2. Academic Validation
  3. A Novel Druggable Dual-Specificity tYrosine-Regulated Kinase3/Calmodulin Kinase-like Vesicle-Associated Signaling Module with Therapeutic Implications in Neuroblastoma

A Novel Druggable Dual-Specificity tYrosine-Regulated Kinase3/Calmodulin Kinase-like Vesicle-Associated Signaling Module with Therapeutic Implications in Neuroblastoma

  • Biomedicines. 2024 Jan 16;12(1):197. doi: 10.3390/biomedicines12010197.
Esteban J Rozen 1 2 3,  Kim Wigglesworth 3,  Jason M Shohet 3
Affiliations

Affiliations

  • 1 Crnic Institute Boulder Branch, BioFrontiers Institute, University of Colorado Boulder, 3415 Colorado Avenue, Boulder, CO 80303, USA.
  • 2 Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, 12700 East 19th Avenue, Aurora, CO 80045, USA.
  • 3 Department of Pediatrics, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01566, USA.
PMID: 38255303 DOI: 10.3390/biomedicines12010197
Abstract

High-risk neuroblastoma is a very aggressive pediatric Cancer, accounting for ~15% of childhood Cancer mortality. Therefore, novel therapeutic strategies for the treatment of neuroblastoma are urgently sought. Here, we focused on the potential implications of the Dual-specificity tYrosine-Regulated Kinase (DYRK) family and downstream signaling pathways. We used bioinformatic analysis of public datasets from neuroblastoma cohorts and cell lines to search correlations between patient survival and expression of DYRK kinases. Additionally, we performed biochemical, molecular, and cellular approaches to validate and characterize our observations, as well as an in vivo orthotopic murine model of neuroblastoma. We identified the DYRK3 kinase as a critical mediator of neuroblastoma cell proliferation and in vivo tumor growth. DYRK3 has recently emerged as a key regulator of several biomolecular condensates and has been linked to the hypoxic response of neuroblastoma cells. Our data suggest a role for DYRK3 as a regulator of the neuroblastoma-specific protein CAMKV, which is also required for neuroblastoma cell proliferation. CAMKV is a very understudied member of the CA2+/calmodulin-dependent protein kinase family, originally described as a pseudokinase. We show that CAMKV is phosphorylated by DYRK3, and that inhibition of DYRK3 kinase activity induces CAMKV aggregation, probably mediated by its highly disordered C-terminal half. Importantly, we provide evidence that the DYRK3/CAMKV signaling module could play an important role for the function of the mitotic spindle during cell division. Our data strongly support the idea that inhibition of DYRK3 and/or CAMKV in neuroblastoma cells could constitute an innovative and highly specific intervention to fight against this dreadful Cancer.

Keywords

CAMKV; DYRK3; biomolecular condensates; cell proliferation; mitotic spindle; neuroblastoma.

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