Skip to main content

Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90.

Publication ,  Journal Article
Xu, W; Mimnaugh, E; Rosser, MF; Nicchitta, C; Marcu, M; Yarden, Y; Neckers, L
Published in: J Biol Chem
February 2, 2001

ErbB receptors are a family of ligand-activated tyrosine kinases that play a central role in proliferation, differentiation, and oncogenesis. ErbB2 is overexpressed in >25% of breast and ovarian cancers and is correlated with poor prognosis. Although ErbB2 and ErbB1 are highly homologous, they respond quite differently to geldanamycin (GA), an antibiotic that is a specific inhibitor of the chaperone protein Hsp90. Thus, although both mature and nascent ErbB2 proteins are down-regulated by GA, only nascent ErbB1 is sensitive to the drug. To reveal the underlying mechanism behind these divergent responses, we made a chimeric receptor (ErbB1/2) composed of the extracellular and transmembrane domains of ErbB1 and the intracellular domain of ErbB2. The ErbB1/2 protein is functional since its kinase activity was stimulated by epidermal growth factor. The sensitivity of ErbB1/2 to GA was similar to that of ErbB2 and unlike that of ErbB1, indicating that the intracellular domain of the chimera confers GA sensitivity. This finding also suggests that the GA sensitivity of mature ErbB2 depends on cytosolic Hsp90, rather than Grp94, a homolog of Hsp90 that is restricted to the lumen of the endoplasmic reticulum, although both chaperones bind to and are inhibited by GA. Lack of Grp94 involvement in mediating ErbB2 sensitivity to GA is further suggested by the fact that a GA derivative with low affinity for Grp94 efficiently depleted ErbB2 protein in treated cells. To localize the specific region of ErbB2 that confers GA sensitivity, we made truncated receptors with progressive deletions of the cytoplasmic domain and tested the GA sensitivity of these molecules. We found that ErbB2 constructs containing an intact kinase domain retained GA sensitivity, whereas those lacking the kinase domain (ErbB2/DK) lost responsiveness to GA completely. Hsp90 co-immunoprecipitated with all ErbB2 constructs that were sensitive to GA, but not with ErbB2/DK or ErbB1. Both tyrosine-phosphorylated and non-phosphorylated ErbB2 proteins were similarly sensitive to GA, as was a kinase-dead ErbB2 mutant. These data suggest that Hsp90 uniquely stabilizes ErbB2 via interaction with its kinase domain and that GA stimulates ErbB2 degradation secondary to disruption of ErbB2/Hsp90 association.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

February 2, 2001

Volume

276

Issue

5

Start / End Page

3702 / 3708

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Sequence Homology, Amino Acid
  • Rifabutin
  • Quinones
  • Protein Structure, Tertiary
  • Phosphotransferases
  • Molecular Sequence Data
  • Molecular Chaperones
  • Membrane Proteins
  • Lactams, Macrocyclic
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Xu, W., Mimnaugh, E., Rosser, M. F., Nicchitta, C., Marcu, M., Yarden, Y., & Neckers, L. (2001). Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90. J Biol Chem, 276(5), 3702–3708. https://doi.org/10.1074/jbc.M006864200
Xu, W., E. Mimnaugh, M. F. Rosser, C. Nicchitta, M. Marcu, Y. Yarden, and L. Neckers. “Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90.J Biol Chem 276, no. 5 (February 2, 2001): 3702–8. https://doi.org/10.1074/jbc.M006864200.
Xu W, Mimnaugh E, Rosser MF, Nicchitta C, Marcu M, Yarden Y, et al. Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90. J Biol Chem. 2001 Feb 2;276(5):3702–8.
Xu, W., et al. “Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90.J Biol Chem, vol. 276, no. 5, Feb. 2001, pp. 3702–08. Pubmed, doi:10.1074/jbc.M006864200.
Xu W, Mimnaugh E, Rosser MF, Nicchitta C, Marcu M, Yarden Y, Neckers L. Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90. J Biol Chem. 2001 Feb 2;276(5):3702–3708.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

February 2, 2001

Volume

276

Issue

5

Start / End Page

3702 / 3708

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Sequence Homology, Amino Acid
  • Rifabutin
  • Quinones
  • Protein Structure, Tertiary
  • Phosphotransferases
  • Molecular Sequence Data
  • Molecular Chaperones
  • Membrane Proteins
  • Lactams, Macrocyclic