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(8): 966-81, 2010 Aug.
Article
em En
| MEDLINE
| ID: mdl-20473571
ABSTRACT
We have demonstrated that an alternative C5a receptor (C5aR) ligand, the homodimer of ribosomal protein S19 (RP S19), contains a unique C-terminus (I(134)-H(145)) that is distinct from the moieties involved in the C5a-C5aR interaction. To examine the role of I(134)-H(145) 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 (L(131)DR) 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 Ca(2+) entry was also suppressed by high concentrations of MgCl(2), which blocks melastatin-type transient receptor potential Ca(2+) 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 I(134)-H(145) 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Ribossômicas
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Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP
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Receptor da Anafilatoxina C5a
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Proteínas Quinases p38 Ativadas por Mitógeno
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article