title: Phosphorylation of epidermal growth factor receptor at serine 1047 by MAP kinase-activated protein kinase-2 in cultured lung epithelial cells treated with flagellin.
abstract: It has been reported that tumor necrosis factor α (TNFα) activated the p38 MAP kinase pathway, followed by phosphorylation of epidermal growth factor receptor (EGFR) at serine 1047 (Ser1047). Although the phosphorylation of Ser1047 reportedly induced an internalization of EGFR, a protein kinase responsible for the phosphorylation has not been elucidated. In the present study, we found that treatment with flagellin of A549 cells, an alveolar epithelial cell line, induced the activation of p38 MAP kinase, followed by phosphorylation of EGFR at Ser1047. The phosphorylation was strongly inhibited by SB203580, an inhibitor of p38 MAP kinase. The flagellin treatment activated MAP kinase-activated protein kinase-2 (MAPKAPK-2), a protein kinase downstream of p38 MAP kinase, and MK2a inhibitor, an inhibitor of MAPKAPK-2, inhibited the flagellin-induced phosphorylation of EGFR at Ser1047. Unlike the flagellin treatment, the TNFα treatment induced the phosphorylation of EGFR at both Ser1047 and Tyr1173. SB203580 and MK2a inhibitor strongly inhibited the phosphorylation of Ser1047 but not Tyr1173 in EGFR. Finally, bacterially expressed and activated MAPKAPK-2 phosphorylated EGFR at Ser1047 in vitro. These results suggest that flagellin regulates the residence time of EGFR on the plasma membrane and thus the signaling of EGFR through phosphorylation of Ser1047 by MAPKAPK-2.
authors.affiliation: Department of Biochemistry, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Noguchi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kondo
authors.forename: Noriko
authors.initials: N
authors.lastname: Maeda
authors.forename: Sayomi
authors.initials: S
authors.lastname: Higa-Nakamine
authors.forename: Seikichi
authors.initials: S
authors.lastname: Toku
authors.forename: Junichi
authors.initials: J
authors.lastname: Maruyama
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Isohama
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kukita
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sugahara
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yamamoto
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005408:Flagellin / Q000494:pharmacology*; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding
chemical_list: D005408:Flagellin; D066246:ErbB Receptors