Differential effects of EGFR ligands on endocytic sorting of the receptor.
Endocytic downregulation is a pivotal mechanism turning off signalling from the EGF receptor (EGFR). It is well established that whereas EGF binding leads to lysosomal degradation of EGFR, transforming growth factor (TGF)-alpha causes receptor recycling. TGF-alpha therefore leads to continuous signalling and is a more potent mitogen than EGF. In addition to EGF and TGF-alpha, five EGFR ligands have been identified. Although many of these ligands are upregulated in cancers, very little is known about their effect on EGFR trafficking. We have compared the effect of six different ligands on endocytic trafficking of EGFR. We find that, whereas they all stimulate receptor internalization, they have very diverse effects on endocytic sorting. Heparin-binding EGF-like growth factor and Betacellulin target all EGFRs for lysosomal degradation. In contrast, TGF-alpha and epiregulin lead to complete receptor recycling. EGF leads to lysosomal degradation of the majority but not all EGFRs. Amphiregulin does not target EGFR for lysosomal degradation but causes fast as well as slow EGFR recycling. The Cbl ubiquitin ligases, especially c-Cbl, are responsible for EGFR ubiquitination after stimulation with all ligands, and persistent EGFR phosphorylation and ubiquitination largely correlate with receptor degradation.
Roepstorff
Kirstine
K
Department of Cellular and Molecular Medicine, The Panum Building, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Grandal
Michael Vibo
MV
Henriksen
Lasse
L
Knudsen
Stine Louise Jeppe
SL
Lerdrup
Mads
M
Grøvdal
Lene
L
Willumsen
Berthe Marie
BM
van Deurs
Bo
B
D066258:Amphiregulin; D000818:Animals; D066259:Betacellulin; D002460:Cell Line; D066255:EGF Family of Proteins; D004705:Endocytosis / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000378:metabolism; D066260:Epiregulin; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D006863:Hydrogen-Ion Concentration; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008024:Ligands; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D054875:Ubiquitination; D033921:Vesicular Transport Proteins / Q000378:metabolism
C587848:AREG protein, human; D066258:Amphiregulin; C587851:BTC protein, human; D066259:Betacellulin; D066255:EGF Family of Proteins; C587880:EREG protein, human; D066260:Epiregulin; D006023:Glycoproteins; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D052118:Lysosomal-Associated Membrane Protein 1; D016211:Transforming Growth Factor alpha; D033921:Vesicular Transport Proteins; C093846:early endosome antigen 1; D004815:Epidermal Growth Factor; D050721:Proto-Oncogene Proteins c-cbl; D066246:ErbB Receptors