Abstract
Proteins containing a caspase recruitment domain (CARD) play pivotal roles in signal transduction leading to apoptosis and NF-kappaB activation and inflammation. Here we identify and characterize human and mouse CARD protein 6 (CARD6), CARD-containing proteins of unique structure. CARD6 associates with microtubules and interacts with receptor-interacting protein (RIP)-like interacting caspase-like apoptosis regulatory protein kinase (RICK), a CARD-containing member of the RIP family of protein kinases. These kinases are involved in multiple NF-kappaB signaling pathways important for innate and adaptive immune responses. Surprisingly, the CARDs of CARD6 and RICK were not required for their interaction; instead, mutational analysis revealed that the CARD of CARD6 negatively controls the association of these molecules. CARD6 also binds to RIP1, a RIP kinase homologue that lacks a CARD but contains a C-terminal death domain. Coexpression of RICK targets CARD6 to aggresomes via a mechanism that requires the CARD of RICK. Importantly, CARD6 expression has a synergistic effect on NF-kappaB activation induced by several independent signal transduction pathways. In summary, our results indicate that CARD6 is a regulator of NF-kappaB activation that modulates the functions of RIP kinase family members.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Adaptor Proteins, Signal Transducing / physiology*
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Animals
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Apoptosis
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Blotting, Northern
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CARD Signaling Adaptor Proteins
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COS Cells
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Cell Line
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Chlorocebus aethiops
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Humans
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Immunohistochemistry
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Immunoprecipitation
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Luciferases / metabolism
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Mice
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Microtubules / metabolism*
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Mutation
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NF-kappa B / metabolism*
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Nuclear Pore Complex Proteins / metabolism
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Protein Binding
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Protein Conformation
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Protein Serine-Threonine Kinases / metabolism
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Protein Structure, Tertiary
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RNA Interference
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RNA, Small Interfering / metabolism
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RNA-Binding Proteins / metabolism
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Receptor-Interacting Protein Serine-Threonine Kinase 2
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Receptor-Interacting Protein Serine-Threonine Kinases
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Time Factors
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Transfection
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Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / metabolism
Substances
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AGFG1 protein, human
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Adaptor Proteins, Signal Transducing
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CARD Signaling Adaptor Proteins
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CARD6 protein, human
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NF-kappa B
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Nuclear Pore Complex Proteins
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RNA, Small Interfering
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RNA-Binding Proteins
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Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
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Luciferases
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Protein Serine-Threonine Kinases
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RIPK2 protein, human
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Receptor-Interacting Protein Serine-Threonine Kinase 2
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Receptor-Interacting Protein Serine-Threonine Kinases
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Ripk2 protein, mouse