ArticleThe Biochemical journal2015
The Tribbles 2 (TRB2) pseudokinase binds to ATP and autophosphorylates in a metal-independent manner.
Article in The Biochemical journal, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 80 citations in OpenAlex.
- Disruption ofAnimals : an open access journal from MDPI · 2026Article
- Inducing TRIB2-targeted protein degradation to reverse chemoresistance in acute myeloid leukaemia.The Biochemical journal · 2026Article
- The Drosophila pseudokinase Tribbles translocates to the fat body membrane in response to fasting to modulate insulin sensitivity.Development (Cambridge, England) · 2025Article
- The role of tribbles homolog 2 in cell proliferation.Cell communication and signaling : CCS · 2025Review
- Diet-induced obesity and aging-induced upregulation of Trib3 interfere with energy homeostasis by downregulating the thermogenic capacity of BAT.Experimental & molecular medicine · 2024Article
- Recent insights into the therapeutic strategies targeting the pseudokinase PTK7 in cancer.Oncogene · 2024Review
- Emerging functions of pseudoenzymes.The Biochemical journal · 2023Review
- miR-100-5p Regulates Skeletal Muscle Myogenesis through theInternational journal of molecular sciences · 2023Article
- PK1 fromOpen biology · 2023Article
- Evolutionary and cellular analysis of the 'dark' pseudokinase PSKH2.The Biochemical journal · 2023Article
- Looking lively: emerging principles of pseudokinase signaling.Trends in biochemical sciences · 2022Review
- Oncogenic TRIB2 interacts with and regulates PKM2 to promote aerobic glycolysis and lung cancer cell procession.Cell death discovery · 2022Article
- Review
- Recent advances in targeting protein kinases and pseudokinases in cancer biology.Frontiers in cell and developmental biology · 2022Review
- A methyltransferase-like 14/miR-99a-5p/tribble 2 positive feedback circuit promotes cancer stem cell persistence and radioresistance via histone deacetylase 2-mediated epigenetic modulation in esophageal squamous cell carcinoma.Clinical and translational medicine · 2021Article
- Review
- Review
- Review
- Tribbles homolog 2 (Trib2), a pseudo serine/threonine kinase in tumorigenesis and stem cell fate decisions.Cell communication and signaling : CCS · 2021Review
- Dimeric Structure of the Pseudokinase IRAK3 Suggests an Allosteric Mechanism for Negative Regulation.Structure (London, England : 1993) · 2021Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
The human Tribbles (TRB)-related pseudokinases are CAMK (calcium/calmodulin-dependent protein kinase)-related family members that have evolved a series of highly unusual motifs in the 'pseudocatalytic' domain. In canonical kinases, conserved amino acids bind to divalent metal ions and align ATP prior to efficient phosphoryl-transfer to substrates. However, in pseudokinases, atypical residues give rise to diverse and often unstudied biochemical and structural features that are thought to be central to cellular functions. TRB proteins play a crucial role in multiple signalling networks and overexpression confers cancer phenotypes on human cells, marking TRB pseudokinases out as a novel class of drug target. In the present paper, we report that the human pseudokinase TRB2 retains the ability to both bind and hydrolyse ATP weakly in vitro. Kinase activity is metal-independent and involves a catalytic lysine residue, which is conserved in TRB proteins throughout evolution alongside several unique amino acids in the active site. A similar low level of autophosphorylation is also preserved in the closely related human TRB3. By employing chemical genetics, we establish that the nucleotide-binding site of an 'analogue-sensitive' (AS) TRB2 mutant can be targeted with specific bulky ligands of the pyrazolo-pyrimidine (PP) chemotype. Our analysis confirms that TRB2 retains low levels of ATP binding and/or catalysis that is targetable with small molecules. Given the significant clinical successes associated with targeting of cancer-associated kinases with small molecule inhibitors, it is likely that similar approaches will be useful for further evaluating the TRB pseudokinases, with the translation of this information likely to furnish new leads for drug discovery.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.