Editorial

3 pages, 196 KiB

Open AccessEditorial

Pseudokinases, Tribbles Proteins and Cancer

by Guillermo Velasco and Wolfgang Link

Cancers 2023, 15(14), 3547; https://doi.org/10.3390/cancers15143547 - 09 Jul 2023

Viewed by 719

The human kinome comprises 518 protein kinases, of which approximately 10% lack one or more of the conserved amino acids necessary for catalytic activity [...] Full article

(This article belongs to the Special Issue Pseudokinases, Tribbles Proteins and Cancer)

Research

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20 pages, 5473 KiB

Open AccessArticle

Comprehensive Profiling of Mammalian Tribbles Interactomes Implicates TRIB3 in Gene Repression

by Miguel Hernández-Quiles, Rosalie Baak, Anouska Borgman, Suzanne den Haan, Paula Sobrevals Alcaraz, Robert van Es, Endre Kiss-Toth, Harmjan Vos and Eric Kalkhoven

Cancers 2021, 13(24), 6318; https://doi.org/10.3390/cancers13246318 - 16 Dec 2021

Cited by 6 | Viewed by 3031

Abstract

The three human Tribbles (TRIB) pseudokinases have been implicated in a plethora of signaling and metabolic processes linked to cancer initiation and progression and can potentially be used as biomarkers of disease and prognosis. While their modes of action reported so far center [...] Read more.

The three human Tribbles (TRIB) pseudokinases have been implicated in a plethora of signaling and metabolic processes linked to cancer initiation and progression and can potentially be used as biomarkers of disease and prognosis. While their modes of action reported so far center around protein–protein interactions, the comprehensive profiling of TRIB interactomes has not been reported yet. Here, we have developed a robust mass spectrometry (MS)-based proteomics approach to characterize Tribbles’ interactomes and report a comprehensive assessment and comparison of the TRIB1, -2 and -3 interactomes, as well as domain-specific interactions for TRIB3. Interestingly, TRIB3, which is predominantly localized in the nucleus, interacts with multiple transcriptional regulators, including proteins involved in gene repression. Indeed, we found that TRIB3 repressed gene transcription when tethered to DNA in breast cancer cells. Taken together, our comprehensive proteomic assessment reveals previously unknown interacting partners and functions of Tribbles proteins that expand our understanding of this family of proteins. In addition, our findings show that MS-based proteomics provides a powerful tool to unravel novel pseudokinase biology. Full article

(This article belongs to the Special Issue Pseudokinases, Tribbles Proteins and Cancer)

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19 pages, 3444 KiB

Open AccessArticle

The Pseudokinase TRIB3 Negatively Regulates the HER2 Receptor Pathway and Is a Biomarker of Good Prognosis in Luminal Breast Cancer

by Alba Orea-Soufi, Sonia Castillo-Lluva, Nélida Salvador-Tormo, Paola Martín-Cabrera, Silvia Recuero, Estíbaliz Gabicagogeascoa, Manuel Moreno-Valladares, Marina Mendiburu-Eliçabe, Adrián Blanco-Gómez, José Miguel Ramos-Pittol, Elena García-Taboada, Alberto Ocaña, Francisco J. Cimas, Ander Matheu, Isabel Álvarez-López, Guillermo Velasco and Mar Lorente

Cancers 2021, 13(21), 5307; https://doi.org/10.3390/cancers13215307 - 22 Oct 2021

Cited by 7 | Viewed by 2458

Abstract

Background: Tribbles pseudokinase 3 (TRIB3) has been proposed to both promote and restrict cancer generation and progression. However, the precise mechanisms that determine this dual role of TRIB3 in cancer remain to be understood. In this study we aimed to investigate the role [...] Read more.

