scholarly journals K63-linked ubiquitination of DYRK1A by TRAF2 alleviates Sprouty 2-mediated degradation of EGFR

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Pengshan Zhang ◽  
Zhe Zhang ◽  
Yinkun Fu ◽  
Ying Zhang ◽  
Michael P. Washburn ◽  
...  
Keyword(s):  
Cell Growth ◽  
Synaptic Transmission ◽  
Tyrosine Phosphorylation ◽  
Glioma Cells ◽  
Vesicle Membrane ◽  
Dual Specificity ◽  
Repeat Domain ◽  
Therapeutic Development ◽  
Cell Growth And Differentiation ◽  
Cellular Pathways

AbstractDual specificity tyrosine phosphorylation regulated kinase 1A, DYRK1A, functions in multiple cellular pathways, including signaling, endocytosis, synaptic transmission, and transcription. Alterations in dosage of DYRK1A leads to defects in neurogenesis, cell growth, and differentiation, and may increase the risk of certain cancers. DYRK1A localizes to a number of subcellular structures including vesicles where it is known to phosphorylate a number of proteins and regulate vesicle biology. However, the mechanism by which it translocates to vesicles is poorly understood. Here we report the discovery of TRAF2, an E3 ligase, as an interaction partner of DYRK1A. Our data suggest that TRAF2 binds to PVQE motif residing in between the PEST and histidine repeat domain (HRD) of DYRK1A protein, and mediates K63-linked ubiquitination of DYRK1A. This results in translocation of DYRK1A to the vesicle membrane. DYRK1A increases phosphorylation of Sprouty 2 on vesicles, leading to the inhibition of EGFR degradation, and depletion of TRAF2 expression accelerates EGFR degradation. Further, silencing of DYRK1A inhibits the growth of glioma cells mediated by TRAF2. Collectively, these findings suggest that the axis of TRAF2–DYRK1A-Sprouty 2 can be a target for new therapeutic development for EGFR-mediated human pathologies.

scholarly journals Dual-Specificity Phosphatases in Neuroblastoma Cell Growth and Differentiation

2019 ◽  
Vol 20 (5) ◽  
pp. 1170 ◽  
Author(s):  
Caroline Nunes-Xavier ◽  
Laura Zaldumbide ◽  
Olaia Aurtenetxe ◽  
Ricardo López-Almaraz ◽  
José López ◽  
...  
Keyword(s):  
Cell Growth ◽  
Map Kinases ◽  
Current Knowledge ◽  
Neuroblastoma Cell ◽  
Neuronal Cell ◽  
Predictive Biomarkers ◽  
Dual Specificity ◽  
Mapk Phosphatases ◽  
Cell Growth And Differentiation ◽  
Dual Specificity Phosphatases

Dual-specificity phosphatases (DUSPs) are important regulators of neuronal cell growth and differentiation by targeting proteins essential to neuronal survival in signaling pathways, among which the MAP kinases (MAPKs) stand out. DUSPs include the MAPK phosphatases (MKPs), a family of enzymes that directly dephosphorylate MAPKs, as well as the small-size atypical DUSPs, a group of low molecular-weight enzymes which display more heterogeneous substrate specificity. Neuroblastoma (NB) is a malignancy intimately associated with the course of neuronal and neuroendocrine cell differentiation, and constitutes the source of more common extracranial solid pediatric tumors. Here, we review the current knowledge on the involvement of MKPs and small-size atypical DUSPs in NB cell growth and differentiation, and discuss the potential of DUSPs as predictive biomarkers and therapeutic targets in human NB.

