Journal
CANCER LETTERS
Volume 277, Issue 1, Pages 108-113Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2008.11.034
Keywords
EGFR; Downregulation; Phosphorylation; Serine 1046/1047; p38 MAPK
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Funding
- Ministry of Education, Science, Sports and Culture of Japan [20790490]
- Grants-in-Aid for Scientific Research [20790490] Funding Source: KAKEN
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The desensitization mechanism of the EGF receptor (EGFR) is important for the regulation of cancer cells. Although the phosphorylation of EGFR at Tyr1045 and Ser1046/1047 (Ser1046/7) reportedly accounts for such desensitization, the precise mechanism still remains unknown. Therefore, the present study investigated the upstream signals of these phosphorylations in SW480 colon cancer cells. Anisomycin, a potent kinase activator, induced the activation of both p38 mitogen-activated protein kinase (MAPK) and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), but not p44/p42 MAPK. Anisomycin caused EGFR degradation and this was abolished by a specific p38 MAPK inhibitor, SB203580. Surprisingly, whereas EGF induced phosphorylation at Tyr1045, but not Ser1046/7, anisomycin induced the phosphorylation of EGFR at Ser1046/7, but not Tyr1045. In addition, though both EGF and anisomycin caused EGFR internalization, the EGFR internalized by anisomycin was not associated with an ubiquitin ligase, c-Cbl. Furthermore, SB203580 or gene silencing using p38 MAPK-siRNA suppressed anisomycin-induced phosphorylation of EGFR at Ser1046/7. These results strongly suggest that p38 MAPK directs EGFR toward desensitization via its phosphorylation at Ser1046/7. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
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