Regulation of RCAN1 Protein Activity by Dyrk1A Protein-mediated Phosphorylation

Jung, Min-Su; Park, Jung-Hwa; Ryu, Young Shin; Choi, Sunhee; Yoon, Song-Hee; Kwen, Mi-Yang; Oh, Ji Youn; Song, Woo-Joo; Chung, Samuel

doi:10.1074/jbc.m111.253971

Cited by 74 publications

(65 citation statements)

References 54 publications

(58 reference statements)

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“…Nuclear Factor of Activated T Cells (NFAT) Luciferase Assay-Luciferase assays were performed as described previously (16). HEK293T cells were first grown in 24-well plates and then transfected with 0.5 ng pCMV-RL reporter (Renilla luciferase, internal standard), 200 ng of pGL3-Basic reporter (NFAT-luciferase, AP-1 promoter), and indicated amounts of expression plasmids encoding empty vector, GSK3␤ WT, or the phosphorylation-defective mutants.…”

Section: Methodsmentioning

confidence: 99%

“…Coimmunoprecipitation (Co-IP) and GST Pulldown AssayCo-IP and the GST pulldown assay were performed as described previously (16). For co-IP, brain lysates (3 mg) from Dyrk1A TG mice or lysates of HEK293T cells (500 g) transfected with the indicated plasmids were incubated with control IgG (R&D Systems), anti-GSK3␤, or anti-Dyrk1A antibodies overnight at 4°C in ristocetin-induced platelet agglutination (RIPA) buffer (50 mM Tris (pH 8.0), 150 mM NaCl, 1% Nonidet P-40, 0.1% SDS, and 0.5% deoxycholic acid) with protease/phosphatase inhibitors and 1 mM PMSF.…”

Section: Methodsmentioning

confidence: 99%

“…and Western blot analysis were performed as described previously (16). Mouse embryonic fibroblast WT and GSK3␤ ( Ϫ/Ϫ ) cells were provided by Dr. Jim Woodgett (University of Toronto, Canada).…”

Section: Preparation Of Cell and Tissue Lysates And Western Blot Analmentioning

confidence: 99%

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Phosphorylation and Inactivation of Glycogen Synthase Kinase 3β (GSK3β) by Dual-specificity Tyrosine Phosphorylation-regulated Kinase 1A (Dyrk1A)

Song

Jung

et al. 2015

Journal of Biological Chemistry

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Background:The regulatory mechanism of GSK3␤ activity is not yet fully understood. Results: Dyrk1A inactivates GSK3␤ by phosphorylation at Thr 356 , which may contribute to an obesity-resistant phenotype. Conclusion: Dyrk1A-mediated phosphorylation is an alternative pathway for GSK3␤ inactivation. Significance: Understanding the mechanism regulating GSK3␤ activity is crucial for developing new therapies against GSK3␤-associated diseases, including obesity.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Phosphorylation and Inactivation of Glycogen Synthase Kinase 3β (GSK3β) by Dual-specificity Tyrosine Phosphorylation-regulated Kinase 1A (Dyrk1A)

Song

Jung

et al. 2015

Journal of Biological Chemistry

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“…BMK1 can phosphorylate RCAN1 at S112, and the BMK1-mediated phosphorylation of RCAN1 promotes the dissociation of RCAN1 from calcineurin, thereby relieving its inhibition of calcineurin activity [33]. In contrast, a recent report showed that Dyrk1A can phosphorylate RCAN1 at S112 and T192, and the phosphorylation of RCAN1 at T192 by Dyrk1A increases its ability to inhibit calcineurin phosphatase activity [36]. The PKA-mediated phosphorylation of RCAN1 at an unknown phosphorylation site has also been shown to enhance its inhibition of calcineurin-mediated gene transcription [37].…”

Section: Discussionmentioning

confidence: 89%

“…RCAN1 has been reported to be phosphorylated by various kinases, such as glycogen synthase kinase 3 (GSK-3) [27,32], ERK2 MAP kinase [27], big MAP kinase 1 (BMK1) [33], NFB-inducing kinase (NIK) [34], TGF-β-activated kinase 1 (TAK1) [35], dual specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) [36] and protein kinase A (PKA) [37]. The phosphorylation of RCAN1 has been shown to regulate calcineurin activity both positively and negatively.…”

Section: Discussionmentioning

confidence: 99%

p38α MAP kinase phosphorylates RCAN1 and regulates its interaction with calcineurin

Tang

Ren

et al. 2012

Sci. China Life Sci.

