Serine mutations that abrogate ligand-induced ubiquitination and internalization of the EGF receptor do not affect c-Cbl association with the receptor

M.P. Oksvold, Christine Thien, J. Widerberg, A. Chantry, H.S. Huitfeldt, Wallace Langdon

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Abstract

In the present study, we examined EGF-induced internalization,degradation and trafficking of the epidermalgrowth factor receptor (EGFR) mutated at serines 1046,1047, 1057 and 1142 located in its cytoplasmic carboxyterminalregion. We found the serine-mutated EGFR to beinhibited in EGF-induced internalization and degradationin NIH3T3 cells. We therefore tested the hypothesis thatthese mutations affect ligand-induced c-Cbl associationwith the receptor, leading to inhibited receptor ubiquitination.EGF was unable to induce ubiquitination of theserine-mutated EGFR, yet EGF-induced phosphorylationof the c-Cbl-binding site at tyrosine 1045, and c-Cbl-EGFR association, was unaffected. To compare therelevance of these serine residues with tyrosine 1045 intheir regulation of c-Cbl binding and receptor ubiquitination,we analysed an EGFR mutated at tyrosine 1045(Y1045F). EGF-induced c-Cbl-EGFR binding was partiallyinhibited, and receptor ubiquitination was abrogatedin cells expressing Y1045F-EGFR. In contrast, ligandinducedinternalization and degradation of the Y1045Fmutant was similar to that of wild-type EGFR. Together,our data indicate that the serine residues and tyrosine1045 are essential for EGF-induced receptor ubiquitination,but only the serine residues are critical for EGFRinternalization and degradation.Oncogene (2003) 22, 8509–8518. doi:10.1038/sj.onc.1207117
Original languageEnglish
Pages (from-to)8509-8518
JournalOncogene
Volume22
Issue number52
DOIs
Publication statusPublished - 2003

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