Musings from the Tribbles Research and Innovation Network

SIMPLE SUMMARY: The Tribbles Research and Innovation Network (TRAIN) was developed in the context of the medical need to understand the contribution that Tribbles (TRIB) proteins make in regulating processes governing the physiological functioning of macrophages and other immune cells, adipocytes and prostate epithelial cells in immuno-metabolic disease (such as obesity) and several cancers. To summarize, TRAIN provided a cohort of PhD students with a unique opportunity to undertake multidisciplinary research aimed at uncovering the cell-specific mechanisms by which TRIBs exert control over immuno-metabolism and impact on prostate cancer progression. The associated training programme was enhanced by contributions from the TRIB community. This review highlights the science that motivated the establishment of TRAIN, including the discovery of how the TRIB1 protein enables the marking of the transcription factor C/EBPα for degradation, and regulatory mechanisms underlying cell-specific TRIB expression. It briefly reflects on the type of TRAIN-associated tools developed for future TRIB research. ABSTRACT: This commentary integrates historical and modern findings that underpin our understanding of the cell-specific functions of the Tribbles (TRIB) proteins that bear on tumorigenesis. We touch on the initial discovery of roles played by mammalian TRIB proteins in a diverse range of cell-types and pathologies, for example, TRIB1 in regulatory T-cells, TRIB2 in acute myeloid leukaemia and TRIB3 in gliomas; the origins and diversity of TRIB1 transcripts; microRNA-mediated (miRNA) regulation of TRIB1 transcript decay and translation; the substantial conformational changes that ensue on binding of TRIB1 to the transcription factor C/EBPα; and the unique pocket formed by TRIB1 to sequester its C-terminal motif bearing a binding site for the E3 ubiquitin ligase COP1. Unashamedly, the narrative is relayed through the perspective of the Tribbles Research and Innovation Network, and its establishment, progress and future ambitions: the growth of TRIB and COP1 research to hasten discovery of their cell-specific contributions to health and obesity-related cancers.