EGFRvIII escapes down-regulation due to impaired internalization and sorting to lysosomes

EGFRvIII is a mutant variant of the epidermal growth factor receptor (EGFR) found exclusively in various cancer types. EGFRvIII lacks a large part of the extracellular domain and is unable to bind ligands; however, the receptor is constitutively phosphorylated and able to activate downstream signali...

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Bibliographic Details
Published in:Carcinogenesis (New York) 2007-07, Vol.28 (7), p.1408-1417
Main Authors: Grandal, Michael V., Zandi, Roza, Pedersen, Mikkel W., Willumsen, Berthe M., van Deurs, Bo, Poulsen, Hans S.
Format: Article
Language:English
Subjects:
Biological and medical sciences
Carcinogenesis, carcinogens and anticarcinogens
Cell Line, Tumor
Cell Membrane - metabolism
Down-Regulation
Endocytosis
Epidermal Growth Factor - pharmacology
GRB2 Adaptor Protein - metabolism
Humans
Lysosomes - metabolism
Medical sciences
Phosphorylation
Protein Transport
Proto-Oncogene Proteins c-cbl - metabolism
Receptor, Epidermal Growth Factor - biosynthesis
Receptor, Epidermal Growth Factor - genetics
Signal Transduction
Tumors
Ubiquitins - metabolism
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Summary:EGFRvIII is a mutant variant of the epidermal growth factor receptor (EGFR) found exclusively in various cancer types. EGFRvIII lacks a large part of the extracellular domain and is unable to bind ligands; however, the receptor is constitutively phosphorylated and able to activate downstream signaling pathways. Failure to attenuate signaling by receptor down-regulation could be one of the major mechanisms by which EGFRvIII becomes oncogenic. Using a cell system expressing either EGFR or EGFRvIII with no expression of other EGFR family members and with endogenous levels of key degradation proteins, we have investigated the down-regulation of EGFRvIII and compared it to that of EGFR. We show that, in contrast to EGFR, EGFRvIII is inefficiently degraded. EGFRvIII is internalized, but the internalization rate of the mutated receptor is significantly less than that of unstimulated EGFR. Moreover, internalized EGFRvIII is recycled rather than delivered to lysosomes. EGFRvIII binds the ubiquitin ligase c-Cbl via Grb2, whereas binding via phosphorylated tyrosine residue 1045 seems to be limited. Despite c-Cbl binding, the receptor fails to become effectively ubiquitinylated. Thus, our results suggest that the long lifetime of EGFRvIII is caused by inefficient internalization and impaired sorting to lysosomes due to lack of effective ubiquitinylation.
ISSN:0143-3334
1460-2180
DOI:10.1093/carcin/bgm058