Apoptosis

, Volume 15, Issue 8, pp 966–981

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

  • Hiroshi Nishiura
  • Kazutaka Tokita
  • Ying Li
  • Koichi Harada
  • Trent M. Woodruff
  • Stephen M. Taylor
  • Tienabe K. Nsiama
  • Norikazu Nishino
  • Tetsuro Yamamoto
Original Paper

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.

Keywords

C5a receptor Gi protein HMC-1 cells p38MAPK PI3K Ribosomal protein S19 

Supplementary material

10495_2010_511_MOESM1_ESM.pdf (5.2 mb)
Supplementary material 1 (DOC 31 kb)

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Hiroshi Nishiura
    • 1
  • Kazutaka Tokita
    • 1
  • Ying Li
    • 1
  • Koichi Harada
    • 2
  • Trent M. Woodruff
    • 3
  • Stephen M. Taylor
    • 3
  • Tienabe K. Nsiama
    • 4
  • Norikazu Nishino
    • 4
  • Tetsuro Yamamoto
    • 1
  1. 1.Department of Molecular Pathology, Faculty of Life SciencesKumamoto University Graduate SchoolKumamotoJapan
  2. 2.Department of Health Preservation, Faculty of MedicineKumamoto UniversityKumamotoJapan
  3. 3.School of Biomedical SciencesUniversity of QueenslandBrisbaneAustralia
  4. 4.Department of Biological Functions and Engineering, Graduate School of Life Science and Systems EngineeringKyushu Institute of TechnologyKitakyushuJapan

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