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RIP3, a novel apoptosis-inducing kinase
1Departments of Molecular Oncology, Genentech, Inc., South San Francisco, California 94080, USA.
The Journal of Biological Chemistry
|June 8, 1999
Summary
Receptor-interacting protein 3 (RIP3) binds RIP and inhibits TNF-induced NF-kappaB activation. RIP3 also potently induces apoptosis by binding initiator caspases.
Area of Science:
- Molecular biology
- Cell signaling
- Apoptosis research
Background:
- Receptor-interacting protein (RIP) and RIP2 are known signaling molecules.
- RIP has a C-terminal death domain, while RIP2 has a caspase activation and recruitment domain.
- RIP3 possesses a unique C-terminal domain distinct from RIP and RIP2.
Purpose of the Study:
- To characterize the novel gene product RIP3.
- To investigate RIP3's interaction with RIP and its role in tumor necrosis factor (TNF) signaling.
- To determine RIP3's function in apoptosis and NF-kappaB activation.
Main Methods:
- Homology analysis of kinase domains.
- Interaction studies between RIP3 and RIP.
- Analysis of RIP3's effect on TNF receptor-1 signaling complex.
- Overexpression studies to assess apoptosis induction and caspase binding.
Main Results:
- RIP3 shares homology with RIP and RIP2 but has a unique C terminus.
- RIP3 binds to RIP via its C-terminal segment and is recruited to the TNF receptor-1 complex.
- RIP3 attenuates RIP and TNF receptor-1-induced NF-kappaB activation.
- RIP3 overexpression potently induces apoptosis and binds large prodomain initiator caspases.
Conclusions:
- RIP3 is a novel regulator of TNF signaling and apoptosis.
- RIP3 acts as an inhibitor of NF-kappaB activation.
- RIP3's unique C terminus is crucial for its function in apoptosis induction.