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PMID: 17030621 Published · ppublish English Journal Article

Loss of Hsp90 association up-regulates Src-dependent ErbB2 activity.

Molecular and cellular biology ·Vol. 27 ·No. 1 ·2007-01-00 ·Pages 220-8

Xu W, Yuan X, Beebe K, Xiang Z, Neckers L

Abstract

The receptor tyrosine kinase ErbB2 plays a crucial role in tumorigenesis. We showed previously that the molecular chaperone Hsp90 protects ErbB2 from proteasome-mediated degradation by binding to a short loop structure in the N-lobe of the kinase domain. Here we show that loss of Hsp90 binding correlates with enhanced ErbB2 kinase activity and its transactivating potential, concomitant with constitutively increased phosphorylation of Tyr877, located in the activation loop of the kinase domain. We show further that Tyr877 phosphorylation is mediated by Src and that it is necessary for the enhanced kinase activity of ErbB2. Finally, computer modeling of the kinase domain suggests a phosphorylation-dependent reorientation of the activation loop, denoting the importance of Tyr877 phosphorylation for ErbB2 activity. These findings suggest that Hsp90 binding to ErbB2 participates in regulation of kinase activity as well as kinase stability.

MeSH Terms
3T3 Cells Amino Acid Sequence Animals COS Cells Chlorocebus aethiops Gene Expression Regulation, Enzymologic HSP90 Heat-Shock Proteins/metabolism,physiology Humans Mice Molecular Sequence Data Proteasome Endopeptidase Complex/metabolism Protein Binding Receptor, ErbB-2/biosynthesis Tyrosine/chemistry Up-Regulation src-Family Kinases/metabolism
Chemicals
HSP90 Heat-Shock Proteins Tyrosine Receptor, ErbB-2 src-Family Kinases Proteasome Endopeptidase Complex
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Xu Wanping
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892-1107, USA.
Yuan Xitong
Beebe Kristin
Xiang Zhexin
Neckers Len
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.00899-06
Published
2007-01-00
Epub
2006-00-09
Pages
220-8
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1800645
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.00899-06 PMC Full Text View journal details
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