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Epidermal growth factor receptor lacking C-terminal autophosphorylation sites retains signal transduction and high sensitivity to epidermal growth factor receptor tyrosine kinase inhibitor
| Content Provider | Scilit |
|---|---|
| Author | Maegawa, Mari Arao, Tokuzo Yokote, Hideyuki Matsumoto, Kazuko Kudo, Kanae Tanaka, Kaoru Kaneda, Hiroyasu Fujita, Yoshihiko Ito, Fumiaki Nishio, Kazuto |
| Copyright Year | 2009 |
| Description | Journal: Cancer Science Constitutively active mutations of epidermal growth factor receptor (EGFR) (delE746_A750) activate downstream signals, such as ERK and Akt, through the phosphorylation of tyrosine residues in the C-terminal region of EGFR. These pathways are thought to be important for cellular sensitivity to EGFR tyrosine kinase inhibitors (TKI). To examine the correlation between phosphorylation of the tyrosine residues in the C-terminal region of EGFR and cellular sensitivity to EGFR TKI, we used wild-type (wt) EGFR, as well as the following constructs: delE746_A750 EGFR; delE746_A750 EGFR with substitution of seven tyrosine residues to phenylalanine in the C-terminal region; and delE746_A750 EGFR with a C-terminal truncation at amino acid 980. These constructs were transfected stably into HEK293 cells and designated HEK293/Wt, HEK293/D, HEK293/D7F, and HEK293/D-Tr, respectively. The HEK293/D cells were found to be 100-fold more sensitive to EGFR TKI (AG1478) than HEK293/Wt. Surprisingly, the HEK293/D7F and HEK293/D-Tr cells, transfected with EGFR lacking the C-terminal autophosphorylation sites, retained high sensitivity to EGFR TKI. In these three high-sensitivity cells, the ERK pathway was activated without ligand stimulation, which was inhibited by EGFR TKI. In addition, although EGFR in the HEK293/D7F and HEK293/D-Tr cells lacked significant tyrosine residues for EGFR signal transduction, phosphorylation of Src homology and collagen homology (Shc) was spontaneously activated in these cells. Our results indicate that tyrosine residues in the C-terminal region of EGFR are not required for cellular sensitivity to EGFR TKI, and that an as-yet-unknown signaling pathway of EGFR may exist that is independent of the C-terminal region of EGFR. |
| Related Links | http://onlinelibrary.wiley.com/doi/10.1111/j.1349-7006.2008.01071.x/pdf |
| Ending Page | 557 |
| Page Count | 6 |
| Starting Page | 552 |
| e-ISSN | 13497006 |
| DOI | 10.1111/j.1349-7006.2008.01071.x |
| Journal | Cancer Science |
| Issue Number | 3 |
| Volume Number | 100 |
| Language | English |
| Publisher | Wiley-Blackwell |
| Publisher Date | 2009-03-01 |
| Access Restriction | Open |
| Subject Keyword | Journal: Cancer Science Biochemistry and Molecular Biology Tyrosine Residues Signal Transduction Cellular Sensitivity Sensitivity To Egfr |
| Content Type | Text |
| Resource Type | Article |
