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

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Transcription Factor-Binding Sites in vertebrate TRIB Gene Promoters.
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fig0035: Transcription Factor-Binding Sites in vertebrate TRIB Gene Promoters.

Mentions: Transcription factor-binding sites were predicted using Transcription Element Search System (TESS) software [96], based on the sequence of the extended 5′ untranslated regions (UTR) sequenced from human and murine TRIB1 (Figure IA), TRIB2 (Figure IB), or TRIB3 (Figure IC) genetic loci. Twelve canonical transcription factor-binding sites identified in the two sets of promoters are colored according to the key. Note that several functional E2F1 and C/EBPα-binding sites on the TRIB2 promoter predicted in this analysis have been experimentally verified [65]. The differences in length of the 5′UTR region of each promoter analyzed are indicated for reference. Note the relatively large predicted number of transcription factor-binding sites for TRIB2 compared with the relatively small number of predicted transcription factor binding sites for TRIB3.


Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease
Transcription Factor-Binding Sites in vertebrate TRIB Gene Promoters.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382568&req=5

fig0035: Transcription Factor-Binding Sites in vertebrate TRIB Gene Promoters.
Mentions: Transcription factor-binding sites were predicted using Transcription Element Search System (TESS) software [96], based on the sequence of the extended 5′ untranslated regions (UTR) sequenced from human and murine TRIB1 (Figure IA), TRIB2 (Figure IB), or TRIB3 (Figure IC) genetic loci. Twelve canonical transcription factor-binding sites identified in the two sets of promoters are colored according to the key. Note that several functional E2F1 and C/EBPα-binding sites on the TRIB2 promoter predicted in this analysis have been experimentally verified [65]. The differences in length of the 5′UTR region of each promoter analyzed are indicated for reference. Note the relatively large predicted number of transcription factor-binding sites for TRIB2 compared with the relatively small number of predicted transcription factor binding sites for TRIB3.

View Article: PubMed Central - PubMed

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.

No MeSH data available.