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Ligand induced EGFR endocytosis and degradation

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The Epidermal growth factor receptor (EGFR) is overexpressed in several types of cancer. Ligand induced EGFR downregulation is tightly controlled, but so far only the effects of two of the ligands (Epidermal growth factor (EGF) and transforming growth factor-α (TGF-α)) have been thouroughly investigated.

Activated EGFR recruits intracellular proteins, which in turn lead to ubiquitination, internalization, and downregulation of the receptor, and here we have investigated the effects of six different EGFR ligands on these events. We show that EGF stimulates degradation to a moderate degree, whereas betacellulin (BTC) and heparin-binding EGF (HB-EGF) cause a high level of receptor degradation. TGF-α, amphiregulin (AR), and epiregulin (EPI) do not stimulate receptor degradation. The lack of EGFR degradation after TGF-α and EPI stimulation is due to complete recycling to the surface, whereas the most potent ligands HB-EGF and BTC caused no receptor recycling. In case of EGF, the receptor was partially recycled. Interestingly, after stimulation with AR the receptor was not fully recycled, even though there was no detectable degradation. Furthermore, we examined the ubiquitination pattern of EGFR after stimulation with the different ligands. For five of the examined ligands, there was a tight correlation between receptor ubiquitination and degradation. Interestingly, AR caused ubiqitination of EGFR in levels similar to EGF even though it had little effect on receptor degradation. This implies that ubiquitination is not the sole determinant of whether internalized EGFR is degraded or recycled. Altogether, this suggests that the various EGFR ligands have very different consequences for EGFR trafficking and degradation, and that the mechanisms involved are more diverse than previously anticipated.
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Document Type: Abstract

Affiliations: 1: Institut for cellulær og molekylær medicin, Københavns universitet, Blegdamsvej 3 2200 Kbh. N 2: Afdelingen for molekylær cellebiologi, Københavns Universitet, Ole Maaløes Vej 5 2200 Kbh. N

Publication date: May 1, 2008

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