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

Trends Cell Biol. 2017 Apr;27(4):284-298. doi: 10.1016/j.tcb.2016.11.002. Epub 2016 Nov 28.


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.

Keywords: E3 ligase; TRIB; TRIB1; TRIB2; TRIB3; Trb; Tribbles; cancer; evolution; pseudokinase; signaling; ubiquitin.

Publication types

  • Review
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Disease*
  • Evolution, Molecular
  • Humans
  • Neoplasms / enzymology
  • Neoplasms / pathology
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction


  • Protein-Serine-Threonine Kinases