The epidermal growth factor receptor engages receptor interacting protein and nuclear factor-kappa B (NF-kappa B)-inducing kinase to activate NF-kappa B. Identification of a novel receptor-tyrosine kinase signalosome

J Biol Chem. 2001 Mar 23;276(12):8865-74. doi: 10.1074/jbc.M008458200. Epub 2000 Dec 14.

Abstract

The transcription factor nuclear factor-kappaB (NF-kappaB) is activated by a diverse number of stimuli including tumor necrosis factor-alpha, interleukin-1, UV irradiation, viruses, as well as receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR). NF-kappaB activation by the tumor necrosis factor receptor (TNFR) involves the formation of a multiprotein complex termed a signalosome. Although previous studies have shown that the activated EGFR can induce NF-kappaB, the mechanism of this activation remains unknown. In this study, we identify components of the signalosome formed by the activated EGFR required to activate NF-kappaB and show that, although the activated EGFR uses mechanisms similar to the TNFR, it recruits a distinct signalosome. We show the EGFR forms a complex with a TNFR-interacting protein (RIP), which plays a key role in TNFR-induced NF-kappaB activation, but not with TRADD, an adaptor protein which serves to recruit RIP to the TNFR. Furthermore, we show that the EGFR associates with NF-kappaB-inducing kinase (NIK) and provide evidence suggesting multiprotein complex formation between the EGFR, RIP, and NIK. Using a dominant negative NIK mutant, we show that NIK activation is required for EGFR-mediated NF-kappaB induction. We also show that a S32/36 IkappaBalpha mutant blocks EGFR-induced NF-kappaB activation. Our studies also suggest that a high level of EGFR expression, a frequent occurrence in human tumors, is optimal for epidermal growth factor-induced NF-kappaB activation. Finally, although protein kinase B/Akt has been implicated in tumor necrosis factor and PDGF-induced NF-kappaB activation, our studies do not support a role for this protein in EGFR-induced NF-kappaB activation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Cell Line
  • DNA Primers
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism
  • ErbB Receptors / physiology*
  • Humans
  • I-kappa B Proteins*
  • Mutation
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Protein Binding
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • Proteins / metabolism
  • Proteins / physiology*
  • Receptor-Interacting Protein Serine-Threonine Kinases

Substances

  • DNA Primers
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Proteins
  • NF-KappaB Inhibitor alpha
  • ErbB Receptors
  • Protein-Serine-Threonine Kinases
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • NF-kappa B kinase