Abstract
The Tribbles (TRIB) pseudokinases control multiple aspects of eukaryotic cell biology and evolved unique features distinguishing them from all other protein kinases. The atypical pseudokinase domain retains a regulated binding platform for substrates, which are ubiquitinated by context-specific E3 ligases. This plastic configuration has also been exploited as a scaffold to support the modulation of canonical MAPK and AKT modules. In this review, we discuss the evolution of TRIBs and their roles in vertebrate cell biology. TRIB2 is the most ancestral member of the family, whereas the emergence of TRIB3 homologs in mammals supports additional biological roles, many of which are currently being dissected. Given their pleiotropic role in diseases, the unusual TRIB pseudokinase conformation provides a highly attractive opportunity for drug design.
Highlights
Introduction and Historical PerspectiveProtein kinases and phosphorylation modulate all aspects of eukaryotic cell biology and, together with members of the Ubiquitin system, have become highly significant for mechanistic drug targeting [1]
The HPW[F/L] motif is involved in binding of MEK1 to TRIB pseudokinases [46,47,48], whereas the DQXVP[D/E] motif is intimately involved in COP1 binding in all TRIB proteins [49,50] and required to drive tumorigenesis in leukemia models [51]
TRIB2 is cyclically expressed during the cell cycle and has the ability to promote the proteasomal degradation of the mitotic regulator CDC25C, which might explain some of the uncontrolled proliferation characteristics of leukemia [25]
Summary
Three distinct TRIB pseudokinase polypeptides evolved in human cells and how they mechanistically support diverse regulatory and disease-associated signaling pathways (Figure 1). An analysis of these issues represents a central focus of this review. To address major knowledge gaps in how the functional specialization of TRIB genes occurred during evolution, we identified and classified TRIB-related sequences from all the major taxonomic groups where they are present (Figure 2) Taxonomic analysis of these sequences demonstrates that they are almost entirely confined to the animal kingdom, and are absent in non-metazoan eukaryote kinomes, including those annotated in fungi, plants, and choanoflagellates. The TRIB3-specific sequence signature appears in all mammalian lineages, and from the extensive data analyzed
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