Background: Tribbles pseudokinase 3 (TRIB3) has been proposed to both promote and restrict cancer generation and progression. However, the precise mechanisms that determine this dual role of TRIB3 in cancer remain to be understood. In this study we aimed to investigate the role of TRIB3 in luminal breast cancer, the most frequent subtype of this malignancy. Methods: We genetically manipulated TRIB3 expression in a panel of luminal breast cancer cell lines and analyzed its impact on cell proliferation, and the phosphorylation, levels, or subcellular localization of TRIB3 and other protein regulators of key signaling pathways in luminal breast cancer. We also analyzed TRIB3 protein expression in samples from luminal breast cancer patients and performed bioinformatic analyses in public datasets. Results: TRIB3 enhanced the proliferation and AKT phosphorylation in luminal A (HER2-) but decreased them in luminal B (HER2+) breast cancer cell lines. TRIB3 negatively regulated the stability of HER2 in luminal B breast cancer cell lines. TRIB3 expression was associated with increased disease-free survival and a better response to therapy in luminal breast cancer patients. Conclusions: Our findings support the exploration of TRIB3 as a potential biomarker and therapeutic target in luminal breast cancer. Full article

(This article belongs to the Special Issue Pseudokinases, Tribbles Proteins and Cancer)

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27 pages, 4473 KiB

Open AccessArticle

Pharmacological or TRIB3-Mediated Suppression of ATF4 Transcriptional Activity Promotes Hepatoma Cell Resistance to Proteasome Inhibitor Bortezomib

by Tiit Örd, Daima Örd, Minna U. Kaikkonen and Tõnis Örd

Cancers 2021, 13(10), 2341; https://doi.org/10.3390/cancers13102341 - 12 May 2021

Cited by 10 | Viewed by 2774

Abstract

The proteasome is an appealing target for anticancer therapy and the proteasome inhibitor bortezomib has been approved for the treatment of several types of malignancies. However, the molecular mechanisms underlying cancer cell resistance to bortezomib remain poorly understood. In the current article, we [...] Read more.

The proteasome is an appealing target for anticancer therapy and the proteasome inhibitor bortezomib has been approved for the treatment of several types of malignancies. However, the molecular mechanisms underlying cancer cell resistance to bortezomib remain poorly understood. In the current article, we investigate how modulation of the eIF2α–ATF4 stress pathway affects hepatoma cell response to bortezomib. Transcriptome profiling revealed that many ATF4 transcriptional target genes are among the most upregulated genes in bortezomib-treated HepG2 human hepatoma cells. While pharmacological enhancement of the eIF2α–ATF4 pathway activity results in the elevation of the activities of all branches of the unfolded protein response (UPR) and sensitizes cells to bortezomib toxicity, the suppression of ATF4 induction delays bortezomib-induced cell death. The pseudokinase TRIB3, an inhibitor of ATF4, is expressed at a high basal level in hepatoma cells and is strongly upregulated in response to bortezomib. To map genome-wide chromatin binding loci of TRIB3 protein, we fused a Flag tag to endogenous TRIB3 in HepG2 cells and performed ChIP-Seq. The results demonstrate that TRIB3 predominantly colocalizes with ATF4 on chromatin and binds to genomic regions containing the C/EBP–ATF motif. Bortezomib treatment leads to a robust enrichment of TRIB3 binding near genes induced by bortezomib and involved in the ER stress response and cell death. Disruption of TRIB3 increases C/EBP–ATF-driven transcription, augments ER stress and cell death upon exposure to bortezomib, while TRIB3 overexpression enhances cell survival. Thus, TRIB3, colocalizing with ATF4 and limiting its transcriptional activity, functions as a factor increasing resistance to bortezomib, while pharmacological over-activation of eIF2α–ATF4 can overcome the endogenous restraint mechanisms and sensitize cells to bortezomib. Full article

(This article belongs to the Special Issue Pseudokinases, Tribbles Proteins and Cancer)

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18 pages, 2113 KiB

Open AccessArticle

Tribbles Pseudokinase 3 Contributes to Cancer Stemness of Endometrial Cancer Cells by Regulating β-Catenin Expression

by Wen-Ling Wang, Guan-Ci Hong, Peng-Ju Chien, Yu-Hao Huang, Hsueh-Te Lee, Po-Hui Wang, Yueh-Chun Lee and Wen-Wei Chang

Cancers 2020, 12(12), 3785; https://doi.org/10.3390/cancers12123785 - 15 Dec 2020

Cited by 11 | Viewed by 2666

Abstract

Endometrial cancer (EC) is the second most common gynecological malignancy worldwide. Tribbles pseudokinase 3 (TRIB3) is a scaffolding protein that regulates intracellular signal transduction, and its role in tumor development is controversial. Here, we investigated the biological function of TRIB3 in EC. We [...] Read more.

