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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

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Abstract

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.

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Acknowledgments

This work was supported by Japan Science and Technology Agency (project code: 09801156) and a Grant-in Aid for Scientific Research (C) (KAKENHI 22590362) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.

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Authors and Affiliations

  1. Department of Molecular Pathology, Faculty of Life Sciences, Kumamoto University Graduate School, Kumamoto, Japan

    Hiroshi Nishiura, Kazutaka Tokita, Ying Li & Tetsuro Yamamoto

  2. Department of Health Preservation, Faculty of Medicine, Kumamoto University, Kumamoto, Japan

    Koichi Harada

  3. School of Biomedical Sciences, University of Queensland, Brisbane, Australia

    Trent M. Woodruff & Stephen M. Taylor

  4. Department of Biological Functions and Engineering, Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Kitakyushu, Japan

    Tienabe K. Nsiama & Norikazu Nishino

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  1. Hiroshi Nishiura
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Correspondence to Hiroshi Nishiura.

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Nishiura, H., Tokita, K., Li, Y. et al. 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. Apoptosis 15, 966–981 (2010). https://doi.org/10.1007/s10495-010-0511-y

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