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

Amyn A. Habib, Sukalyan Chatterjee, Song Kyu Park, Rajiv R. Ratan, Sharon Lefebvre, Timothy Vartanian

Research output: Contribution to journalArticle

103 Citations (Scopus)

Abstract

The transcription factor nuclear factor-κB (NF-κB) is activated by a diverse number of stimuli including tumor necrosis factor-α, interleukin-1, UV irradiation, viruses, as well as receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR). NF-κB 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-κB, 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-κB 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-κB 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-κB-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-κB induction. We also show that a S32/36 IκB mutant blocks EGFR-induced NF-κB 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-κB activation. Finally, although protein kinase B/Akt has been implicated in tumor necrosis factor and PDGF-induced NF-κB activation, our studies do not support a role for this protein in EGFR-induced NF-κB activation.

Original languageEnglish (US)
Pages (from-to)8865-8874
Number of pages10
JournalJournal of Biological Chemistry
Volume276
Issue number12
DOIs
StatePublished - Mar 23 2001

Fingerprint

Receptor-Interacting Protein Serine-Threonine Kinases
Receptor Protein-Tyrosine Kinases
Epidermal Growth Factor Receptor
Phosphotransferases
Chemical activation
Tumor Necrosis Factor Receptors
Multiprotein Complexes
TNF Receptor-Associated Death Domain Protein
Tumor Necrosis Factor-alpha
Virus Receptors
Proto-Oncogene Proteins c-akt
Interleukin-1
Epidermal Growth Factor
Protein-Tyrosine Kinases
Tumors
Proteins
Transcription Factors

ASJC Scopus subject areas

  • Biochemistry

Cite this

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. / Habib, Amyn A.; Chatterjee, Sukalyan; Park, Song Kyu; Ratan, Rajiv R.; Lefebvre, Sharon; Vartanian, Timothy.

In: Journal of Biological Chemistry, Vol. 276, No. 12, 23.03.2001, p. 8865-8874.

Research output: Contribution to journalArticle

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abstract = "The transcription factor nuclear factor-κB (NF-κB) is activated by a diverse number of stimuli including tumor necrosis factor-α, interleukin-1, UV irradiation, viruses, as well as receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR). NF-κB 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-κB, 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-κB 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-κB 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-κB-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-κB induction. We also show that a S32/36 IκB mutant blocks EGFR-induced NF-κB 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-κB activation. Finally, although protein kinase B/Akt has been implicated in tumor necrosis factor and PDGF-induced NF-κB activation, our studies do not support a role for this protein in EGFR-induced NF-κB activation.",
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