Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Apr;27(4):284-298.
doi: 10.1016/j.tcb.2016.11.002. Epub 2016 Nov 28.

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

Patrick A Eyers  1 , Karen Keeshan  2 , Natarajan Kannan  3
Affiliations
Review

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

Patrick A Eyers et al. Trends Cell Biol. 2017 Apr.

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.

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

PubMed Disclaimer

Figures

Figure 1
Figure 1
Classical Tribbles (TRIB) Signaling Features. All TRIB polypeptides contain a variable N-terminal ‘PEST’ domain, a pseudokinase domain lacking a canonical ‘DFG’ (metal-binding) motif, and a unique C-tail, which contains two key regulatory elements. The HPW[F/L] motif at the beginning of the pseudokinase C-tail targets MAPKK/MEK family members, giving TRIBs the potential to regulate and/or integrate distinct stress and proliferative MAPK modules. The conserved structural C-terminal DQXVP[D/E] peptide motif supports a direct association with E3 ubiquitin ligases, including COP1, which specifies K48-linked ubiquitin chains in substrates such as C/EBPα, thereby regulating transcription factor stability via the ubiquitin proteasome system. TRIBs can also modulate AKT/FOXO signaling modules, although the molecular details for individual pseudokinases remain to be clarified. Overall, a series of shared mechanisms contribute to TRIB-regulated signaling pathways that support cell context-specific programs of cellular differentiation, proliferation, and survival. Abbreviations: P, phosphate; Ub, ubiquitin.
Figure 2
Figure 2
Taxonomic Coverage and Analysis of Tribbles (TRIB) Family Kinases. The number of TRIB1, TRIB2, and TRIB3 orthologs detected across all the major metazoan species for which accurate genomic kinome data are available are shown. Each row represents a single species and the number of TRIB orthologs identified in each species is indicated. Orthologs were identified by scanning a hierarchical sequence profile of diverse ePKs and TRIB family members against sequenced proteomes contained in the latest nonredundant proteome sequence set in Uniprot (downloaded October 2016) using the MAPGAPS program . The most significant hits to TRIB1, TRIB2, and TRIB3 profiles were annotated as putative orthologs. Fragmentary sequences of less than 150 amino acids in length were filtered out. Reptilian TRIB3 orthologs were detected in larger sequence databases (NCBI nr, EST) and all three TRIB pseudokinases are observed in reptilian species (including alligator) in the corresponding Uniprot proteome sequence set.
Figure 3
Figure 3
Distinguishing Sequence and Structural Features of Tribbles (TRIB) Pseudokinases. (A) Constraints that help distinguish TRIB kinases from all other kinases are shown in a contrast hierarchical alignment, where representative TRIB kinases from diverse organisms constitute the display alignment; all TRIB-like sequences available (492 sequences, September 2016) constitute the foreground alignment, and related CAMK sequences (79 487 sequences) constitute the background alignment. Complete foreground and background alignments are not shown due to the hundreds of text pages required. Instead, information encoded in these large alignments is shown as residue frequencies directly below the display alignment where, for example, the number ‘5′ indicates that the corresponding residue occurs 50–60% of the time at the corresponding position. The histogram above the alignment plots the strength of the selective pressure shifting residues at each position in the TRIB kinases away from the residue composition observed at the corresponding positions in CAMKs. Residue positions subject to the strongest constraints are highlighted with chemically similar amino acids colored similarly; weakly conserved positions and nonconserved positions are shown in dark and light gray, respectively. Dots below the histograms indicate those residue positions that most strikingly distinguish TRIB kinases from CAMKs as selected by the Bayesian pattern partitioning procedure . Key secondary structural