Chaperone-dependent E3 ubiquitin ligase CHIP mediates a degradative pathway for c-ErbB2/Neu.
Overexpression of the transmembrane receptor tyrosine kinase ErbB2 is common in multiple malignancies, including breast and ovarian cancer. ErbB2 is resistant to degradation mediated by c-Cbl, the E3 ubiquitin ligase responsible for ligand-induced ubiquitination of ErbB1 (epidermal growth factor receptor). Because of its resistance to degradation, ErbB2 is the preferred dimerization partner for other members of the ErbB family, and its overexpression in vivo is associated with poor prognosis. We now show that the chaperone-binding ubiquitin ligase CHIP efficiently ubiquitinates and down-regulates ErbB2. CHIP expression shortens the half-life of both nascent and mature ErbB2 protein. In vitro ubiquitination assay shows that CHIP serves as a ubiquitin ligase for ErbB2, and both exogenously expressed and endogenous CHIP coprecipitate with the kinase. Furthermore, CHIP association with ErbB2 requires a chaperone intermediate and is increased by the chaperone-binding drug geldanamycin, a potent stimulator of ErbB2 ubiquitination and degradation. These data describe a previously unrecognized pathway, amenable to pharmacologic manipulation, that mediates ErbB2 stability.
Xu
Wanping
W
Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, Rockville, MD 20850, USA.
Marcu
Monica
M
Yuan
Xitong
X
Mimnaugh
Edward
E
Patterson
Cam
C
Neckers
Len
L
D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D003513:Cycloheximide / Q000494:pharmacology; D015536:Down-Regulation; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D008025:Ligases / Q000378:metabolism* / Q000502:physiology; D011233:Precipitin Tests; D011485:Protein Binding; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism* / Q000502:physiology; D013997:Time Factors; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D003513:Cycloheximide; D018841:HSP90 Heat-Shock Proteins; D008025:Ligases; D011500:Protein Synthesis Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C467728:STUB1 protein, human