title: Mutant epidermal growth factor receptor undergoes less protein degradation due to diminished binding to c-Cbl.
abstract: Gefitinib (Iressa) sensitivity in non-small cell lung cancer (NSCLC) is associated with activating mutations in epidermal growth factor receptor (EGFR). It was reported that autophosphorylation of the mutant EGFR is prolonged compared with wild-type EGFR. To explore the mechanism of sustained autophosphorylation, the mutant and wild-type EGFR degradation activities were examined in NSCLC cell lines. EGFR degradation activity was measured by 125I-EGF. The degradation rate of EGFR was lower in the PC-9 NSCLC cell line, which expressed 15-bp deletion mutant EGFR, compared with that in the PC-14 NSCLC (wild-type EGFR). To clarify the mechanism, the stable transfected cell lines, 293_pEGFR and 293_pdelta15, expressing wild-type and mutant EGFR, respectively, were used. In 293_pdelta15, EGFR degradation and binding of c-Cbl ubiquitin ligase to this receptor were reduced compared with 293_pEGFR. Based on these results, we conclude that the mutant EGFR underwent less protein degradation due to diminished binding to c-Cbl.
authors: First Department of Internal Medicine, Showa University School of Medicine, Hatanodai 1-5-8, Shinagawa-ku, Tokyo 142-8555, Japan.
authors: Takamichi
authors: T
authors: Hosaka
authors: Fumiko
authors: F
authors: Inoue
authors: Koichi
authors: K
authors: Ando
authors: Hiroo
authors: H
authors: Ishida
authors: Sojiro
authors: S
authors: Kusumoto
authors: Tomohide
authors: T
authors: Sugiyama
authors: Takao
authors: T
authors: Shirai
authors: Kentaro
authors: K
authors: Okuda
authors: Takashi
authors: T
authors: Hirose
authors: Tsukasa
authors: T
authors: Ohnishi
authors: Naoya
authors: N
authors: Horichi
authors: Nagahiro
authors: N
authors: Saijo
authors: Mitsuru
authors: M
authors: Adachi
authors: Toshio
authors: T
authors: Nakadate
authors: Toshio
authors: T
authors: Kuroki
authors: Tohru
authors: T
authors: Ohmori
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D025801:Ubiquitin; D050721:Proto-Oncogene Proteins c-cbl; D066246:ErbB Receptors; C067419:CBL protein, human