Dual Specificity, Tyrosine phosphorylation Regulated Kinases (DYRKs) in human disease: the therapeutic potential of pharmacological inhibitors

Dual-specificity tyrosine phosphorylation-regulated kinases (DYRK1A, 1B, 2-4) and cdc2-like kinases (CLK1-4) belong to the CMGC group of serine/threonine kinases. These protein kinases are involved in multiple cellular functions, including intracellular signaling, mRNA splicing, chromatin transcription, DNA damage repair, cell survival, cell cycle control, differentiation, homocysteine/methionine/folate regulation, body temperature regulation, endocytosis, neuronal development, synaptic plasticity, etc. Abnormal expression and/or activity of some of these kinases, DYRK1A in particular, is seen in many human nervous system diseases, such as cognitive deficits associated with Down syndrome, Alzheimer’s disease and related diseases, tauopathies, dementia, Pick’s disease, Parkinson’s disease and other neurodegenerative diseases, Phelan-McDermid syndrome, autism, and CDKL5 deficiency disorder. DYRKs and CLKs are also involved in diabetes, abnormal folate/methionine metabolism, osteoarthritis, several solid cancers (glioblastoma, breast, and pancreatic cancers) and leukemias (acute lymphoblastic leukemia, acute megakaryoblastic leukemia), viral infections (influenza, HIV-1, HCMV, HCV, CMV, HPV), as well as infections caused by unicellular parasites (Leishmania, Trypanosoma, Plasmodium). This variety of pathological implications calls for (1) a better understanding of the regulations and substrates of DYRKs and CLKs and (2) the development of potent and selective inhibitors of these kinases and their evaluation as therapeutic drugs. This article briefly reviews the current knowledge about DYRK/CLK kinases and their implications in human disease.

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Dual-specificity tyrosine phosphorylation-regulated kinase 1A is a NFAT kinase mediating negative feedback on Calcineurin/NFAT signaling in cardiac myocytes

European Journal of Heart Failure Supplements ◽

10.1016/s1567-4215(08)60569-x ◽

2008 ◽

Vol 7 ◽

pp. 206-207

Author(s):

T SEIDLER ◽

C GREBE ◽

T KLINGEBIEL ◽

B UNSOELD ◽

G HASENFUSS

Keyword(s):

Tyrosine Phosphorylation ◽

Cardiac Myocytes ◽

Negative Feedback ◽

Dual Specificity

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Avances moleculares en el síndrome de Down y su posible aplicación en neurología

Archivos de Neurociencias ◽

10.31157/archneurosciencesmex.v20i1.73 ◽

2015 ◽

Vol 20 (1) ◽

pp. 65-78

Author(s):

Manuel Ramos-Kuri ◽

Enrique Salgado-Sánchez

Keyword(s):

Tyrosine Phosphorylation ◽

Dual Specificity

Se revisan los avances recientes en el síndrome de Down (SD), haciendo énfasis en su terapia molecular y potencial terapéutico en enfermedades como Alzheimer (EA) y otros trastornos de déficit cognoscitivo. El SD es la principal causa de retraso mental a nivel mundial, causado por la trisomía completa o parcial del cromosoma 21, y es bien conocida su estrecha relación con la EA, de inicio muy temprano. La sobre-expresión de genes del cromosoma 21 es la principal causa del SD, pero se han identificado algunos genes especialmente importantes. Por ejemplo, el gen DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase) participa en el déficit cognitivo tanto en SD como en la EA. Su fisiopatología es porque el exceso de DYRK1A hiper fosforila a la proteína precursora de amiliode (APP) y a la unidad asociada a tubulina (TAU) proteínas bien conocidas en la génesis de la EA. Otra aplicación potencial es que los pacientes con SD presentan menor incidencia de tumores sólidos; su mecanismo es inhibiendo angiogénesis, por inhibición del factor de crecimiento vascular endotelial (VEGF) a través de la inhibición de calcineurina, gracias a la sobre-expresión del gen DSCR-1 presente en el cromosoma 21. Aunque el SD aún no cuenta con terapia específica, se realiza terapia molecular en modelos murinos con SD, con dos péptidos intestinales vasoactivos NAP y SAL. Los ratones así tratados mostraron una clara disminución en el déficit cognoscitivo, sugiriendo un alto potencial terapéutico para el SD; así como, otros tipos de retardo mental y déficit de aprendizaje.

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Characterization of Atypical Protein Tyrosine Kinase (PTK) Genes and Their Role in Abiotic Stress Response in Rice

Plants ◽

10.3390/plants9050664 ◽

2020 ◽

Vol 9 (5) ◽

pp. 664

Author(s):

Allimuthu Elangovan ◽

Monika Dalal ◽

Gopinathan Kumar Krishna ◽

Sellathdurai Devika ◽

Ranjeet Ranjan Kumar ◽

...