Endometrial cancer (EC) is the second most common gynecological malignancy worldwide. Tribbles pseudokinase 3 (TRIB3) is a scaffolding protein that regulates intracellular signal transduction, and its role in tumor development is controversial. Here, we investigated the biological function of TRIB3 in EC. We found that the messenger RNA (mRNA) expression level of TRIB3 was significantly and positively correlated with shorter overall survival of EC patients in The Cancer Genome Atlas database. The protein expression of TRIB3 was found to be significantly increased in EC cancer stem cells (CSCs) enriched by tumorsphere cultivation. Knockdown of TRIB3 in EC cells suppressed tumorsphere formation, the expression of cancer stemness genes, and the in vivo tumorigenesis. The expression of β-catenin at both the protein and the mRNA levels was downregulated upon TRIB3 silencing. TRIB3 was found to interact with E74 Like ETS transcription factor 4 (ELF4) in the nucleus and bound to ELF4 consensus sites within the catenin beta 1 (CTNNB1) promoter in EC cell lines. These data indicated that TRIB3 may regulate CTNNB1 transcription by enhancing the recruitment of ELF4 to the CTNNB1 promoter. In conclusion, our results suggest that TRIB3 plays an oncogenic role in EC and positively regulates the self-renewal and tumorigenicity of EC-CSCs. Targeting TRIB3 is considered as a potential therapeutic strategy in future EC therapy. Full article

(This article belongs to the Special Issue Pseudokinases, Tribbles Proteins and Cancer)

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20 pages, 3511 KiB

Open AccessArticle

Harmine and Piperlongumine Revert TRIB2-Mediated Drug Resistance

by Susana Machado, Andreia Silva, Ana Luísa De Sousa-Coelho, Isabel Duarte, Inês Grenho, Bruno Santos, Victor Mayoral-Varo, Diego Megias, Fátima Sánchez-Cabo, Ana Dopazo, Bibiana I. Ferreira and Wolfgang Link

Cancers 2020, 12(12), 3689; https://doi.org/10.3390/cancers12123689 - 09 Dec 2020

Cited by 15 | Viewed by 3221

Abstract

Therapy resistance is responsible for most relapses in patients with cancer and is the major challenge to improving the clinical outcome. The pseudokinase Tribbles homologue 2 (TRIB2) has been characterized as an important driver of resistance to several anti-cancer drugs, including the dual [...] Read more.

Therapy resistance is responsible for most relapses in patients with cancer and is the major challenge to improving the clinical outcome. The pseudokinase Tribbles homologue 2 (TRIB2) has been characterized as an important driver of resistance to several anti-cancer drugs, including the dual ATP-competitive PI3K and mTOR inhibitor dactolisib (BEZ235). TRIB2 promotes AKT activity, leading to the inactivation of FOXO transcription factors, which are known to mediate the cell response to antitumor drugs. To characterize the downstream events of TRIB2 activity, we analyzed the gene expression profiles of isogenic cell lines with different TRIB2 statuses by RNA sequencing. Using a connectivity map-based computational approach, we identified drug-induced gene-expression profiles that invert the TRIB2-associated expression profile. In particular, the natural alkaloids harmine and piperlongumine not only produced inverse gene expression profiles but also synergistically increased BEZ235-induced cell toxicity. Importantly, both agents promote FOXO nuclear translocation without interfering with the nuclear export machinery and induce the transcription of FOXO target genes. Our results highlight the great potential of this approach for drug repurposing and suggest that harmine and piperlongumine or similar compounds might be useful in the clinic to overcome TRIB2-mediated therapy resistance in cancer patients. Full article

(This article belongs to the Special Issue Pseudokinases, Tribbles Proteins and Cancer)

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21 pages, 2952 KiB

Open AccessArticle

Genomic and Functional Regulation of TRIB1 Contributes to Prostate Cancer Pathogenesis

by Parastoo Shahrouzi, Ianire Astobiza, Ana R. Cortazar, Verónica Torrano, Alice Macchia, Juana M. Flores, Chiara Niespolo, Isabel Mendizabal, Ruben Caloto, Amaia Ercilla, Laura Camacho, Leire Arreal, Maider Bizkarguenaga, Maria L. Martinez-Chantar, Xose R. Bustelo, Edurne Berra, Endre Kiss-Toth, Guillermo Velasco, Amaia Zabala-Letona and Arkaitz Carracedo

Cancers 2020, 12(9), 2593; https://doi.org/10.3390/cancers12092593 - 11 Sep 2020

Cited by 11 | Viewed by 4293

Abstract

Prostate cancer is the most frequent malignancy in European men and the second worldwide. One of the major oncogenic events in this disease includes amplification of the transcription factor cMYC. Amplification of this oncogene in chromosome 8q24 occurs concomitantly with the copy number [...] Read more.

