Neuroepithelial Transforming Gene 1 (Net1) Binds to Caspase Activation and Recruitment Domain (CARD)- and Membrane-associated Guanylate Kinase-like Domain-containing (CARMA) Proteins and Regulates Nuclear Factor kappaB Activation.

The molecular complexes containing CARMA proteins have been recently identified as a key components in the signal transduction pathways that regulate activation of nuclear factor kappaB (NF-kappaB) transcription factor. Here, we used immunoprecipitation coupled with mass spectrometry to identify cellular binding partners of CARMA proteins. Our data indicate that the Rho guanine nucleotide exchange factor Net1 binds to CARMA1 and CARMA3 in resting and activated cells. Net1 expression induces NF-kappaB activation and cooperates with BCL10 and CARMA proteins in inducing NF-kappaB activity. Conversely, shRNA-mediated abrogation of Net1 results in impaired NF-kappaB activation following stimuli that require correct CARMA-BCL10-MALT1 complex formation and functioning. Microarray expression data are consistent with a positive role for Net1 on NF-kappaB activation. Thus, this study identifies Net1 as a CARMA-interacting molecule and brings important information on the molecular mechanisms that control NF-kappaB transcriptional activity.