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A more recent version of this article appeared on April 1, 2004
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Submitted on August 15, 2003
Revised on December 10, 2003
Accepted on December 22, 2003
1 Structural Cell Biology Unit, Department of Medical Anatomy, The Panum Institute, University of Copenhagen, Copenhagen 2200 N, Denmark
* Corresponding author. E-mail address: b.v.deurs{at}mai.ku.dk.
In contrast to the EGF receptor, ErbB2 is known to remain at the plasma membrane after ligand binding and dimerization. However, why ErbB2 is not efficiently down-regulated has remained elusive. Basically two possibilities exist: ErbB2 is internalization resistant or it is efficiently recycled after internalization. By a combination of confocal microscopy, immunogold labeling electron microscopy and biochemical techniques we here show that ErbB2 is preferentially associated with membrane protrusions. Moreover, it is efficiently excluded from clathrin-coated pits and is not seen in transferrin receptor (TfR)-containing endosomes. This pattern is not changed after binding of EGF, Heregulin, or Herceptin. The exclusion from coated pits is so pronounced that it cannot just be explained by lack of an internalization signal. Although ErbB2 is a raft-associated protein, the localization of ErbB2 to protrusions is not a result of raft-binding. Also, an intact actin cytoskeleton is not required for keeping ErbB2 away from coated pits. However, after efficient cross-linking, ErbB2 is removed from protrusions to appear on the bulk membrane, in coated pits, and in endosomes. These data show that ErbB2 is a remarkably internalization-resistant receptor and suggest that the mechanism underlying the firm association of ErbB2 with protrusions also is the reason for this resistance.
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