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RICK, a novel protein kinase containing a caspase recruitment domain, interacts with CLARP and regulates
N Inohara1, L del Peso, T Koseki
1Department of Pathology and Comprehensive Cancer Center, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Abstract:
Signaling through the CD95/Fas/APO-1 death receptor plays a critical role in the homeostasis of the immune system. RICK, a novel protein kinase that regulates CD95-mediated apoptosis was identified and characterized. RICK is composed of an N-terminal serine-threonine kinase catalytic domain and a C-terminal region containing a caspase-recruitment domain. RICK physically interacts with CLARP, a caspase-like molecule known to bind to Fas-associated protein with death domain (FADD) and caspase-8. Expression of RICK promoted the activation of caspase-8 and potentiated apoptosis induced by Fas ligand, FADD, CLARP, and caspase-8. Deletion mutant analysis revealed that both the kinase domain and caspase-recruitment domain were required for RICK to promote apoptosis. Significantly, expression of a RICK mutant in which the lysine of the putative ATP-binding site at position 38 was replaced by a methionine functioned as an inhibitor of CD95-mediated apoptosis. Thus, RICK represents a novel kinase that may regulate apoptosis induced by the CD95/Fas receptor pathway.
Insights
Researchers identified RICK, a novel protein kinase regulating CD95/Fas-mediated apoptosis. RICK
Area of Science:
- Molecular Biology
- Immunology
- Cell Death Research
Background:
- CD95/Fas/APO-1 death receptor signaling is crucial for immune system homeostasis.
- Dysregulation of apoptosis contributes to various diseases.
Purpose of the Study:
- To identify and characterize novel regulators of CD95/Fas-mediated apoptosis.
- To elucidate the role of the newly identified protein kinase, RICK, in apoptosis.
Main Methods:
- Protein expression and purification.
- Co-immunoprecipitation assays to study protein interactions.
- Caspase activity assays.
- Analysis of apoptosis induction using deletion mutants.
Main Results:
- RICK, a novel serine-threonine kinase with a caspase-recruitment domain, was identified.
- RICK physically interacts with CLARP, FADD, and caspase-8.
- RICK expression potentiates CD95/Fas-induced apoptosis.
- Both kinase and caspase-recruitment domains are essential for RICK's pro-apoptotic function.
- A catalytically inactive RICK mutant inhibits CD95/Fas-mediated apoptosis.
Conclusions:
- RICK is a novel kinase that positively regulates CD95/Fas-mediated apoptosis.
- RICK's kinase and caspase-recruitment domains are critical for its function.
- RICK represents a potential therapeutic target for modulating apoptosis in immune-related diseases.