Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease. Issue 4 (April 2017) - Eyers, Patrick A.
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. Trends: Pseudoenzymes are inactive counterparts of classical enzymes and have evolved in all kingdoms of life, where they regulate a vast array of biological processes. The pseudokinases are one of the best-studied families of human pseudoenzymes. Eukaryotic TRIB pseudokinases evolved from a common ancestor (the human TRIB2 homolog), and contain a highly atypical pseudokinase domain fused to a unique docking site in an extended C tail that binds to ubiquitin E3 ligases. TRIB evolution has led to the appearance of three mammalian TRIB pseudokinases, termed TRIB1, TRIB2, and TRIB3, which contain both unique and shared features. In cells, TRIB pseudokinases act as modulators of substrate ubiquitination and as molecular scaffolds for the assembly and regulation of signaling modules, including the C/EBPα transcription factor and AKT and ERK networks. TRIB1 and TRIB2 have potent oncogenic activities in vertebrate cells, and recent evidence also suggests that TRIB2 acts as a tumour suppressor, consistent with the requirement for balanced TRIB signaling in the regulation of transcription, differentiation, proliferation, and apoptosis.