Inhibition by 5′-methylthioadenosine of cell growth and tyrosine kinase activity stimulated by fibroblast growth factor receptor in human gliomas

1995 ◽  
Vol 83 (4) ◽  
pp. 690-697 ◽  
Author(s):  
Katsuya Miyaji ◽  
Eiichi Tani ◽  
Atsuhisa Nakano ◽  
Hideyasu Ikemoto ◽  
Keizo Kaba
Keyword(s):  
Growth Factor ◽  
Cell Growth ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Protein Tyrosine Kinase ◽  
Kinase Activity ◽  
Glioma Cells ◽  
Protein Tyrosine Phosphorylation ◽  
Tyrosine Kinase Activity ◽  
Protein Tyrosine

✓ Stimulation of three human glioma cell lines with basic fibroblast growth factor (bFGF) led to the enhancement of cell growth and the rapid tyrosine phosphorylation of cellular proteins, including major substrates of 90 kD. A methyltransferase inhibitor, 5′-methylthioadenosine (MTA), inhibited dose dependently the bFGF-stimulated cell growth and protein tyrosine phosphorylation in glioma cells by blocking both receptor autophosphorylation and substrate phosphorylation, as shown by immunoblotting with antiphosphotyrosine antibodies and cross-linking bFGF to receptors. The antiproliferative activity of MTA correlated quantitatively with its potency as an inhibitor of bFGF-stimulated protein tyrosine kinase activity. The methyltransferase inhibitor MTA had no effect on either epidermal growth factor— or platelet-derived growth factor—stimulated protein tyrosine phosphorylation in glioma cells, but inhibited specifically bFGF-stimulated protein tyrosine kinase activity. The concentration of MTA required for inhibition of protein methylation correlated well with the concentration required for inhibition of bFGF-stimulated cell growth and protein tyrosine phosphorylation. Because MTA had no effect on numbers and dissociation constants of high- and low-affinity bFGF receptors, the inhibition of bFGF-stimulated bFGF receptor tyrosine kinase activity is not likely to be the result of a reduction in bFGF receptor and bFGF binding capacity. In fact, MTA delayed and reduced the internalization and nuclear translocation of bFGF, and the internalized bFGF was submitted to a limited proteolysis that converted it to lower molecular peptides whose presence remained for at least 22 hours. The effect of MTA on bFGF-stimulated tyrosine phosphorylation was immediate and readily reversible.

scholarly journals Tyrosine Phosphorylation of Grb2: Role in Prolactin/Epidermal Growth Factor Cross Talk in Mammary Epithelial Cell Growth and Differentiation

2009 ◽  
Vol 29 (10) ◽  
pp. 2505-2520 ◽  
Author(s):  
Eric Haines ◽  
Parham Minoo ◽  
Zhenqian Feng ◽  
Nazila Resalatpanah ◽  
Xin-Min Nie ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Cell Growth ◽  
Epithelial Cell ◽  
Epidermal Growth Factor ◽  
Tyrosine Phosphorylation ◽  
Mammary Epithelial Cell ◽  
Mammary Epithelial ◽  
Cell Growth And Differentiation ◽  
Epidermal Growth

ABSTRACT Characterizing mechanisms regulating mammary cell growth and differentiation is vital, as they may contribute to breast carcinogenesis. Here, we examine a cross talk mechanism(s) downstream of prolactin (PRL), a primary differentiation hormone, and epidermal growth factor (EGF), an important proliferative factor, in mammary epithelial cell growth and differentiation. Our data indicate that EGF exerts inhibitory effects on PRL-induced cellular differentiation by interfering with Stat5a-mediated gene expression independent of the PRL-proximal signaling cascade. Additionally, our data show that PRL is a potent inhibitor of EGF-induced cell proliferation. We identify tyrosine phosphorylation of the growth factor receptor-bound protein 2 (Grb2) as a critical mechanism by which PRL antagonizes EGF-induced cell proliferation by attenuating the activation of the Ras/mitogen-activated protein kinase (MAPK) pathway. Together, our results define a novel negative cross-regulation between PRL and EGF involving the Jak2/Stat5a and Ras/MAPK pathways through tyrosine phosphorylation of Grb2.

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

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.

scholarly journals Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

2021 ◽  
Vol 22 (11) ◽  
pp. 6047
Author(s):  
Mattias F. Lindberg ◽  
Laurent Meijer
Keyword(s):  
Tyrosine Phosphorylation ◽  
Human Disease ◽  
Intracellular Signaling ◽  
Neuronal Development ◽  
Viral Infections ◽  
Current Knowledge ◽  
Lymphoblastic Leukemia ◽  
Cell Cycle Control ◽  
Megakaryoblastic Leukemia ◽  
Dual Specificity

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.

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

Plants ◽  
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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