The epidermal growth factor receptor engages receptor interacting protein and nuclear factor-κB (NF-κB)-inducing kinase to activate NF-κB: Identification of a novel receptor-tyrosine kinase signalosome Academic Article uri icon

Overview

MeSH Major

  • I-kappa B Proteins
  • NF-kappa B
  • Protein-Serine-Threonine Kinases
  • Proteins
  • Receptor, Epidermal Growth Factor

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 date

  • March 23, 2001

Research

keywords

  • Academic Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1074/jbc.M008458200

PubMed ID

  • 11116146

Additional Document Info

start page

  • 8865

end page

  • 74

volume

  • 276

number

  • 12