fragment(s) of 50 kDa containing the COOH-terminal region. On the basis of independent means of identification, two adjacent sequence motifs have been identified in ErbB-2 that are required for GA-induced degradation. These motifs encompass residues 776–783 and 784–786 within the NH₂-terminal lobe of the ErbB-2 kinase domain. This is also a region in which the epidermal growth factor receptor and ErbB-2 kinase domains differ significantly in sequence. Although mutations in this region abrogate GA-induced ErbB-2 degradation, the tyrosine kinase activity of ErbB-2 is not disrupted. Interestingly, these ErbB-2 mutants are specifically resistant to GA-induced degradation but retain sensitivity to other drugs, such as staurospore and curcumin, which are also able to provoke ErbB-2 degradation.

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