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

TY - JOUR

T1 - EGFRvIII escapes down-regulation due to impaired internalization and sorting to lysosomes.

AU - Grandal, Michael V

AU - Zandi, Roza

AU - Pedersen, Mikkel W

AU - Willumsen, Berthe M

AU - van Deurs, Bo

AU - Poulsen, Hans S

N1 - Keywords: Cell Line, Tumor; Cell Membrane; Down-Regulation; Endocytosis; Epidermal Growth Factor; GRB2 Adaptor Protein; Humans; Lysosomes; Phosphorylation; Protein Transport; Proto-Oncogene Proteins c-cbl; Receptor, Epidermal Growth Factor; Signal Transduction; Ubiquitins

PY - 2007

Y1 - 2007

N2 - 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.

AB - 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.

U2 - 10.1093/carcin/bgm058

DO - 10.1093/carcin/bgm058

M3 - Journal article

C2 - 17372273

SN - 0143-3334

VL - 28

SP - 1408

EP - 1417

JO - Carcinogenesis

JF - Carcinogenesis

IS - 7

ER -