Mutant epidermal growth factor receptor undergoes less protein degradation due to diminished binding to c-Cbl.
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.
Hosaka
Takamichi
T
First Department of Internal Medicine, Showa University School of Medicine, Hatanodai 1-5-8, Shinagawa-ku, Tokyo 142-8555, Japan.
Inoue
Fumiko
F
Ando
Koichi
K
Ishida
Hiroo
H
Kusumoto
Sojiro
S
Sugiyama
Tomohide
T
Shirai
Takao
T
Okuda
Kentaro
K
Hirose
Takashi
T
Ohnishi
Tsukasa
T
Horichi
Naoya
N
Saijo
Nagahiro
N
Adachi
Mitsuru
M
Nakadate
Toshio
T
Kuroki
Toshio
T
Ohmori
Tohru
T
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
D025801:Ubiquitin; D050721:Proto-Oncogene Proteins c-cbl; D066246:ErbB Receptors; C067419:CBL protein, human