Tribbles homolog 2 (Trib2), a pseudo serine/threonine kinase in tumorigenesis and stem cell fate decisions

Yu, Fenglei; Zekiy, Angelina Olegovna; Ghaedrahmati, Farhoodeh; Timoshin, Anton; Farzaneh, Maryam; Anbiyaiee, Amir; Khoshnam, Seyed Esmaeil

doi:10.1186/s12964-021-00725-y

Cited by 13 publications

(6 citation statements)

References 79 publications

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“…With its pseudo serine/threonine kinase domain, TRIB2 functions as a scaffold or adaptor in the signaling pathways of physiological and pathological processes [ 33 ]. Whether TRIB2 participates the regulation of kinase activities in cell metabolism remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic TRIB2 interacts with and regulates PKM2 to promote aerobic glycolysis and lung cancer cell procession

et al. 2022

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PKM2 is an important regulator of the aerobic glycolysis that plays a vital role in cancer cell metabolic reprogramming. In general, Trib2 is considered as a “pseudokinase”, contributing to different kinds of cancer. However, the detailed roles of TRIB2 in regulating cancer metabolism by PKM2 remain unclear. This study demonstrated that TRIB2, not a “pseudokinase”, has the kinase activity to directly phosphorylate PKM2 at serine 37 in cancer cells. The elevated pSer37-PKM2 would subsequently promote the PKM2 dimers to enter into nucleus and increase the expression of LDHA, GLUT1, and PTBP1. The aerobic glycolysis is then elevated to promote cancer cell proliferation and migration in TRIB2- or PKM2-overexpressed cultures. The glucose uptake and lactate production increased, but the ATP content decreased in TRIB2- or PKM2-treated cultures. Experiments of TRIB2−/− mice further supported that TRIB2 could regulate aerobic glycolysis by PKM2. Thus, these results reveal the new kinase activity of TRIB2 and its mechanism in cancer metabolism may be related to regulating PKM2 to promote lung cancer cell proliferation in vitro and in vivo, suggesting promising therapeutic targets for cancer therapy by controlling cancer metabolism.

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Section: Discussionmentioning

confidence: 99%

Oncogenic TRIB2 interacts with and regulates PKM2 to promote aerobic glycolysis and lung cancer cell procession

et al. 2022

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“…Nevertheless, among the shared upregulated genes, we found COL6A1, COL6A2, SEMA3A, EFNB1, ECE1, IL13RA2, TNC, and TRIB2 (Figure 5K, Supplementary Figure 5C), all of which have been associated with cancer cell stemness, migration, invasion, aggressiveness, and poor prognosis in various cancer types, including glioma [26][27][28][29][30][31][32][33]. Notably, SEMA3A functions as an axon guidance factor, playing a pivotal role in navigating the axonal network during neural development, while also regulating synaptogenesis and synaptic plasticity [34].…”

Section: Medulloblastoma Tumor Cells Home Towards the Hindbrain Regio...mentioning

confidence: 98%

Development of an orthotopic medulloblastoma zebrafish model for rapid drug testing

van Bree,

Oppelt,

Lindström

et al. 2024

Preprint

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Medulloblastoma (MB) is one of the most common malignant brain tumors in children. Current preclinicalin vivomodel systems for MB have increased our understanding of molecular mechanisms regulating MB development; however, they may not be suitable for high-throughput screening efforts. We demonstrate here that transplantation of seven different MB cell lines or patient-derived cells into the blastula stage of zebrafish embryos leads to orthotopic tumor cell growth that can be observed within 24 hours after transplantation. Importantly, the homing of transplanted cells to the hindbrain region and the aggressiveness of tumor growth are enhanced by pre-culturing cells in a neural stem cell-like medium. The change in culture conditions rewires the transcriptome towards a more migratory and neuronal progenitor phenotype, including the expression of guidance molecules SEMA3A and EFNB1, both of which correlate with lower overall survival in MB patients. Furthermore, we highlight that the orthotopic zebrafish MB xenograft model has the potential to be used for high-throughput drug screening.Key pointsMedulloblastoma cells home to the hindbrain region in developing zebrafish embryos.Neural stem cell culture conditions improve the homing capacity of MB tumor cells.Medulloblastoma-transplanted zebrafish embryos can be used as a high-throughputin vivomodel for drug screening.Importance of the StudyOne of the challenges of accurately modeling medulloblastoma is the large heterogeneity in tumor characteristics. To accurately model this heterogeneous disease, patient-derived xenograft mouse models are currently the standard. However, such mouse models are labor intensive, time-consuming, and not suitable for high-throughput studies. Here, we describe a quick and straightforward zebrafish xenograft model that provides a promising alternative to these existing mouse models. We demonstrate that this model can be utilized to study tumor cell growth of several major medulloblastoma subgroups. More importantly, our model facilitates high-throughput drug testing, providing a scalable opportunity forin vivodrug screenings that will support the discovery of novel therapeutic compounds against medulloblastoma.

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“…Over two-thirds of pseudokinases have been implicated in a range of human pathologies . For example, mutations within the pseudokinase domain of JAK2 underlie human blood cell malignancies , (for inhibitors targeting the pseudokinase domain of the Janus kinase TYK2, see the allosteric inhibitor section) and TRIB2 plays a role in driving AML via degradation of the CCAAT-enhancer-binding protein α (C/EBPα) mediated by the pseudokinase. , …”

Section: Opportunities and Challengesmentioning

confidence: 99%

“…205 For example, mutations within the pseudoki-nase domain of JAK2 underlie human blood cell malignancies 206,207 (for inhibitors targeting the pseudokinase domain of the Janus kinase TYK2, see the allosteric inhibitor section) and TRIB2 plays a role in driving AML via degradation of the CCAAT-enhancer-binding protein α (C/EBPα) mediated by the pseudokinase. 208,209 An interesting recent example highlighting the role of pseudokinases was reported by Khan et al shedding light on the mechanism of the FDA-approved allosteric MEK inhibitor trametinib (84, Figure 19) involving the pseudokinases KSR1 and KSR2 (kinase suppressor of Ras 1 and 2). 210 KSR1/2 are related to the RAF family kinases and are known to cooperate with MEK1/2 in regulating the MAPK/ERK pathway.…”

Section: ■ Opportunities and Challengesmentioning

confidence: 99%

Chemical Probes for Understudied Kinases: Challenges and Opportunities

et al. 2021

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Over twenty years after the approval of the first-in-class protein kinase inhibitor imatinib, the biological function of a significant fraction of the human kinome remains poorly understood while most research continues to be focused on few well-validated targets. Given the strong genetic evidence for involvement of many kinases in health and disease, the understudied fraction of the kinome holds a large and unexplored potential for future therapies. Specific chemical probes are indispensable tools to interrogate biology enabling proper preclinical validation of novel kinase targets. In this Perspective, we highlight recent case studies illustrating the development of highquality chemical probes for less-studied kinases and their application in target validation. We spotlight emerging techniques and approaches employed to the generation of chemical probes for protein kinases and beyond and discuss the associated challenges and opportunities.

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Tribbles homolog 2 (Trib2), a pseudo serine/threonine kinase in tumorigenesis and stem cell fate decisions

Cited by 13 publications

References 79 publications

Oncogenic TRIB2 interacts with and regulates PKM2 to promote aerobic glycolysis and lung cancer cell procession

Oncogenic TRIB2 interacts with and regulates PKM2 to promote aerobic glycolysis and lung cancer cell procession

Development of an orthotopic medulloblastoma zebrafish model for rapid drug testing

Chemical Probes for Understudied Kinases: Challenges and Opportunities

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