Inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 2 perturbs 26S proteasome-addicted neoplastic progression

Banerjee, Sourav; Wei, Tiantian; Wang, Jue; Lee, Jenna J; Gutierrez, Haydee L.; Chapman, Owen; Wiley, Sandra E.; Mayfield, Joshua E.; Tandon, Vasudha; Juarez, Edwin F.; Chávez, Lukas; Liang, Ruqi; Sah, Robert L.; Costello, Caitlin; Vega, Laureano de la; Cooper, Kimberly L.; Dixon, Jack E.; Xiao, Junyu; Lei, Xiaoguang

doi:10.1073/pnas.1912033116

Cited by 43 publications

(98 citation statements)

References 49 publications

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“…In 2013, Soundararajan et al presented DYRK2 protein structure (PDB: 3KL2) [4]. In a major advance in 2018, Banerjee et al described DYRK2 crystal structure with curcumine (PDB: 5ZTN) [13] and 1 year later with LDN192960 (PDB: 6K0J) [14]. There have also been numerous studies to investigate the functional roles of DYRK2 domains.…”

Section: Sequence and Structurementioning

confidence: 99%

“…In 2016, Guo et al revealed the DYRK2 implications in 26S proteasome complex as the primary Rpt3 Thr25 phosphorylation kinase controlling G1/S transition. DYRK2 inactivation and consequent loss of phosphorylation are enough to reduce protein activity, slowdown cell proliferation, and potentiate bortezomib anti-growth effect [13,14,66].…”

Section: Biological Functionsmentioning

confidence: 99%

“…Nevertheless, not all works state that DYRK2 negatively regulates invasion and metastatic potential of cancer cells. For example, it has been reported that DYRK2 inhibition by LDN192960 affects the tumorigenic potential of triple-negative breast cancer cells due to DYRK2 activity on 26S proteasome [13,14].…”

Section: Dyrk2 and Diseasementioning

confidence: 99%

“…It also inhibits other DYRK family members (DYRK1A, IC 50 : 122 nM; DYRK3, IC 50 : < 3 nM). Like curcumin, different approximations have demonstrated its ability to inhibit neoplastic progression in triple-negative breast cancer and multiple myeloma cell lines [14].…”

Section: Pharmacological Inhibition Of Dyrk2mentioning

confidence: 99%

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Updating dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2): molecular basis, functions and role in diseases

Correa-Sáez

Jiménez‐Izquierdo

Garrido‐Rodríguez

et al. 2020

Cell. Mol. Life Sci.

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Members of the dual-specificity tyrosine-regulated kinase (DYRKs) subfamily possess a distinctive capacity to phosphorylate tyrosine, serine, and threonine residues. Among the DYRK class II members, DYRK2 is considered a unique protein due to its role in disease. According to the post-transcriptional and post-translational modifications, DYRK2 expression greatly differs among human tissues. Regarding its mechanism of action, this kinase performs direct phosphorylation on its substrates or acts as a priming kinase, enabling subsequent substrate phosphorylation by GSK3β. Moreover, DYRK2 acts as a scaffold for the EDVP E3 ligase complex during the G2/M phase of cell cycle. DYRK2 functions such as cell survival, cell development, cell differentiation, proteasome regulation, and microtubules were studied in complete detail in this review. We have also gathered available information from different bioinformatic resources to show DYRK2 interactome, normal and tumoral tissue expression, and recurrent cancer mutations. Then, here we present an innovative approach to clarify DYRK2 functionality and importance. DYRK2 roles in diseases have been studied in detail, highlighting this kinase as a key protein in cancer development. First, DYRK2 regulation of c-Jun, c-Myc, Rpt3, TERT, and katanin p60 reveals the implication of this kinase in cell-cycle-mediated cancer development. Additionally, depletion of this kinase correlated with reduced apoptosis, with consequences on cancer patient response to chemotherapy. Other functions like cancer stem cell formation and epithelial-mesenchymal transition regulation are also controlled by DYRK2. Furthermore, the pharmacological modulation of this protein by different inhibitors (harmine, curcumine, LDN192960, and ID-8) has enabled to clarify DYRK2 functionality.

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Section: Sequence and Structurementioning

confidence: 99%

Section: Biological Functionsmentioning

confidence: 99%

Section: Dyrk2 and Diseasementioning

confidence: 99%

Section: Pharmacological Inhibition Of Dyrk2mentioning

confidence: 99%

See 2 more Smart Citations

Updating dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2): molecular basis, functions and role in diseases

Correa-Sáez

Jiménez‐Izquierdo

Garrido‐Rodríguez

et al. 2020

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

show abstract

“…Harmine, compound LDN192960, and curcumin have been described as inhibitors of DYRK2 activity that could potentially be tested for antitumor therapy (Fig. 4) [75][76][77] .…”

Section: Dyrk2mentioning

confidence: 99%

DYRK2 controls a key regulatory network in chronic myeloid leukemia stem cells

Park

Lacorazza

2020

Exp Mol Med

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Chronic myeloid leukemia is a hematological cancer driven by the oncoprotein BCR-ABL1, and lifelong treatment with tyrosine kinase inhibitors extends patient survival to nearly the life expectancy of the general population. Despite advances in the development of more potent tyrosine kinase inhibitors to induce a durable deep molecular response, more than half of patients relapse upon treatment discontinuation. This clinical finding supports the paradigm that leukemia stem cells feed the neoplasm, resist tyrosine kinase inhibition, and reactivate upon drug withdrawal depending on the fitness of the patient’s immune surveillance. This concept lends support to the idea that treatment-free remission is not achieved solely with tyrosine kinase inhibitors and that new molecular targets independent of BCR-ABL1 signaling are needed in order to develop adjuvant therapy to more efficiently eradicate the leukemia stem cell population responsible for chemoresistance and relapse. Future efforts must focus on the identification of new targets to support the discovery of potent and safe small molecules able to specifically eradicate the leukemic stem cell population. In this review, we briefly discuss molecular maintenance in leukemia stem cells in chronic myeloid leukemia and provide a more in-depth discussion of the dual-specificity kinase DYRK2, which has been identified as a novel actionable checkpoint in a critical leukemic network. DYRK2 controls the activation of p53 and proteasomal degradation of c-MYC, leading to impaired survival and self-renewal of leukemia stem cells; thus, pharmacological activation of DYRK2 as an adjuvant to standard therapy has the potential to induce treatment-free remission.

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Chemoproteomics, A Broad Avenue to Target Deconvolution

Gao,

Ma,

et al. 2023

Advanced Science

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As a vital project of forward chemical genetic research, target deconvolution aims to identify the molecular targets of an active hit compound. Chemoproteomics, either with chemical probe‐facilitated target enrichment or probe‐free, provides a straightforward and effective approach to profile the target landscape and unravel the mechanisms of action. Canonical methods rely on chemical probes to enable target engagement, enrichment, and identification, whereas click chemistry and photoaffinity labeling techniques improve the efficiency, sensitivity, and spatial accuracy of target recognition. In comparison, recently developed probe‐free methods detect protein‐ligand interactions without the need to modify the ligand molecule. This review provides a comprehensive overview of different approaches and recent advancements for target identification and highlights the significance of chemoproteomics in investigating biological processes and advancing drug discovery processes.

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Inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 2 perturbs 26S proteasome-addicted neoplastic progression

Cited by 43 publications

References 49 publications

Updating dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2): molecular basis, functions and role in diseases

Updating dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2): molecular basis, functions and role in diseases

DYRK2 controls a key regulatory network in chronic myeloid leukemia stem cells

Chemoproteomics, A Broad Avenue to Target Deconvolution

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