The DTX Protein Family: An Emerging Set of E3 Ubiquitin Ligases in Cancer

Abstract

Until recently, Deltex (DTX) proteins have been considered putative E3 ligases, based on the presence of an E3 RING domain in their protein coding sequence. The human DTX family includes DTX1, DTX2, DTX3, DTX3L and DTX4. Despite the fact that our knowledge of this class of E3-ubiquitin ligases is still at an early stage, our understanding of their role in oncogenesis is beginning to unfold. In fact, recently published studies allow us to define specific biological scenarios and further consolidate evidence-based working hypotheses. According to the current evidence, all DTX family members are involved in the regulation of Notch signaling, suggesting a phylogenetically conserved role in the regulation of this pathway. Indeed, additional evidence reveals a wider involvement of these proteins in other signaling complexes and cancer-promoting mechanisms beyond NOTCH signaling. DTX3, in particular, had been known to express two isoform variants (DTX3a and DTX3b). The recent identification and cloning of a third isoform variant in cancer (DTX3c), and its specific involvement in EphB4 degradation in cancer cells, sheds further light on this group of proteins and their specific role in cancer. Herein, we review the cumulative knowledge of this family of E3 Ubiquitin ligases with a specific focus on the potential oncogenic role of DTX isoforms in light of the rapidly expanding findings regarding this protein family's cellular targets and regulated signaling pathways. Furthermore, using a comparative and bioinformatic approach, we here disclose a new putative motif of a member of this family which may help in understanding the biological and contextual differences between the members of these proteins.

Keywords: DTC, Deltex C-terminal (region); Degron; Deltex, DTX; H2-RING, synonym of C3H2C3-RING; HC-RING, synonym of C3HC4-RING; RING, really interesting new gene (motifs); RNF, Ring Finger (domain); UbE3L, Ubiquitin E3 Ligase; pDegron, Phospho-Degron; piDegron, Phospho-inhibited Degron.

Figure 1

The Drosophila and human DTX protein domain structure. WWE, WWE tandem domains; DTX3-NTa, DTX3a N-Terminal variant (isoform 1); DTX3-NTb, DTX3b N-Terminal variant (isoform 2), D, D-Domain; H2-RING, canonical Ring finger motif (H2)-containing domain; HC-RING, C3HC4 finger motif-containing domain; DTC, Deltex C-Terminal Domain. DTX3c N-Terminal domain retains both 1a and 1b exons to generate a new isoform (isoform 3) with N-terminus 3D unique distribution differing from the canonical DTX3a and DTX3b isoforms.

Figure 2

Sequence comparison and consensus (bold) of the RING motifs in DTX proteins. Bolded sequences, consensus sequence within each RING category, red letters under the asterisk indicate consensus residues shared among all DTX proteins RING motifs; black asterisks are the conserved C residues concurring to the Ring domain numbering; red asterisks correspond to positions in the RING domain alignment supporting the H2 versus HC RING acronym.

Figure 3

DTX3 isoforms N-terminal domain (N-terminal 100aa) predicted tridimensional structure. The structures projections shown on the left were selected to display the different N-terminal end orientation of DTX3c (in the red dotted circle) compared to isoforms a and b. The diagram on the right displays different projections of the DTX3 isoform Nt-100 structures shown on the left corresponding to the computational nodes (in the center) calculated out of 40,000 potential conformations (adapted from Scalia et al. 2023 [8]). The functional implications of DTX3c unique N-terminal spatial configuration are discussed in the text.