A long-standing focus on our group has been the role of MALT1 and the CBM (CARD-CC/BCL10/MALT1) signaling complex. The CARD-CC family proteins consists of CARD9, -10, -11 and -14 in jawed vertebrates. The CARD-CC proteins represent the apical component in the CBM signaling complexes and most of the regulation of the CBM complex signaling is at the level of the CARD-CC protein. The four CARD-CC proteins split early in the vertebrate evolution and have evolved in parallel for at least 500 million years. Using chimeric proteins, we have established that conserved domains are interchangeable and that the intramolecular autoinhibition is conserved. This also enabled us to translate gain-of-function (GOF) mutations from CARD11 and CARD14 to CARD9 and CARD10. We now aim to do deep mutational screening (DMS) in all 4 CARD-CC proteins to get a complete catalog of GOF, LOF, hypermorphic and hypomorphic mutations. Comparisons across the CARD-CC family will provide further validation.