Prostate cancer is the most frequent malignancy in European men and the second worldwide. One of the major oncogenic events in this disease includes amplification of the transcription factor cMYC. Amplification of this oncogene in chromosome 8q24 occurs concomitantly with the copy number increase in a subset of neighboring genes and regulatory elements, but their contribution to disease pathogenesis is poorly understood. Here we show that TRIB1 is among the most robustly upregulated coding genes within the 8q24 amplicon in prostate cancer. Moreover, we demonstrate that TRIB1 amplification and overexpression are frequent in this tumor type. Importantly, we find that, parallel to its amplification, TRIB1 transcription is controlled by cMYC. Mouse modeling and functional analysis revealed that aberrant TRIB1 expression is causal to prostate cancer pathogenesis. In sum, we provide unprecedented evidence for the regulation and function of TRIB1 in prostate cancer. Full article

(This article belongs to the Special Issue Pseudokinases, Tribbles Proteins and Cancer)

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Review

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14 pages, 1541 KiB

Open AccessFeature PaperReview

Structure vs. Function of TRIB1—Myeloid Neoplasms and Beyond

by Hamish D McMillan, Karen Keeshan, Anita K Dunbier and Peter D Mace

Cancers 2021, 13(12), 3060; https://doi.org/10.3390/cancers13123060 - 19 Jun 2021

Cited by 5 | Viewed by 2857

Abstract

The Tribbles family of proteins—comprising TRIB1, TRIB2, TRIB3 and more distantly related STK40—play important, but distinct, roles in differentiation, development and oncogenesis. Of the four Tribbles proteins, TRIB1 has been most well characterised structurally and plays roles in diverse cancer types. The most [...] Read more.

The Tribbles family of proteins—comprising TRIB1, TRIB2, TRIB3 and more distantly related STK40—play important, but distinct, roles in differentiation, development and oncogenesis. Of the four Tribbles proteins, TRIB1 has been most well characterised structurally and plays roles in diverse cancer types. The most well-understood role of TRIB1 is in acute myeloid leukaemia, where it can regulate C/EBP transcription factors and kinase pathways. Structure–function studies have uncovered conformational switching of TRIB1 from an inactive to an active state when it binds to C/EBPα. This conformational switching is centred on the active site of TRIB1, which appears to be accessible to small-molecule inhibitors in spite of its inability to bind ATP. Beyond myeloid neoplasms, TRIB1 plays diverse roles in signalling pathways with well-established roles in tumour progression. Thus, TRIB1 can affect both development and chemoresistance in leukaemia; glioma; and breast, lung and prostate cancers. The pervasive roles of TRIB1 and other Tribbles proteins across breast, prostate, lung and other cancer types, combined with small-molecule susceptibility shown by mechanistic studies, suggests an exciting potential for Tribbles as direct targets of small molecules or biomarkers to predict treatment response. Full article

(This article belongs to the Special Issue Pseudokinases, Tribbles Proteins and Cancer)

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19 pages, 12862 KiB

Open AccessReview

Tribbles Pseudokinases in Colorectal Cancer

by Bibiana I. Ferreira, Bruno Santos, Wolfgang Link and Ana Luísa De Sousa-Coelho

Cancers 2021, 13(11), 2825; https://doi.org/10.3390/cancers13112825 - 05 Jun 2021

Cited by 8 | Viewed by 3044

Abstract

The Tribbles family of pseudokinases controls a wide number of processes during cancer on-set and progression. However, the exact contribution of each of the three family members is still to be defined. Their function appears to be context-dependent as they can act as [...] Read more.

