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MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1
N L Malinin1, M P Boldin, A V Kovalenko
1Department of Membrane Research and Biophysics, The Weizmann Institute of Science, Rehovot, Israel.
Abstract:
Several members of the tumour-necrosis/nerve-growth factor (TNF/NGF) receptor family activate the transcription factor NF-kappaB through a common adaptor protein, Traf2 (refs 1-5), whereas the interleukin 1 type-I receptor activates NF-kappaB independently of Traf2 (ref. 4). We have now cloned a new protein kinase, NIK, which binds to Traf2 and stimulates NF-kappaB activity. This kinase shares sequence similarity with several MAPKK kinases. Expression in cells of kinase-deficient NIK mutants fails to stimulate NF-kappaB and blocks its induction by TNF, by either of the two TNF receptors or by the receptor CD95 (Fas/Apo-1), and by TRADD, RIP and MORT1/FADD, which are adaptor proteins that bind to these receptors. It also blocked NF-kappaB induction by interleukin-1. Our findings indicate that NIK participates in an NF-kappaB-inducing signalling cascade common to receptors of the TNF/NGF family and to the interleukin-1 type-I receptor.
Insights
A new protein kinase, NIK, binds to Traf2 and stimulates NF-kappaB. Kinase-deficient NIK mutants block NF-kappaB induction by TNF and IL-1 receptors, indicating NIK
Area of Science:
- Cellular signaling pathways
- Molecular biology
- Immunology
Background:
- Tumor necrosis factor (TNF)/nerve growth factor (NGF) receptors activate NF-kappaB via Traf2.
- Interleukin-1 type-I receptor activates NF-kappaB independently of Traf2.
Purpose of the Study:
- To identify novel proteins involved in NF-kappaB activation.
- To elucidate the signaling cascade for NF-kappaB induction by TNF/NGF receptors and IL-1 receptor.
Main Methods:
- Cloning of a novel protein kinase, NIK.
- Expression of kinase-deficient NIK mutants in cells.
- Assessment of NF-kappaB activity induction by various receptors and adaptor proteins.
Main Results:
- NIK binds to Traf2 and stimulates NF-kappaB activity.
- Kinase-deficient NIK mutants inhibit NF-kappaB induction by TNF/NGF receptors, CD95, TRADD, RIP, and MORT1/FADD.
- NIK also blocks NF-kappaB induction by interleukin-1.
Conclusions:
- NIK is a key component in the NF-kappaB-inducing signaling cascade.
- This cascade is common to both TNF/NGF receptor family and the interleukin-1 type-I receptor.