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

Eyers, Patrick A.; Keeshan, Karen; Kannan, Natarajan

doi:10.1016/j.tcb.2016.11.002

Cited by 190 publications

(219 citation statements)

References 96 publications

(135 reference statements)

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“…The tribbles ( trbl ) family of pseudokinases play multiple critical roles in physiology and disease (Eyers, Keeshan, & Kannan, 2016). These pseudokinases are thought to both link substrate binding to specific protein stability by recruiting ubiquitin ligases and as regulators of MAPK and AKT/FOXO - signaling (Eyers et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…These pseudokinases are thought to both link substrate binding to specific protein stability by recruiting ubiquitin ligases and as regulators of MAPK and AKT/FOXO - signaling (Eyers et al, 2016). There is one version of the trbl pseudokinase in Drosophila melanogaster and Caenorhabditis elegans (Kim, Thakur, Piggott, Omi, Polanowska, Jin, & Pujol, 2016; Mata, Curado, Ephrussi, & Rorth, 2000; Pujol, Cypowyj, Ziegler, Millet, Astrain, Goncharov, Jin, Chisholm, & Ewbank, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…There is one version of the trbl pseudokinase in Drosophila melanogaster and Caenorhabditis elegans (Kim, Thakur, Piggott, Omi, Polanowska, Jin, & Pujol, 2016; Mata, Curado, Ephrussi, & Rorth, 2000; Pujol, Cypowyj, Ziegler, Millet, Astrain, Goncharov, Jin, Chisholm, & Ewbank, 2008). Mouse and man have three, named trbl 1, 2, and 3 (Boudeau, Miranda-Saavedra, Barton, & Alessi, 2006; Eyers et al, 2016). There is wide-spread expression of the three mammalian trbl products in brain and the D. melanogaster trbl gene is expressed in the developing nervous system (Aime, Sun, Zareen, Rao, Berman, Volpicelli-Daley, Bernd, Crary, Levy, & Greene, 2015; Fisher, Li, Hammonds, Brown, Pfeiffer, Weiszmann, MacArthur, Thomas, Stamatoyannopoulos, Eisen, Bickel, Biggin, & Celniker, 2012; Ord, Innos, Lillevali, Tekko, Sutt, Ord, Koks, Vasar, & Ord, 2014).…”

Section: Introductionmentioning

confidence: 99%

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The Drosophila melanogaster tribbles pseudokinase is necessary for proper memory formation

LaFerriere

Zars

2017

Neurobiology of Learning and Memory

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The tribbles (trbl) pseudokinases play important roles in signaling and physiology in multiple contexts, ranging from innate immunity to cancer, suggesting fundamental cellular functions for the trbls’ gene products. Despite expression of the trbl pseudokinases in the nervous systems of invertebrate and vertebrate animals, and evidence that they have a function within mouse and human dopamine neurons, there is no clear case for a function of a Trbl protein that influences behavior. Indeed, the first and only evidence for this type of function comes from Drosophila melanogaster, where a mutation of the single trbl gene was identified in a genetic screen for short-term memory mutant flies. The current study tested flies containing multiple trbl mutant alleles and potential transgenic rescue in both operant place memory and classical olfactory memory paradigms. Genetic complementation tests and transgenic rescue of memory phenotypes in both paradigms show that the D. melanogaster trbl pseudokinase is essential for proper memory formation. Expression analysis with a polyclonal antiserum against Trbl shows that the protein is expressed widely in the fly brain, with higher expression in the cellular rind than the neuropil. Rescue of the behavioral phenotype with transgenic expression indicates the trbl function can be localized to a subset of the nervous system. Thus, we provide the first compelling case for the function of a trbl pseudokinase in the regulation of behavior.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Drosophila melanogaster tribbles pseudokinase is necessary for proper memory formation

LaFerriere

Zars

2017

Neurobiology of Learning and Memory

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“…TRIB pseudokinases are classified based on sequence homology as serine/threonine pseudokinases that either lack (TRIB1), or exhibit low (TRIB2 and TRIB3) vestigial ATP affinity and phosphotransferase capacity (Bailey et al, 2015, Murphy et al, 2015. In addition, TRIB1 and TRIB2 are more similar (possessing a sequence homology of ~71%) compared to the most recently evolved family member TRIB3 (Eyers et al, 2017), whose homology with both TRIB1 and TRIB2 is only ~55%, suggesting mechanistic and functional divergence. Indeed earlier studies showed that when highly expressed, TRIB1 and TRIB2 but not TRIB3, degrade the myeloid transcription factor C/EBP, inhibit myeloid differentiation, and drive AML (Keeshan et al, 2006, Dedhia et al, 2010.…”

