Pseudokinases: a tribble‐edged sword

Richmond, Laura; Keeshan, Karen

doi:10.1111/febs.15096

Cited by 42 publications

(44 citation statements)

References 87 publications

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“…Cellular overexpression of TRIB2, the most ancestral of the TRIBs, has been most strongly associated with different human cancer subtypes, including drug‐resistant malignant melanoma . In addition, TRIB2 regulates the WNT, YAP and C/EBPα pathways in hepatic cancer and C/EBPα in a model of non‐small‐cell lung cancer , as well as possessing complex oncogenic/tumour‐suppressive outputs in the aetiology of AML and ALL . The TRIB1 pseudokinase functions as a dynamic signalling scaffold that recruits substrates to be ubiquitinated as part of a pseudokinase/E3/pseudosubstrate ternary complex .…”

Section: Evaluating the Underexplored And ‘Dark’ Pseudokinomementioning

confidence: 99%

Cataloguing the dead: breathing new life into pseudokinase research

et al. 2020

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Pseudoenzymes are present within many, but not all, known enzyme families and lack one or more conserved canonical amino acids that help define their catalytically active counterparts. Recent findings in the pseudokinase field confirm that evolutionary repurposing of the structurally defined bilobal protein kinase fold permits distinct biological functions to emerge, many of which rely on conformational switching, as opposed to canonical catalysis. In this analysis, we evaluate progress in evaluating several members of the 'dark' pseudokinome that are pertinent to help drive this expanding field. Initially, we discuss how adaptions in erythropoietin-producing hepatocellular carcinoma (Eph) receptor tyrosine kinase domains resulted in two vertebrate pseudokinases, EphA10 and EphB6, in which co-evolving sequences generate new motifs that are likely to be important for both nucleotide binding and catalysis-independent signalling. Secondly, we discuss how conformationally flexible Tribbles pseudokinases, which have radiated in the complex vertebrates, control fundamental aspects of cell signalling that may be targetable with covalent small molecules. Finally, we show how species-level adaptions in the duplicated canonical kinase protein serine kinase histone (PSKH)1 sequence have led to the appearance of the pseudokinase PSKH2, whose physiological role remains mysterious. In conclusion, we show how the patterns we discover are selectively conserved within specific pseudokinases, and that when they are modelled alongside closely related canonical kinases, many are found to be located in functionally important regions of the conserved kinase fold. Interrogation of these patterns will be useful for future evaluation of these, and other, members of the unstudied human kinome.

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Section: Evaluating the Underexplored And ‘Dark’ Pseudokinomementioning

confidence: 99%

Cataloguing the dead: breathing new life into pseudokinase research

et al. 2020

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“…The Tribbles (TRIB) family of serine/threonine pseudokinases include TRIB1, TRIB2 and TRIB3, which represent atypical members of the serine/threonine kinase superfamily [1][2][3][4] and are homologues of the Drosophila pseudokinase "Tribbles" [5,6]. Pseudokinase proteins play critical nonenzymatic roles in the regulation of diverse cellular processes and have been associated with numerous key biological pathways [7]. Although they lack canonical phosphotransferase activity, pseudokinases play important roles as signal transduction mediators and protein scaffolds promoting degradation or stability of their target substrates.…”

Section: Introductionmentioning

confidence: 99%

“…Instead of direct phosphorylation of target proteins, Tribbles interact with various signaling molecules and transcription factors and act as adaptors in signaling pathways for important cellular functions and neoplastic transformations [8,9]. Functionally, Tribbles pseudokinases share a PEST domain, which mediates protein degradation in the N-terminal region, a Trib domain that is homologous to protein serine/threonine kinases but lacks a catalytic function, a constitutive photomorphogenesis 1 (COP1) site allowing key proteins to be targeted to the proteasome for degradation, and a MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) Kinase 1 (MEK1) binding site that modulates MAPK activity [7,10]. The MEK1 and COP1 binding sites located at the C-terminal region facilitate, respectively, TRIB-mediated modulation of the MAPK/ERK signal transduction pathway through increased ERK phosphorylation, and proteasomal degradation by interacting with COP1 E3 ubiquitin ligase [7,11,12].…”