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RCAN1, also known as DSCR1, is an endogenous regulator of calcineurin, a serine/threonine protein phosphatase that plays a critical role in many physiological processes. In this report, we demonstrate that p38 MAP kinase can phosphorylate RCAN1 at multiple sites in vitro and show that phospho-RCAN1 is a good protein substrate for calcineurin. In addition, we found that unphosphorylated RCAN1 noncompetitively inhibits calcineurin protein phosphatase activity and that the phosphorylation of RCAN1 by p38 MAP kinase decreases the binding affinity of RCAN1 for calcineurin. These findings reveal the molecular mechanism by which p38 MAP kinase regulates the function of RCAN1/calcineurin through phosphorylation. [9]. The most thoroughly characterized calcineurin substrates are the nuclear factor of activated T cells (NFAT) family transcription factors. Two distinct calcineurin docking motifs from NFAT, the PxIxIT and LxVP binding motifs, have been identified [1013]. The PxIxIT motif is proposed to be the main calcineurin binding site, and it is present in many other calcineurin substrates and regulatory proteins. NFAT transcription factors are expressed in most immune cell types and play a central role in the regulation of cytokine gene expression. The localization of NFAT is regulated by its phosphorylation status. Calcineurin dephosphorylates multiple residues within the regulatory domain of NFAT, leading to its nuclear translocation and the activation of target genes including PTGS2 (COX-2) and TNF- (TNFA) [11,14].The regulation of calcineurin phosphatase activity by cellular inhibitors may have potential as novel modulators for the treatment of calcineurin-related diseases. Several endogenous proteins can inhibit the catalytic activity of calcineurin. Modulatory calcineurin interacting proteins (also called RCAN proteins) are unique among these proteins in terms of their expression pattern, and they function in a negative feedback loop to regulate calcineurin activity. The RCAN proteins comprise a family of endogenous calcineurin regulators that are conserved from yeast to humans and are essential for normal calcineurin signaling. Previous studies have shown that RCAN1 phosphorylation alters its effect on calcineurin. Human RCAN1 is encoded within the Down syndrome critical region on chromosome 21. It is

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Exosome release and cargo in Down syndrome

Hamlett

LaRosa

Mufson

et al. 2019

Developmental Neurobiology

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Down syndrome (DS) is a multisystem disorder affecting 1 in 800 births worldwide. Advancing technology, medical treatment, and social intervention have dramatically increased life expectancy, yet there are many etiologies of this disorder that are in need of further research. The advent of the ability to capture extracellular vesicles (EVs) in blood from specific cell types allows for the investigation of novel intracellular processes. Exosomes are one type of EVs that have demonstrated great potential in uncovering new biomarkers of neurodegeneration and disease, and also that appear to be intricately involved in the transsynaptic spread of pathogenic factors underlying Alzheimer's disease and other neurological diseases. Exosomes are nanosized vesicles, generated in endosomal multivesicular bodies (MVBs) and secreted by most cells in the body. Since exosomes are important mediators of intercellular communication and genetic exchange, they have emerged as a major research focus and have revealed novel biological sequelae involved in conditions afflicting the DS population. This review summarizes current knowledge on exosome biology in individuals with DS, both early in life and in aging individuals. Collectively these studies have demonstrated that complex multicellular processes underlying DS etiologies may include abnormal formation and secretion of extracellular vesicles such as exosomes.

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Regulation of RCAN1 Protein Activity by Dyrk1A Protein-mediated Phosphorylation

Cited by 74 publications

References 54 publications

Phosphorylation and Inactivation of Glycogen Synthase Kinase 3β (GSK3β) by Dual-specificity Tyrosine Phosphorylation-regulated Kinase 1A (Dyrk1A)

Phosphorylation and Inactivation of Glycogen Synthase Kinase 3β (GSK3β) by Dual-specificity Tyrosine Phosphorylation-regulated Kinase 1A (Dyrk1A)

p38α MAP kinase phosphorylates RCAN1 and regulates its interaction with calcineurin

Exosome release and cargo in Down syndrome

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