Pro- and anti-apoptotic dual functions of the C5a receptor: involvement of regulator of G protein signaling 3 and extracellular signal-regulated kinase

Lab Invest. 2009 Jun;89(6):676-94. doi: 10.1038/labinvest.2009.27. Epub 2009 Mar 30.


When apoptosis is initiated by manganese (II) loading, hyperthermia or thapsigargin treatment, human HL-60 and AsPC-1 cells initiate de novo synthesis of the C5a receptor (C5aR) and generation of its ligand, the ribosomal protein S19 (RP S19) homodimer. The ligand-receptor interaction, in an autocrine/paracrine fashion, promotes apoptosis, which can be bypassed by exogenous administration of C5a, another ligand. The proapoptotic function of the RP S19 dimer is reproduced by a C5a/RPS19 chimera that contains the body of C5a and the C-terminal region (Ile134-His145) of RP S19. The RP S19 dimer or C5a/RPS19 and C5a inversely regulate the expression of Regulator of G protein Signaling 3 (RGS3) gene in the apoptosis-initiated cells. Namely, the RP S19-type proteins upregulate RGS3 expression, whereas the C5a reduce it. Transformation of HL-60 cells to overexpress RGS3 promotes apoptosis in association with the downregulation of the Extracellular signal-Regulated Kinase (ERK) signal, and vice versa in the RGS3 knocked-down cells. Consistent with this result, an inhibitor of ERK phosphorylation effectively enhances the apoptotic rate in wild-type HL-60 cells. Moreover, a dominant negative effect on the RP S19 dimer production encourages apoptosis-initiated HL-60 cells with a longer lifespan in mouse than the natural effect. Our data indicate that, in apoptosis-initiated cells, the ligand-dependent C5aR-mediated dual signal affects the fate of cells, either apoptosis execution or survival, through regulation of RGS3 gene expression and subsequent modulation of ERK signal.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis / physiology*
  • Cell Line, Tumor
  • Chemotaxis, Leukocyte
  • Extracellular Signal-Regulated MAP Kinases / physiology*
  • Female
  • GTP-Binding Proteins / physiology*
  • GTPase-Activating Proteins / physiology*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Molecular Sequence Data
  • Neoplasm Transplantation
  • Phosphorylation
  • Protein Binding
  • Protein Multimerization
  • RGS Proteins
  • Receptor, Anaphylatoxin C5a / agonists
  • Receptor, Anaphylatoxin C5a / physiology*
  • Ribosomal Proteins / metabolism
  • Signal Transduction / physiology*


  • GTPase-Activating Proteins
  • RGS Proteins
  • RGS3 protein, human
  • Receptor, Anaphylatoxin C5a
  • Ribosomal Proteins
  • ribosomal protein S19
  • Extracellular Signal-Regulated MAP Kinases
  • GTP-Binding Proteins