Nod2 is a member of the Nod1/Apaf-1 family, characterized by two N-terminal CARDs, a nucleotide-binding domain (NBD), and multiple C-terminal leucine-rich repeats (LRRs). Unlike Nod1 and Apaf-1, which are broadly expressed in tissues, Nod2 is highly restricted to monocytes. Nod2 activates NF-κB through interactions with the serine-threonine kinase RICK via a homophilic CARD-CARD interaction. This activation requires IKKγ and is inhibited by dominant negative mutants of IκBα, IKKα, IKKβ, and IKKγ. Nod2's ability to activate NF-κB correlates with its interaction with RICK, and a truncated RICK mutant containing its CARD specifically inhibits this activity. Nod2 defines a subfamily of Apaf-1-like proteins that function through RICK to activate the NF-κB signaling pathway. Nod2 activates NF-κB through its two CARDs, which are necessary and sufficient for this activity. Nod2 also induces apoptosis when overexpressed, but this effect is enhanced by caspase-9 expression. Nod2 activates NF-κB through the IKK complex, requiring IKKγ, and is inhibited by dominant negative forms of IKKs and RICK. Nod2 interacts with RICK via a homophilic CARD-CARD interaction, and this interaction is essential for NF-κB activation. Enforced oligomerization of Nod2 induces NF-κB activation, and this effect is enhanced by the presence of the LRRs. Nod2 is expressed primarily in monocytes and may serve as an intracellular receptor for bacterial lipopolysaccharides and other bacterial products, transducing signals that lead to NF-κB activation and transcription of regulatory genes. Nod2 and Nod1 share structural and functional similarities, and both activate NF-κB through interactions with RICK. The presence of two CARDs in Nod2 is unique and may enhance its ability to interact with RICK. The molecular basis for the requirement of both CARDs in Nod2 for RICK binding remains unclear, but the presence of both CARDs may enhance the affinity for the CARD of RICK. Nod2 and Nod1 are functional counterparts of plant R proteins, and their LRRs may recognize different sets of intracellular stimuli that mediate their oligomerization and association with RICK. Nod2 is expressed primarily in monocytes and may serve as an intracellular receptor for bacterial lipopolysaccharides and other bacterial products, transducing signals that lead to NF-κB activation and transcription of regulatory genes.Nod2 is a member of the Nod1/Apaf-1 family, characterized by two N-terminal CARDs, a nucleotide-binding domain (NBD), and multiple C-terminal leucine-rich repeats (LRRs). Unlike Nod1 and Apaf-1, which are broadly expressed in tissues, Nod2 is highly restricted to monocytes. Nod2 activates NF-κB through interactions with the serine-threonine kinase RICK via a homophilic CARD-CARD interaction. This activation requires IKKγ and is inhibited by dominant negative mutants of IκBα, IKKα, IKKβ, and IKKγ. Nod2's ability to activate NF-κB correlates with its interaction with RICK, and a truncated RICK mutant containing its CARD specifically inhibits this activity. Nod2 defines a subfamily of Apaf-1-like proteins that function through RICK to activate the NF-κB signaling pathway. Nod2 activates NF-κB through its two CARDs, which are necessary and sufficient for this activity. Nod2 also induces apoptosis when overexpressed, but this effect is enhanced by caspase-9 expression. Nod2 activates NF-κB through the IKK complex, requiring IKKγ, and is inhibited by dominant negative forms of IKKs and RICK. Nod2 interacts with RICK via a homophilic CARD-CARD interaction, and this interaction is essential for NF-κB activation. Enforced oligomerization of Nod2 induces NF-κB activation, and this effect is enhanced by the presence of the LRRs. Nod2 is expressed primarily in monocytes and may serve as an intracellular receptor for bacterial lipopolysaccharides and other bacterial products, transducing signals that lead to NF-κB activation and transcription of regulatory genes. Nod2 and Nod1 share structural and functional similarities, and both activate NF-κB through interactions with RICK. The presence of two CARDs in Nod2 is unique and may enhance its ability to interact with RICK. The molecular basis for the requirement of both CARDs in Nod2 for RICK binding remains unclear, but the presence of both CARDs may enhance the affinity for the CARD of RICK. Nod2 and Nod1 are functional counterparts of plant R proteins, and their LRRs may recognize different sets of intracellular stimuli that mediate their oligomerization and association with RICK. Nod2 is expressed primarily in monocytes and may serve as an intracellular receptor for bacterial lipopolysaccharides and other bacterial products, transducing signals that lead to NF-κB activation and transcription of regulatory genes.