The Tribbles family of pseudokinases controls a wide number of processes during cancer on-set and progression. However, the exact contribution of each of the three family members is still to be defined. Their function appears to be context-dependent as they can act as oncogenes or tumor suppressor genes. They act as scaffolds modulating the activity of several signaling pathways involved in different cellular processes. In this review, we discuss the state-of-knowledge for TRIB1, TRIB2 and TRIB3 in the development and progression of colorectal cancer. We take a perspective look at the role of Tribbles proteins as potential biomarkers and therapeutic targets. Specifically, we chronologically systematized all available articles since 2003 until 2020, for which Tribbles were associated with colorectal cancer human samples or cell lines. Herein, we discuss: (1) Tribbles amplification and overexpression; (2) the clinical significance of Tribbles overexpression; (3) upstream Tribbles gene and protein expression regulation; (4) Tribbles pharmacological modulation; (5) genetic modulation of Tribbles; and (6) downstream mechanisms regulated by Tribbles; establishing a comprehensive timeline, essential to better consolidate the current knowledge of Tribbles’ role in colorectal cancer. Full article

(This article belongs to the Special Issue Pseudokinases, Tribbles Proteins and Cancer)

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17 pages, 547 KiB

Open AccessReview

The Critical Role of TRIB2 in Cancer and Therapy Resistance

by Victor Mayoral-Varo, Lucía Jiménez and Wolfgang Link

Cancers 2021, 13(11), 2701; https://doi.org/10.3390/cancers13112701 - 30 May 2021

Cited by 20 | Viewed by 4490

Abstract

The Tribbles pseudokinases family consists of TRIB1, TRIB2, TRIB3 and STK40 and, although evolutionarily conserved, they have distinctive characteristics. Tribbles members are expressed in a context and cell compartment-dependent manner. For example, TRIB1 and TRIB2 have potent oncogenic activities in vertebrate cells. Since [...] Read more.

The Tribbles pseudokinases family consists of TRIB1, TRIB2, TRIB3 and STK40 and, although evolutionarily conserved, they have distinctive characteristics. Tribbles members are expressed in a context and cell compartment-dependent manner. For example, TRIB1 and TRIB2 have potent oncogenic activities in vertebrate cells. Since the identification of Tribbles proteins as modulators of multiple signalling pathways, recent studies have linked their expression with several pathologies, including cancer. Tribbles proteins act as protein adaptors involved in the ubiquitin-proteasome degradation system, as they bridge the gap between substrates and E3 ligases. Between TRIB family members, TRIB2 is the most ancestral member of the family. TRIB2 is involved in protein homeostasis regulation of C/EBPα, β-catenin and TCF4. On the other hand, TRIB2 interacts with MAPKK, AKT and NFkB proteins, involved in cell survival, proliferation and immune response. Here, we review the characteristic features of TRIB2 structure and signalling and its role in many cancer subtypes with an emphasis on TRIB2 function in therapy resistance in melanoma, leukemia and glioblastoma. The strong evidence between TRIB2 expression and chemoresistance provides an attractive opportunity for targeting TRIB2. Full article

(This article belongs to the Special Issue Pseudokinases, Tribbles Proteins and Cancer)

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13 pages, 2440 KiB

Open AccessReview

Tribbles Pseudokinase 3 Regulation and Contribution to Cancer

by Bojana Stefanovska, Fabrice André and Olivia Fromigué

Cancers 2021, 13(8), 1822; https://doi.org/10.3390/cancers13081822 - 11 Apr 2021

Cited by 18 | Viewed by 3237

Abstract

The first Tribbles protein was identified as critical for the coordination of morphogenesis in Drosophila melanogaster. Three mammalian homologs were subsequently identified, with a structure similar to classic serine/threonine kinases, but lacking crucial amino acids for the catalytic activity. Thereby, the very weak [...] Read more.

