Tribbles pseudokinases: Fine tuning of cell signaling with implications in metabolism, inflammation and cancer.

Within the family of protein kinases there is a subgroup of 'evolutionarily related members of the total human kinome' that are devoid (or have very limited) enzymatic activity. These proteins, so-called pseudokinases, play important functions thanks to their capacity to establish regulatory protein-protein interactions. Specifically, this opinion article focuses on a group of pseudokinases called Tribbles. Tribbles (Trbl) was originally discovered in Drosophila, followed by the subsequent identification of their orthologs in mammals (TRIB1, TRIB2, TRIB3, and STK40). Work over the last decades has shown how these proteins contribute to fine-tuning key signaling pathways involved in the regulation of proliferation, differentiation, inflammation and adaptation to nutritional changes. Accordingly, dysregulation of Tribbles proteins (TRIBs) contributes to the establishment and progression of insulin resistance, obesity, type II diabetes, atherosclerosis and cancer. Here, we will discuss some of the mechanisms by which Tribbles pseudokinases carry out their functions and the crucial importance of cell context in defining the precise role played by each of the TRIBs, with emphasis on TRIB1 and TRIB3, under different physiopathological situations.