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The role of the ribosomal protein S19 C-terminus in Gi protein-dependent alternative activation of p38 MAP kinase via the C5a receptor in HMC-1 cells 西浦, 弘志 104580 斎田, 和孝 104581 原田, 幸一 104582 西野, 憲和 104583 山本, 哲郎 104584 Nishiura, Hiroshi 104566 Tokita, Kazutaka 104567 Li, Ying 104568 Harada, Koichi 104569 Trent, M. Woodruff 104570 Stephen, M. Taylor 104571 Tienabe, Kipassa Nsiama 104572 Nishino, Norikazu 104573 山本, 哲郎 94588 ヤマモト, テツロウ Yamamoto, Tetsuro 491 C5a receptor Gi protein HMC-1 cells p38MAPK PI3K Ribosomal protein S19 application/pdf 論文(Article) We have demonstrated that an alternative C5a receptor (C5aR) ligand, the homodimer of ribosomal protein S19 (RP S19), contains a unique C-terminus (I134–H145) that is distinct from the moieties involved in the C5a–C5aR interaction. To examine the role of I134–H145 in the ligand–C5aR interaction, we connected this peptide to the C-terminus of C5a (C5a/RP S19) and found that it endowed the second binding moiety of RP S19 (L131DR) with a relatively higher binding affinity to the C5aR on a human mast cell line, HMC-1. In contrast to the C5aR, the second C5aR C5L2 worked as a decoy receptor. As a result, the mitogen-activated protein kinase (MAPK) downstream of the Gi protein exchanged extracellular-signal regulated kinase for p38MAPK. This alternative p38MAPK activation could be pharmacologically suppressed not only by the downregulation of phosphoinositide 3-kinase (PI3K) by LY294002, but also by the over-activation of protein kinase C by phorbol 12-myristate 13-acetate. The activation was reproduced upon C5a–C5aR interaction by a simultaneous suppression of PI3K and phospholipase C with LY294002 and U73122 at low concentrations. Moreover, p38MAPK phosphorylation upstream of the pertussis toxin-dependent extracellular Ca2+ entry was also suppressed by high concentrations of MgCl2, which blocks melastatin-type transient receptor potential Ca2+ channels (TRPMs). The active conformation of C5aR upon the ligation by C5a, at least on HMC-1 cells, is changed by the additional interaction of the I134–H145 peptide, which seems to guide the alternative activation of p38MAPK. This activation is then amplified by a novel positive feedback loop between p38MAPK and TRPM. Electronic supplementary material The online version of this article (doi:10.1007/s10495-010-0511-y) contains supplementary material, which is available to authorized users. http://www.springerlink.com/content/w47x84142mw45723/ journal article Springer Netherlands 2010-08 AM application/pdf Apoptosis 8 15 966 981 https://kumadai.repo.nii.ac.jp/record/23781/files/Apoptosis_HIRO minor revised paper_r.pdf http://hdl.handle.net/2298/20582 https://kumadai.repo.nii.ac.jp/records/23781 eng 20473571 13608185 © Springer Science+Business Media