Competition between members of the tribbles pseudokinase protein family shapes their interactions with mitogen activated protein kinase pathways

Abstract

Spatio-temporal regulation of intracellular signalling networks is key to normal cellular physiology; dysregulation of which leads to disease. The family of three mammalian tribbles proteins has emerged as an important controller of signalling via regulating the activity of mitogen activated protein kinases (MAPK), the PI3-kinase induced signalling network and E3 ubiquitin ligases. However, the importance of potential redundancy in the action of tribbles and how the differences in affinities for the various binding partners may influence signalling control is currently unclear. We report that tribbles proteins can bind to an overlapping set of MAPK-kinases (MAPKK) in live cells and dictate the localisation of the complexes. Binding studies in transfected cells reveal common regulatory mechanisms and suggest that tribbles and MAPKs may interact with MAPKKs in a competitive manner. Computational modelling of the impact of tribbles on MAPK activation suggests a high sensitivity of this system to changes in tribbles levels, highlighting that these proteins are ideally placed to control the dynamics and balance of activation of concurrent signalling pathways.

Myeloid Tribbles 1 induces early atherosclerosis via enhanced foam cell expansion

“…Our data also show that by doubling m Trib1 expression, we removed the requirement for an external stimulus to up-regulate OLR1 expression and the consequent clinical sequelae. The phenotype observed in response to this rise in m Trib1 expression fits well with earlier computational modeling studies that indicated that relatively modest changes in TRIB1 would have a major impact on the activity of mitogen-activated protein kinase pathways; thus, defining the concentration of these proteins is critical for shaping cell function ( 31 ).…”

Hsa-miR-99b/let-7e/miR-125a Cluster Regulates Pathogen Recognition Receptor-Stimulated Suppressive Antigen-Presenting Cells

“…The pseudokinase TRIB2 acts as scaffold protein and mediates ubiquitination of substrates ( 27 ). Thereby TRIB2 negatively regulates MAPkinase signaling ( 31 ), the cascade that is a hallmark of R848-stimulated APCs. The qRT PCR analyses in Figure 3 A show that TRIB2 is significantly downregulated in R848-stimulated APCs and the Western blot data (Figure 3 B) confirm that result on protein level.…”

Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease

“…The TRIB C-terminal tail is defined by two unique sequences: the HPW[F/L] and DQXVP[D/E] motifs near the extreme N and C-terminal regions of the C-tail, respectively (Figure 4A). The HPW[F/L] motif is involved in binding of MEK1 (and other MAPKK dual-specificity kinases) 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]. Although these motifs are not observed in the C-terminal tail of other protein kinases, they are predicted to engage with the TRIB pseudokinase domains in a manner analogous to canonical, well-studied protein kinases, such as PKA and MAP kinases, which utilize these flanking regions to drive regulatory mechanisms involved in kinase activation and substrate phosphorylation (Figure 4B).…”