Section: Introductionmentioning

confidence: 99%

Tribbles Pseudokinase 2 (TRIB2) Regulates Expression of Binding Partners in Bovine Granulosa Cells

Warma

Lussier

Ndiaye

2021

IJMS

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Members of the Tribbles (TRIB) family of pseudokinases are critical components of intracellular signal transduction pathways in physiological and pathological processes. TRIBs, including TRIB2, have been previously shown as signaling mediators and scaffolding proteins regulating numerous cellular events such as proliferation, differentiation and cell death through protein stability and activity. However, the signaling network associated with TRIB2 and its binding partners in granulosa cells during ovarian follicular development is not fully defined. We previously reported that TRIB2 is differentially expressed in growing dominant follicles while downregulated in ovulatory follicles following the luteinizing hormone (LH) surge or human chorionic gonadotropin (hCG) injection. In the present study, we used the yeast two-hybrid screening system and in vitro coimmunoprecipitation assays to identify and confirm TRIB2 interactions in granulosa cells (GCs) of dominant ovarian follicles (DFs), which yielded individual candidate binding partners including calmodulin 1 (CALM1), inhibin subunit beta A (INHBA), inositol polyphosphate phosphatase-like 1 (INPPL1), 5’-nucleotidase ecto (NT5E), stearoyl-CoA desaturase (SCD), succinate dehydrogenase complex iron sulfur subunit B (SDHB) and Ras-associated protein 14 (RAB14). Further analyses showed that all TRIB2 binding partners are expressed in GCs of dominant follicles but are differentially regulated throughout the different stages of follicular development. CRISPR/Cas9-driven inhibition along with pQE-driven overexpression of TRIB2 showed that TRIB2 differently regulates expression of binding partners, which reveals the importance of TRIB2 in the control of gene expression linked to various biological processes such as proliferation, differentiation, cell migration, apoptosis, calcium signaling and metabolism. These data provide a larger view of potential TRIB2-regulated signal transduction pathways in GCs and provide strong evidence that TRIB2 may act as a regulator of target genes during ovarian follicular development.

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“…The kinase suppressors of Ras 1 and 2, KSR1/2, are pseudokinases which act as allosteric regulators of RAF kinase activity and as scaffold anchors of the signalling hub Raf-MEK-ERK [ 11–13 ]. Some pseudokinases function as spatial modulators, controlling sub-cellular localisation of substrates [ 3 , 5 ], while others regulate protein trafficking and degradation, like the Tribble family which is involved in COP1-dependent ubiquitylation [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

A small molecule inhibitor of HER3: a proof-of-concept study

Colomba

Fitzek

George

et al. 2020

Biochemical Journal

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Despite being catalytically defective, pseudokinases are typically essential players of cellular signalling, acting as allosteric regulators of their active counterparts. Deregulation of a growing number of pseudokinases has been linked to human diseases, making pseudokinases therapeutic targets of interest. Pseudokinases can be dynamic, adopting specific conformations critical for their allosteric function. Interfering with their allosteric role, with small molecules that would lock pseudokinases in a conformation preventing their productive partner interactions, is an attractive therapeutic strategy to explore.  As a well-known allosteric activator of EGFR family members, and playing a major part in cancer progression, the pseudokinase HER3 is a relevant context in which to address the potential of pseudokinases as drug targets for the development of allosteric inhibitors. In this proof-of-concept study, we developed a multiplex, medium throughput thermal-shift assay screening strategy to assess over 100,000 compounds and identify selective small molecule inhibitors that would trap HER3 in a conformation which is unfavourable for the formation of an active HER2-HER3 heterodimer. As a proof-of-concept compound, AC3573 bound with some specificity to HER3 and abrogated HER2-HER3 complex formation and downstream signalling in cells. Our study highlights the opportunity to identify new molecular mechanisms of action interfering with the biological function of pseudokinases.

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Pseudokinases: a tribble‐edged sword

Cited by 42 publications

References 87 publications

Cataloguing the dead: breathing new life into pseudokinase research

Cataloguing the dead: breathing new life into pseudokinase research

Tribbles Pseudokinase 2 (TRIB2) Regulates Expression of Binding Partners in Bovine Granulosa Cells

A small molecule inhibitor of HER3: a proof-of-concept study

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