Regulation of Hsp90 client proteins by a Cullin5-RING E3 ubiquitin ligase.
We report a link between Cullin5 (Cul5) E3 ubiquitin ligase and the heat shock protein 90 (Hsp90) chaperone complex. Hsp90 participates in the folding of its client proteins into their functional conformation. Many Hsp90 clients have been reported to be aberrantly expressed in a number of cancers. We demonstrate Cul5 interaction with members of the Hsp90 chaperone complex as well as the Hsp90 client, ErbB2. We observed recruitment of Cul5 to the site of ErbB2 at the plasma membrane and subsequent induction of polyubiquitination and proteasomal degradation. We also demonstrate Cul5 involvement in regulation of another Hsp90 client, Hif-1alpha. We observed Cul5 degradation of ErbB2 to occur independently of ElonginB-ElonginC function. The involvement of Cul5 in Hsp90 client regulation has implications in the effectiveness of Hsp90 targeted chemotherapy, which is currently undergoing clinical trials. The link between Cul5 and Hsp90 client regulation may represent an avenue for cancer drug development.
Ehrlich
Elana S
ES
Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Wang
Tao
T
Luo
Kun
K
Xiao
Zuoxiang
Z
Niewiadomska
Anna Maria
AM
Martinez
Tara
T
Xu
Wanping
W
Neckers
Len
L
Yu
Xiao-Fang
XF
D015153:Blotting, Western; D002460:Cell Line; D044842:Cullin Proteins / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D047468:Immunoprecipitation; D008856:Microscopy, Fluorescence; D018832:Molecular Chaperones / Q000378:metabolism*; D017510:Protein Folding; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D054875:Ubiquitination
D044842:Cullin Proteins; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018832:Molecular Chaperones; D018719:Erb-b2 Receptor Tyrosine Kinases; C496871:CUL5 protein, human; C497442:HIF1A protein, human; C508053:ERBB2 protein, human