TAK1 is recruited to the tumor necrosis factor-α (TNF-α) receptor 1 complex in a receptor-interacting protein (RIP)-dependent manner and cooperates with MEKK3 leading to NF-κB activation

Marzenna Blonska, Prashant B. Shambharkar, Masayuki Kobayashi, Dongyu Zhang, Hiroaki Sakurai, Bang Su, Xin Lin

Research output: Contribution to journalArticle

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Abstract

Receptor-interacting protein (RIP) plays a critical role in tumor necrosis factor-α (TNF-α)-induced IκB kinase (IKK) activation and subsequent activation of transcription factor NF-κB. However, the molecular mechanism by which RIP mediates TNF-α-induced NF-κB activation is not completely defined. In this study, we have found that TAK1 is recruited to the TNF-α receptor complex in a RIP-dependent manner following the stimulation of TNF-α receptor 1 (TNF-R1). Moreover, a forced recruitment of TAK1 to TNF-R1 in the absence of RIP is sufficient to mediate TNF-α-induced NF-κB activation, indicating that the major function of RIP is to recruit its downstream kinases to the TNF-R1 complex. Interestingly, we also find that TAK1 and MEKK3 form a functional complex, in which TAK1 regulates autophosphorylation of MEKK3. The TAK1-mediated regulation of MEKK3 phosphorylation is dependent on the kinase activity of TAK1. Although TAK1-MEKK3 interaction is not affected by overexpressed TAB1, TAB1 is required for TAK1 activation and subsequent MEKK3 phosphorylation. Together, we conclude that TAK1 is recruited to the TNF-R1 complex via RIP and likely cooperates with MEKK3 to activate NF-κB in TNF-α signaling.

Original languageEnglish (US)
Pages (from-to)43056-43063
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number52
DOIs
StatePublished - Dec 30 2005
Externally publishedYes

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Receptor-Interacting Protein Serine-Threonine Kinases
Tumor Necrosis Factor Receptors
Tumor Necrosis Factor-alpha
Chemical activation
Phosphorylation
Phosphotransferases
Transcription Factors

ASJC Scopus subject areas

  • Biochemistry

Cite this

TAK1 is recruited to the tumor necrosis factor-α (TNF-α) receptor 1 complex in a receptor-interacting protein (RIP)-dependent manner and cooperates with MEKK3 leading to NF-κB activation. / Blonska, Marzenna; Shambharkar, Prashant B.; Kobayashi, Masayuki; Zhang, Dongyu; Sakurai, Hiroaki; Su, Bang; Lin, Xin.

In: Journal of Biological Chemistry, Vol. 280, No. 52, 30.12.2005, p. 43056-43063.

Research output: Contribution to journalArticle

Blonska, Marzenna ; Shambharkar, Prashant B. ; Kobayashi, Masayuki ; Zhang, Dongyu ; Sakurai, Hiroaki ; Su, Bang ; Lin, Xin. / TAK1 is recruited to the tumor necrosis factor-α (TNF-α) receptor 1 complex in a receptor-interacting protein (RIP)-dependent manner and cooperates with MEKK3 leading to NF-κB activation. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 52. pp. 43056-43063.
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abstract = "Receptor-interacting protein (RIP) plays a critical role in tumor necrosis factor-α (TNF-α)-induced IκB kinase (IKK) activation and subsequent activation of transcription factor NF-κB. However, the molecular mechanism by which RIP mediates TNF-α-induced NF-κB activation is not completely defined. In this study, we have found that TAK1 is recruited to the TNF-α receptor complex in a RIP-dependent manner following the stimulation of TNF-α receptor 1 (TNF-R1). Moreover, a forced recruitment of TAK1 to TNF-R1 in the absence of RIP is sufficient to mediate TNF-α-induced NF-κB activation, indicating that the major function of RIP is to recruit its downstream kinases to the TNF-R1 complex. Interestingly, we also find that TAK1 and MEKK3 form a functional complex, in which TAK1 regulates autophosphorylation of MEKK3. The TAK1-mediated regulation of MEKK3 phosphorylation is dependent on the kinase activity of TAK1. Although TAK1-MEKK3 interaction is not affected by overexpressed TAB1, TAB1 is required for TAK1 activation and subsequent MEKK3 phosphorylation. Together, we conclude that TAK1 is recruited to the TNF-R1 complex via RIP and likely cooperates with MEKK3 to activate NF-κB in TNF-α signaling.",
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AU - Blonska, Marzenna

AU - Shambharkar, Prashant B.

AU - Kobayashi, Masayuki

AU - Zhang, Dongyu

AU - Sakurai, Hiroaki

AU - Su, Bang

AU - Lin, Xin

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