Abstract
Simple SummaryTribbles pseudokinases represent a sub-branch of the CAMK (Ca2+/calmodulin-dependent protein kinase) subfamily and are associated with disease-associated signaling pathways associated with various cancers, including melanoma, lung, liver, and acute leukemia. The ability of this class of molecules to regulate cell proliferation was first recognized in the model organism Drosophila and the fruit fly genetic model and continues to provide insight into the molecular mechanism by which this family of adapter molecules regulates both normal development and disease associated with corruption of their proper regulation and function.The Tribbles (Trib) family of pseudokinase proteins regulate cell growth, proliferation, and differentiation during normal development and in response to environmental stress. Mutations in human Trib isoforms (Trib1, 2, and 3) have been associated with metabolic disease and linked to leukemia and the formation of solid tumors, including melanomas, hepatomas, and lung cancers. Drosophila Tribbles (Trbl) was the first identified member of this sub-family of pseudokinases and shares a conserved structure and similar functions to bind and direct the degradation of key mediators of cell growth and proliferation. Common Trib targets include Akt kinase (also known as protein kinase B), C/EBP (CAAT/enhancer binding protein) transcription factors, and Cdc25 phosphatases, leading to the notion that Trib family members stand athwart multiple pathways modulating their growth-promoting activities. Recent work using the Drosophila model has provided important insights into novel facets of conserved Tribbles functions in stem cell quiescence, tissue regeneration, metabolism connected to insulin signaling, and tumor formation linked to the Hippo signaling pathway. Here we highlight some of these recent studies and discuss their implications for understanding the complex roles Tribs play in cancers and disease pathologies.
Highlights
The Tribbles (Trib) family of pseudokinase proteins regulate cell growth, proliferation, and differentiation during normal development and in response to environmental stress
The primary structure of all Trib family members is marked by three features: (1) a central kinase-like domain that shares considerable homology to CAM-II kinases, (2) a divergent N-terminus that in some isoforms contains multiple PEST motifs (peptide sequence that is rich in proline [P], glutamic acid [E], serine [S], and threonine [T] that likely mediate protein turnover, and (3) a C-terminal tail that contains a conserved binding sites for MAPK
A more detailed understanding of the role of Trbl in tissue regeneration comes from the work of Leo Otsuki and Andrea Brand, who focused on the reactivation of quiescent neural stem cells (NSCs) that occurs at the larva-to-adult transition [113]
Summary
The primary structure of all Trib family members is marked by three features: (1) a central kinase-like domain that shares considerable homology to CAM-II kinases, (2) a divergent N-terminus that in some isoforms contains multiple PEST motifs (peptide sequence that is rich in proline [P], glutamic acid [E], serine [S], and threonine [T] that likely mediate protein turnover, and (3) a C-terminal tail that contains a conserved binding sites for MAPK (mitogen-activated protein kinase) proteins and COP1 E3 ubiquitin ligases. Based on structural analysis of Trib, substrate binding triggers dynamic interactions among the SLE loop, alpha-C helix, and C-terminal tail leading to target degradation, and studies in Drosophila will be useful to understand better how these conserved motifs mediate the conformational changes that contribute to protein activity.
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