elements are indicated above the alignment; amino acid numbering corresponds to human TRIB2. Identifiers for TRIB sequences used in the display alignment can be compared with canonical kinase sequences by inspecting Box 1. (B,C) Modeling of the structural disposition of TRIB-specific residues forming the regulatory activation loop, atypical DFG motif (E[S/N]LED), and αC helix in human TRIB2. The kinked αC-helix is shown in yellow and the activation loop (A-loop) is shown in magenta. TRIB family conserved residues are shown in green. Putative hydrogen-bonding interactions in the modeled structure are shown by broken lines and the putative substrate-binding site in the C-lobe is labeled. Structural image was generated using PyMoL. Specific TRIB gene identifiers are listed in the legend to Figure 4.
Figure 4
Figure 4
The C-tail, A Unique ‘Degrading’ Feature of Tribbles (TRIB) Pseudokinase Polypeptides. (A) Alignment of TRIB pseudokinase C-tail segment highlighting key conserved residues and motifs found in eukaryotic TRIB pseudokinases. See Figure 2 legends for details. Unique TRIB gene identifiers are: Trib1 Human Q96RU8; Trib1 Mouse Q8K4K4; Trib1 Cow A6QLF4; Trib1 Elephant G3T9X9; Trib1 Chicken H9L0P6; Trib1 Green anole G1KJZ8; Trib1 Alligator A0A151P7Z3; Trib1 Frog F7BWB1; Trib1 Coelacanth H3ALB4; Trib1 Zebrafish E7FD70; Trib2 Human Q92519; Trib2 Mouse Q8K4K3; Trib2 Cow Q5GLH2; Trib2 Elephant G3TC04; Trib2 Chicken Q7ZZY2; Trib2 Green anole G1K8G5; Trib2 Alligator A0A151N8V7; Trib2 Frog Q76D08; Trib2 Coelacanth H3A37; Trib2 Zebrafish E7F3S2; Trib2 Fire ant XP_011171156.1; Trib2 Acorn Worm XP_002742313.1; Trib2 Threadworm A0A0K0E067; Trib2 Sea hare XP_005101496.1; Trib2 Sea urchin XP_792075.2; Trib2 Sponge I1G1T0; Trib3 Human Q96RU7; Trib3 Mouse Q8K4K2; Trib3 Cow Q0VCE3; Trib3 Elephant G3SZ76; Trib3 Alligator A0A151NVV1. (B) Common mechanism for structural tethering of the C-tail to the kinase domain in TRIB2 (model based on TRIB1 X-ray analysis, Protein Data Ban ID: 5CEM) and two canonical kinase families, with PKA representing the AGC kinases and ERK2 representing the MAP kinases . All three subfamilies of (pseudo)kinase are regulated by conformational changes in the C-terminal tail that directly engage the kinase domain in cis.
Figure 5
Figure 5
Tribbles 1 (TRIB1) and TRIB2 Pro- and Anti-tumorigenic Activities Associated with Vertebrate Leukemias. (A) Murine cancer models in which TRIB1 and TRIB2 function as oncogenes when TRIB1 or TRIB2 are overexpressed (+TRIB1,  + TRIB2) leading to fully penetrant, fatal acute myeloid (AML, green), but not lymphoid (T cell acute lymphoblastic; T-ALL) leukemias. Elevated TRIB1 expression also contributes to chemotherapy resistance (a protumorigenic response) in APL (indicated in a PML/RARA + MYC model). (B) Mouse models in which the loss of TRIB2 reveals a tumor-suppressive activity. This is shown through homozygous TRIB2 knockout, which results in an accelerated lymphoid (T-ALL induced by active NOTCH1, red), but not myeloid, leukemia. Abbreviations: ATRA, all-trans-retinoic-acid, an APL therapy; APL, acute promyelocytic leukemia (a subtype of AML); BM, bone marrow; Cebpa–/–, C/EBPα-knockout mouse; Trib2–/–, Trib2-knockout mouse; WT, wildtype mouse. Citations refer to in vivo mouse models of leukemia demonstrating oncogenic or tumor-suppressive TRIB biology.
Figure I
Figure I
CAMK Subfamily Sequence Alignment of selected (Pseudo)Kinase Domains.
Figure I
Figure I
Transcription Factor-Binding Sites in vertebrate TRIB Gene Promoters.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Cohen P., Tcherpakov M. Will the ubiquitin system furnish as many drug targets as protein kinases? Cell. 2010;143:686–693. - PubMed
    1. Hunter T. The age of crosstalk: phosphorylation, ubiquitination, and beyond. Mol. Cell. 2007;28:730–738. - PubMed
    1. Manning G. The protein kinase complement of the human genome. Science. 2002;298:1912–1934. - PubMed
    1. Boudeau J. Emerging roles of pseudokinases. Trends Cell Biol. 2006;16:443–452. - PubMed
    1. Lohan F., Keeshan K. The functionally diverse roles of tribbles. Biochem. Soc. Trans. 2013;41:1096–1100. - PubMed

Substances