Tribbles (TRIB) proteins are pseudokinase mediators of eukaryotic signalling that have evolved important roles in lipoprotein metabolism, immune function and cellular differentiation and proliferation. In addition, an evolutionary-conserved modulation of PI3K/AKT signalling pathways highlights them as novel and rather unusual pharmaceutical targets. The three human TRIB family members are uniquely defined by an acidic pseudokinase domain containing a ‘broken’ α C-helix and a MEK (MAPK/ERK)-binding site at the end of the putative C-lobe and a distinct C-terminal peptide motif that interacts directly with a small subset of cellular E3 ubiquitin ligases. This latter interaction drives proteasomal-dependent degradation of networks of transcription factors, whose rate of turnover determines the biological attributes of individual TRIB family members. Defining the function of individual Tribs has been made possible through evaluation of individual TRIB knockout mice, siRNA/overexpression approaches and genetic screening in flies, where the single TRIB gene was originally described 15 years ago. The rapidly maturing TRIB field is primed to exploit chemical biology approaches to evaluate endogenous TRIB signalling events in intact cells. This will help define how TRIB-driven protein–protein interactions and the atypical TRIB ATP-binding site, fit into cellular signalling modules in experimental scenarios where TRIB-signalling complexes remain unperturbed. In this mini-review, we discuss how small molecules can reveal rate-limiting signalling outputs and functions of Tribs in cells and intact organisms, perhaps serving as guides for the development of new drugs. We predict that appropriate small molecule TRIB ligands will further accelerate the transition of TRIB pseudokinase analysis into the mainstream of cell signalling.
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October 2015
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Review Article|
October 09 2015
Tribbles pseudokinases: novel targets for chemical biology and drug discovery?
Daniel M. Foulkes;
Daniel M. Foulkes
*Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, U.K.
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Dominic P. Byrne;
Dominic P. Byrne
*Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, U.K.
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Fiona P. Bailey;
Fiona P. Bailey
*Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, U.K.
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Patrick A. Eyers
Patrick A. Eyers
1
*Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, U.K.
1To whom correspondence should be addressed (emailPatrick.eyers@liverpool.ac.uk).
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Publisher: Portland Press Ltd
Received:
May 07 2015
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2015 Authors; published by Portland Press Limited
2015
Biochem Soc Trans (2015) 43 (5): 1095–1103.
Article history
Received:
May 07 2015
Citation
Daniel M. Foulkes, Dominic P. Byrne, Fiona P. Bailey, Patrick A. Eyers; Tribbles pseudokinases: novel targets for chemical biology and drug discovery?. Biochem Soc Trans 1 October 2015; 43 (5): 1095–1103. doi: https://doi.org/10.1042/BST20150109
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