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confidence: 99%

The Tribble with APL: A New Road to Therapy

Carmody

Keeshan

2017

Cancer Cell

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SummaryThe t(15;17) translocation generates a PML-RARα fusion protein causative for acute promyelocytic leukemia (APL). Li et al. identify the pseudokinase stress protein TRIB3 as an important factor in APL disease progression and therapy resistance. Targeting the interaction of TRIB3 and PML-RARα using peptide technology provides a novel therapeutic approach. Main TextAcute promyelocytic leukemia (APL) is a distinct subtype (5-15%) of acute myeloid leukemia (AML) characterized by a t(15:17) chromosomal translocation in myeloid precursor cells, leading to the expression of the PML-RARα oncofusion gene. PML-RARα expression blocks promyelocyte differentiation leading to the proliferation of leukemia blasts. The molecular basis for the effects of PML-RARα lies in its activity as a constitutive repressor of RARα and RXR target genes and in its dominant negative effects on PML, a protein that is necessary for the formation of nuclear bodies that have extensive influence on the activity of many transcription factors, including p53. Current therapies for APL include treatment with pharmacological doses of all-trans-retinoic-acid (ATRA) and arsenic trioxide (As2O3), both of which lead to the SUMOylation and ubiquitination dependent degradation of PML-RARα, and APL cell differentiation. These treatments are effective with ~75% of patients cured of the disease, however therapy resistance and disease relapse remains an unmet clinical need.

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“…TRIB3 acts as a member of tribbles homolog family that are fundamental regulators of cell cycle, differentiation, metabolism, proliferation, and cell stress, and is involved in chronic inflammatory and malignant disease through their interactions with intracellular signaling and functional proteins [4]. Our previous study revealed that TRIB3 promoted cancer development and progression by interacting with the signaling molecule SMAD3 or a selective autophagy receptor p62/SQSTM1 [5,6].…”

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confidence: 99%

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2017

Oncotarget

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Extensive studies have led to the identification of protein-protein interaction (PPI) cores and intersections that are critical for the acquisition and maintenance of properties of malignant transformation [1]. With technological advances in PPI modulator discovery and validation of PPI-targeting agents, for instance, several small-molecule PPI antagonists that target the interactions of MDM2/p53, XIAP/caspase-9 and BCL2/beclin1 are being studied in clinical trials for cancer patients; targeting of PPI interfaces as an anticancer strategy has come to a reality gradually. This development is likely to continue in light of the huge market and application prospects [1]. Therefore, identifying new small-molecule PPI modulators have advanced clinical perspective for cancer therapy.Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML-RARα that induces the differentiation block and the transcriptional repression, and promotes APL-initiating cell self-renewal. Recent studies have shown that PML-RARα also affects PML sumoylation and PML nuclear bodies assembly, which regulate stem cell self-renewal [2]. Combined retinoic acid (RA) with arsenic trioxide (ATO) dramatically improves the prognosis of APL patients and cure most patients. Mechanistically both agents directly target the PML-RARα-mediated transcriptional repression and protein stability which induce promyelocyte differentiation and eliminate leukemia-initiating cells. At the molecular level, RA and ATO bind to the RARα moiety or PML moiety of PNL-RARα respectively. ATO further induces PML/PML-RARα sumoylation and sumoylated PML/ PML-RARα interacts with E3 ubiquitin-ligase RNF4, ubiquitin, proteasomes and other sumoylated proteins, and recruits them onto PML nuclear bodies (PML-NBs), where ATO integrates the ubiquitination and degradation of PML-RARα/PML. Despite that combination of RA and ATO makes APL highly curable, relapsed and refractory APL still occur among all prognostic subgroups of APL patients. Therefore, searching for PPIs modulators promoting PML-RARα degradation, based on these two novel agents, may bring about new therapeutic options for APL therapy.Indeed, we recently report that TRIB3, a member of pseudokinase family, promotes APL progression through stabilization of the oncoprotein PML-RARα and inhibition of p53-mediated senescence [3]. TRIB3 acts as a member of tribbles homolog family that are fundamental regulators of cell cycle, differentiation, metabolism, proliferation, and cell stress, and is involved in chronic inflammatory and malignant disease through their interactions with intracellular signaling and functional proteins [4]. Our previous study revealed that TRIB3 promoted cancer development and progression by interacting with the signaling molecule SMAD3 or a selective autophagy receptor p62/SQSTM1 [5,6]. An α-helical peptide, which disturbs the interaction of TRIB3 and p62, displays an effective activation of autophagic flux, and significantly suppresses tumor growth and metastasis. In our current study, we find that t...

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

Cited by 190 publications

References 96 publications

The Drosophila melanogaster tribbles pseudokinase is necessary for proper memory formation

The Drosophila melanogaster tribbles pseudokinase is necessary for proper memory formation

The Tribble with APL: A New Road to Therapy

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