p38 MAP kinase controls EGF receptor downregulation via phosphorylation at Ser1046/1047

Cancer Letters
Seiji AdachiOsamu Kozawa

Abstract

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 phospho...Continue Reading

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Citations

Jun 8, 2011·The Journal of Biological Chemistry·Seiji AdachiOsamu Kozawa
Dec 14, 2011·PloS One·Eva M Galan-MoyaRicardo Sánchez-Prieto
Feb 14, 2013·The Journal of Biological Chemistry·Meryem BektasDavid S Rubenstein
Feb 23, 2017·The Journal of Endocrinology·Lorena GonzálezDaniel Turyn
Dec 12, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Michelandrea De CesareValentina Zuco

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