Activation of ERK1/2 and cPLA(2) by the p55 TNF receptor occurs independently of FAN

Biochem Biophys Res Commun. 2000 Aug 2;274(2):506-12. doi: 10.1006/bbrc.2000.3173.

Abstract

The generation of proinflammatory eicosanoids in response to tumor necrosis factor (TNF) involves the activation of cytosolic phospholipase A(2) (cPLA(2)), presumably by phosphorylation through extracellular signal-regulated kinases (ERK). Earlier results had suggested that a pathway involving the p55 TNF receptor (TNF-R55), neutral sphingomyelinase (N-SMase), and c-Raf-1 activates ERK and cPLA(2). We have previously shown that a cytoplasmic region of TNF-R55 distinct from the death domain regulates the activation of N-SMase through binding of the adapter protein FAN. Analysis of embryonal fibroblasts from FAN knockout mice revealed that TNF-induced activation of both ERK and cPLA(2) occurs without involvement of FAN. Furthermore, we provide evidence that the TNF-dependent activation of ERK and cPLA(2) requires the intact death domain of TNF-R55. Finally, we demonstrate that in murine fibroblasts cPLA(2) is phosphorylated in response to TNF solely by ERK, but not by p38 mitogen-activated protein kinase, suggesting a signaling pathway from TNF-R55 via the death domain to ERK and cPLA(2).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Arachidonic Acid / biosynthesis
  • B-Lymphocytes / cytology
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / metabolism
  • Cells, Cultured
  • Cytoplasm / metabolism
  • Drug Synergism
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / enzymology*
  • Intracellular Signaling Peptides and Proteins
  • Ionophores / pharmacology
  • MAP Kinase Kinase Kinase 1*
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phospholipases A / metabolism*
  • Phosphorylation / drug effects
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Structure, Tertiary / genetics
  • Proteins / genetics
  • Proteins / metabolism
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Receptors, Tumor Necrosis Factor, Type I
  • Sequence Deletion
  • Signal Transduction / drug effects
  • Sphingomyelin Phosphodiesterase / metabolism
  • Tetradecanoylphorbol Acetate / pharmacology
  • Tumor Necrosis Factor-alpha / pharmacology
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Antigens, CD
  • Intracellular Signaling Peptides and Proteins
  • Ionophores
  • Nsmaf protein, mouse
  • Proteins
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha
  • Arachidonic Acid
  • Protein Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human
  • Map3k1 protein, mouse
  • Phospholipases A
  • Sphingomyelin Phosphodiesterase
  • Tetradecanoylphorbol Acetate