Tumor Necrosis Factor Receptor-Associated Factor 6 (TRAF6) Stimulates Extracellular Signal-Regulated Kinase (ERK) Activity in CD40 Signaling Along a Ras-Independent Pathway

J Exp Med. 1998 Jan 19;187(2):237-44. doi: 10.1084/jem.187.2.237.

Abstract

CD40 activates nuclear factor kappa B (NF kappa B) and the mitogen-activated protein kinase (MAPK) subfamily, including extracellular signal-regulated kinase (ERK). The CD40 cytoplasmic tail interacts with tumor necrosis factor receptor-associated factor (TRAF)2, TRAF3, TRAF5, and TRAF6. These TRAF proteins, with the exception of TRAF3, are required for NF kappa B activation. Here we report that transient expression of TRAF6 stimulated both ERK and NF kappa B activity in the 293 cell line. Coexpression of the dominant-negative H-Ras did not affect TRAF6-mediated ERK activity, suggesting that TRAF6 may activate ERK along a Ras-independent pathway. The deletion mutant of TRAF6 lacking the NH2-terminal domain acted as a dominant-negative mutant to suppress ERK activation by full-length CD40 and suppress prominently ERK activation by a deletion mutant of CD40 only containing the binding site for TRAF6 in the cytoplasmic tail (CD40 delta 246). Transient expression of the dominant-negative H-Ras significantly suppressed ERK activation by full-length CD40, but marginally suppressed ERK activation by CD40 delta 246, compatible with the possibility that TRAF6 is a major transducer of ERK activation by CD40 delta 246, whose activity is mediated by a Ras-independent pathway. These results suggest that CD40 activates ERK by both a Ras-dependent pathway and a Ras-independent pathway in which TRAF6 could be involved.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD40 Antigens / physiology*
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Carrier Proteins / immunology
  • Carrier Proteins / physiology*
  • Cell Line
  • Enzyme Activation / drug effects
  • Enzyme Activation / immunology
  • Humans
  • Kidney
  • NF-kappa B / drug effects
  • NF-kappa B / metabolism
  • Proteins*
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Receptors, Tumor Necrosis Factor / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / immunology*
  • TNF Receptor-Associated Factor 6
  • ras Proteins / immunology
  • ras Proteins / physiology*

Substances

  • CD40 Antigens
  • Carrier Proteins
  • NF-kappa B
  • Proteins
  • Receptors, Tumor Necrosis Factor
  • TNF Receptor-Associated Factor 6
  • Calcium-Calmodulin-Dependent Protein Kinases
  • ras Proteins