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MBC in Press, published online ahead of print July 11, 2007
Mol. Biol. Cell 10.1091/mbc.E07-01-0025

A more recent version of this article appeared on September 1, 2007
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Submitted on January 12, 2007
Revised on June 6, 2007
Accepted on June 29, 2007

Endocytic Down-Regulation of ErbB2 Is Stimulated by Cleavage of Its C-Terminus

Mads Lerdrup,* Silas Bruun,* Michael V. Grandal, Kirstine Roepstorff, Malene M. Kristensen, Anette M. Hommelgaard, and Bo van Deurs

Department of Cellular and Molecular Medicine, University of Copenhagen, The Panum Institute, DK-2200 Copenhagen N, Denmark

Monitoring Editor: Robert Parton

High ErbB2 levels are associated with cancer, and impaired endocytosis of ErbB2 could contribute to its overexpression. Therefore, knowledge about the mechanisms underlying endocytic down-regulation of ErbB2 is warranted. The C-terminus of ErbB2 can be cleaved after various stimuli, and after inhibition of HSP90 with geldanamycin this cleavage is accompanied by proteasome-dependent endocytosis of ErbB2. However, it is unknown whether C-terminal cleavage is linked to endocytosis. To study ErbB2 cleavage and endocytic trafficking, we fused YFP and CFP to the N- and C-terminus of ErbB2, respectively (YFP-ErbB2-CFP). After geldanamycin stimulation YFP-ErbB2-CFP became cleaved in nonapoptotic cells in a proteasome-dependent manner, and a markedly larger relative amount of cleaved YFP-ErbB2-CFP was observed in early endosomes than in the plasma membrane. Furthermore, cleavage took place at the plasma membrane, and cleaved ErbB2 was internalized and degraded far more efficiently than full-length ErbB2. Concordantly, a C-terminally truncated ErbB2 was also readily endocytosed and degraded in lysosomes compared with full-length ErbB2. Altogether, we suggest that geldanamycin leads to C-terminal cleavage of ErbB2, which releases the receptor from a retention mechanism and causes endocytosis and lysosomal degradation of ErbB2.

*These authors contributed equally to this work.

Address correspondence to: Bo van Deurs (b.v.deurs{at}mai.ku.dk)




This article has been cited by other articles:


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 Mol Cancer ResHome page
N. M. Pedersen, I. H. Madshus, C. Haslekas, and E. Stang
Geldanamycin-Induced Down-Regulation of ErbB2 from the Plasma Membrane Is Clathrin Dependent but Proteasomal Activity Independent
Mol. Cancer Res., March 1, 2008; 6(3): 491 - 500.
[Abstract] [Full Text] [PDF]


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