Keyword(s):

Abiotic Stress ◽

Stress Response ◽

Tyrosine Kinase ◽

Tyrosine Phosphorylation ◽

Rice Genome ◽

Kinase Domain ◽

Tyrosine Kinase Domain ◽

Protein Tyrosine ◽

Dual Specificity ◽

Submergence Stress

Tyrosine phosphorylation constitutes up to 5% of the total phophoproteome. However, only limited studies are available on protein tyrosine kinases (PTKs) that catalyze protein tyrosine phosphorylation in plants. In this study, domain analysis of the 27 annotated PTK genes in rice genome led to the identification of 18 PTKs with tyrosine kinase domain. The kinase domain of rice PTKs shared high homology with that of dual specificity kinase BRASSINOSTEROID-INSENSITIVE 1 (BRI1) of Arabidopsis. In phylogenetic analysis, rice PTKs clustered with receptor-like cytoplasmic kinases-VII (RLCKs-VII) of Arabidopsis. mRNAseq analysis using Genevestigator revealed that rice PTKs except PTK9 and PTK16 express at moderate to high level in most tissues. PTK16 expression was highly abundant in panicle at flowering stage. mRNAseq data analysis led to the identification of drought, heat, salt, and submergence stress regulated PTK genes in rice. PTK14 was upregulated under all stresses. qRT-PCR analysis also showed that all PTKs except PTK10 were significantly upregulated in root under osmotic stress. Tissue specificity and abiotic stress mediated differential regulation of PTKs suggest their potential role in development and stress response of rice. The candidate dual specificity PTKs identified in this study paves way for molecular analysis of tyrosine phosphorylation in rice.

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dDYRK2: a novel dual-specificity tyrosine-phosphorylation-regulated kinase in Drosophila

Biochemical Journal ◽

10.1042/bj20030500 ◽

2003 ◽

Vol 374 (2) ◽

pp. 381-391 ◽

Cited By ~ 30

Author(s):

Pamela A. LOCHHEAD ◽

Gary SIBBET ◽

Ross KINSTRIE ◽

Tava CLEGHON ◽

Margie RYLATT ◽

...

Keyword(s):

Tyrosine Phosphorylation ◽

Protein Kinases ◽

Mutational Analysis ◽

Kinase Domain ◽

Activation Loop ◽

Embryonic Neurogenesis ◽

Founding Family ◽

Dual Specificity ◽

Eukaryotic Organisms

Dual-specificity tyrosine-phosphorylation-regulated kinases (DYRKs) are an emerging family of protein kinases that have been identified in all eukaryotic organisms examined to date. DYRK family members are involved in regulating key developmental and cellular processes such as neurogenesis, cell proliferation, cytokinesis and cellular differentiation. Two distinct subgroups exist, nuclear and cytosolic. In Drosophila, the founding family member minibrain, whose human orthologue maps to the Down syndrome critical region, belongs to the nuclear subclass and affects post-embryonic neurogenesis. In the present paper, we report the isolation of dDYRK2, a cytosolic DYRK and the putative product of the smell-impaired smi35A gene. This is the second such kinase described in Drosophila, but the first to be characterized at the molecular and biochemical level. dDYRK2 is an 81 kDa dual-specificity kinase that autophosphorylates on tyrosine and serine/threonine residues, but appears to phosphorylate exogenous substrates only on serine/threonine residues. It contains a YXY motif in the activation loop of the kinase domain in the same location as the TXY motif in mitogenactivated protein kinases. dDYRK2 is tyrosine-phosphorylated in vivo, and mutational analysis reveals that the activation loop tyrosines are phosphorylated and are essential for kinase activity. Finally, dDYRK2 is active at all stages of fly development, with elevated levels observed during embryogenesis and pupation.

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Proglucagon-Derived Peptides: Mechanisms of Action and Therapeutic Potential

Physiology ◽

10.1152/physiol.00030.2005 ◽

2005 ◽

Vol 20 (5) ◽

pp. 357-365 ◽

Cited By ~ 54

Author(s):

Elaine M Sinclair ◽

Daniel J. Drucker

Keyword(s):

Type 2 Diabetes ◽

Human Disease ◽

Clinical Relevance ◽

Therapeutic Potential ◽

Mechanisms Of Action ◽

Receptor Antagonists ◽

Glucagon Receptor ◽

Receptor Agonists ◽

Glucagon Like Peptide

Glucagon is used for the treatment of hypoglycemia, and glucagon receptor antagonists are under development for the treatment of type 2 diabetes. Moreover, glucagon-like peptide (GLP)-1 and GLP-2 receptor agonists appear to be promising therapies for the treatment of type 2 diabetes and intestinal disorders, respectively. This review discusses the physiological, pharmacological, and therapeutic actions of the proglucagon-derived peptides, with an emphasis on clinical relevance of the peptides for the treatment of human disease.

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Dual Specificity Phosphatases: From Molecular Mechanisms to Biological Function

International Journal of Molecular Sciences ◽

10.3390/ijms20184372 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4372 ◽

Cited By ~ 1

Author(s):

Rafael Pulido ◽

Roland Lang

Keyword(s):

Protein Tyrosine Phosphatase ◽

Human Disease ◽

Molecular Mechanisms ◽

Biological Function ◽

Tyrosine Phosphatase ◽

Heterogeneous Group ◽

Class I ◽

Protein Tyrosine ◽

Dual Specificity ◽

Dual Specificity Phosphatases

Dual specificity phosphatases (DUSPs) constitute a heterogeneous group of enzymes, relevant in human disease, which belong to the class I Cys-based group of protein tyrosine phosphatase (PTP) gene superfamily [...]

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