p38 MAP kinase controls EGF receptor downregulation via phosphorylation at Ser1046/1047.
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.
Adachi
Seiji
S
Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan.
Natsume
Hideo
H
Yamauchi
Junichi
J
Matsushima-Nishiwaki
Rie
R
Joe
Andrew K
AK
Moriwaki
Hisataka
H
Kozawa
Osamu
O
D000841:Anisomycin / Q000494:pharmacology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D050721:Proto-Oncogene Proteins c-cbl / Q000502:physiology; D012694:Serine / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D012694:Serine; D000841:Anisomycin; D050721:Proto-Oncogene Proteins c-cbl; D066246:ErbB Receptors; D048051:p38 Mitogen-Activated Protein Kinases; C067419:CBL protein, human