title: Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease.
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.
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, L69 7ZB, UK. Electronic address: Patrick.eyers@liverpool.ac.uk.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Eyers
authors.affiliation: Paul O'Gorman Leukemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 0YN, UK. Electronic address: karen.keeshan@glasgow.ac.uk.
authors.forename: Karen
authors.initials: K
authors.lastname: Keeshan
authors.affiliation: Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA. Electronic address: nkannan@uga.edu.
authors.forename: Natarajan
authors.initials: N
authors.lastname: Kannan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004194:Disease; D019143:Evolution, Molecular; D006801:Humans; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D017346:Protein Serine-Threonine Kinases
keywords: E3 ligase; TRIB; TRIB1; TRIB2; TRIB3; Trb; Tribbles; cancer; evolution; pseudokinase; signaling; ubiquitin