Genetic studies in Drosophila identified deltex as a positive regulator of Notch signaling, while the Drosophila homologue of ITCH (AIP4) was identified as a negative regulator of Notch signaling and named suppressor of deltex. ITCH and DTX1 interact and form a complex, as determined by co-immunoprecipitaion experiments in human embryonic kidney cell line HEK293 in which tagged recombinant human DTX1 and ITCH were expressed. It is not known whether this complex involves other proteins, but its formation is NOTCH-independent. Both DTX1 and ITCH are ubiquitin ligases. DTX1 is a RING-type ubiquitin ligase, while ITCH is a HECT-type ubiquitin ligase. The ubiquitin ligase activity of either protein is not needed for the formation of the DTX1:ITCH complex, and the inactive ITCH mutant co-immunoprecipitates more DTX1 than the wild-type ITCH, implicating the ubiquitin ligase activity of ITCH in DTX1 degradation.