Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB.
Apaf-1 and Nod1 are members of a protein family, each of which contains a caspase recruitment domain (CARD) linked to a nucleotide-binding domain, which regulate apoptosis and/or NF-kappaB activation. Nod2, a third member of the family, was identified. Nod2 is composed of two N-terminal CARDs, a nucleotide-binding domain, and multiple C-terminal leucine-rich repeats. Although Nod1 and Apaf-1 were broadly expressed in tissues, the expression of Nod2 was highly restricted to monocytes. Nod2 induced nuclear factor kappaB (NF-kappaB) activation, which required IKKgamma and was inhibited by dominant negative mutants of IkappaBalpha, IKKalpha, IKKbeta, and IKKgamma. Nod2 interacted with the serine-threonine kinase RICK via a homophilic CARD-CARD interaction. Furthermore, NF-kappaB activity induced by Nod2 correlated with its ability to interact with RICK and was specifically inhibited by a truncated mutant form of RICK containing its CARD. The identification of Nod2 defines a subfamily of Apaf-1-like proteins that function through RICK to activate a NF-kappaB signaling pathway.
Ogura
Y
Y
Department of Pathology and Comprehensive Cancer Center, the University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Inohara
N
N
Benito
A
A
Chen
F F
FF
Yamaoka
S
S
Nunez
G
G
D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D053477:Apoptotic Protease-Activating Factor 1; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D002460:Cell Line; D002885:Chromosomes, Human, Pair 16; D019281:Dimerization; D006801:Humans; D051550:I-kappa B Kinase; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism*; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D017386:Sequence Homology, Amino Acid
C506592:APAF1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D053477:Apoptotic Protease-Activating Factor 1; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C119067:NOD1 protein, human; C429018:NOD2 protein, human; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D011506:Proteins; D012333:RNA, Messenger; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human