The first Tribbles protein was identified as critical for the coordination of morphogenesis in Drosophila melanogaster. Three mammalian homologs were subsequently identified, with a structure similar to classic serine/threonine kinases, but lacking crucial amino acids for the catalytic activity. Thereby, the very weak ATP affinity classifies TRIB proteins as pseudokinases. In this review, we provide an overview of the regulation of TRIB3 gene expression at both transcriptional and post-translational levels. Despite the absence of kinase activity, TRIB3 interferes with a broad range of cellular processes through protein–protein interactions. In fact, TRIB3 acts as an adaptor/scaffold protein for many other proteins such as kinase-dependent proteins, transcription factors, ubiquitin ligases, or even components of the spliceosome machinery. We then state the contribution of TRIB3 to cancer development, progression, and metastasis. TRIB3 dysregulation can be associated with good or bad prognosis. Indeed, as TRIB3 interacts with and regulates the activity of many key signaling components, it can act as a tumor-suppressor or oncogene in a context-dependent manner. Full article

(This article belongs to the Special Issue Pseudokinases, Tribbles Proteins and Cancer)

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16 pages, 1825 KiB

Open AccessReview

Control of Cell Growth and Proliferation by the Tribbles Pseudokinase: Lessons from Drosophila

by Leonard L. Dobens, Christopher Nauman, Zachary Fischer and Xiaolan Yao

Cancers 2021, 13(4), 883; https://doi.org/10.3390/cancers13040883 - 20 Feb 2021

Cited by 14 | Viewed by 2993

Abstract

The Tribbles (Trib) family of pseudokinase proteins regulate cell growth, proliferation, and differentiation during normal development and in response to environmental stress. Mutations in human Trib isoforms (Trib1, 2, and 3) have been associated with metabolic disease and linked to leukemia and the [...] Read more.

The Tribbles (Trib) family of pseudokinase proteins regulate cell growth, proliferation, and differentiation during normal development and in response to environmental stress. Mutations in human Trib isoforms (Trib1, 2, and 3) have been associated with metabolic disease and linked to leukemia and the formation of solid tumors, including melanomas, hepatomas, and lung cancers. Drosophila Tribbles (Trbl) was the first identified member of this sub-family of pseudokinases and shares a conserved structure and similar functions to bind and direct the degradation of key mediators of cell growth and proliferation. Common Trib targets include Akt kinase (also known as protein kinase B), C/EBP (CAAT/enhancer binding protein) transcription factors, and Cdc25 phosphatases, leading to the notion that Trib family members stand athwart multiple pathways modulating their growth-promoting activities. Recent work using the Drosophila model has provided important insights into novel facets of conserved Tribbles functions in stem cell quiescence, tissue regeneration, metabolism connected to insulin signaling, and tumor formation linked to the Hippo signaling pathway. Here we highlight some of these recent studies and discuss their implications for understanding the complex roles Tribs play in cancers and disease pathologies. Full article

(This article belongs to the Special Issue Pseudokinases, Tribbles Proteins and Cancer)

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15 pages, 2924 KiB

Open AccessCommentary

Musings from the Tribbles Research and Innovation Network

by Miriam Ruiz-Cantos, Claire E. Hutchison and Carol C. Shoulders

Cancers 2021, 13(18), 4517; https://doi.org/10.3390/cancers13184517 - 08 Sep 2021

Cited by 2 | Viewed by 1859

Abstract

This commentary integrates historical and modern findings that underpin our understanding of the cell-specific functions of the Tribbles (TRIB) proteins that bear on tumorigenesis. We touch on the initial discovery of roles played by mammalian TRIB proteins in a diverse range of cell-types [...] Read more.

This commentary integrates historical and modern findings that underpin our understanding of the cell-specific functions of the Tribbles (TRIB) proteins that bear on tumorigenesis. We touch on the initial discovery of roles played by mammalian TRIB proteins in a diverse range of cell-types and pathologies, for example, TRIB1 in regulatory T-cells, TRIB2 in acute myeloid leukaemia and TRIB3 in gliomas; the origins and diversity of TRIB1 transcripts; microRNA-mediated (miRNA) regulation of TRIB1 transcript decay and translation; the substantial conformational changes that ensue on binding of TRIB1 to the transcription factor C/EBPα; and the unique pocket formed by TRIB1 to sequester its C-terminal motif bearing a binding site for the E3 ubiquitin ligase COP1. Unashamedly, the narrative is relayed through the perspective of the Tribbles Research and Innovation Network, and its establishment, progress and future ambitions: the growth of TRIB and COP1 research to hasten discovery of their cell-specific contributions to health and obesity-related cancers. Full article

(This article belongs to the Special Issue Pseudokinases, Tribbles Proteins and Cancer)

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