DUSP4 Regulates Neuronal Differentiation and Calcium Homeostasis by Modulating ERK1/2 Phosphorylation

Overview

Journal Stem Cells Dev

Date 2014 Nov 15

PMID 25397900

Citations 22

Authors

Sun Young Kim

Yong-Mahn Han

Mihee Oh

Won-Kon Kim

Kyoung-Jin Oh

Sang Chul Lee

Kwang-Hee Bae

Baek-Soo Han

Affiliations

Soon will be listed here.

Abstract

Protein tyrosine phosphatases have been recognized as critical components of multiple signaling regulators of fundamental cellular processes, including differentiation, cell death, and migration. In this study, we show that dual specificity phosphatase 4 (DUSP4) is crucial for neuronal differentiation and functions in the neurogenesis of embryonic stem cells (ESCs). The endogenous mRNA and protein expression levels of DUSP4 gradually increased during mouse development from ESCs to postnatal stages. Neurite outgrowth and the expression of neuron-specific markers were markedly reduced by genetic ablation of DUSP4 in differentiated neurons, and these effects were rescued by the reintroduction of DUSP4. In addition, DUSP4 knockdown dramatically enhanced extracellular signal-regulated kinase (ERK) activation during neuronal differentiation. Furthermore, the DUSP4-ERK pathway functioned to balance calcium signaling, not only by regulating Ca(2+)/calmodulin-dependent kinase I phosphorylation, but also by facilitating Cav1.2 expression and plasma membrane localization. These data are the first to suggest a molecular link between the MAPK-ERK cascade and calcium signaling, which provides insight into the mechanism by which DUSP4 modulates neuronal differentiation.

Citing Articles

Dual-Specificity Protein Phosphatase 4 (DUSP4) Overexpression Improves Learning Behavior Selectively in Female 5xFAD Mice, and Reduces β-Amyloid Load in Males and Females.

Pan A, Audrain M, Sakakibara E, Joshi R, Zhu X, Wang Q Cells. 2022; 11(23).

PMID: 36497141 PMC: 9737364. DOI: 10.3390/cells11233880.

Early Transcriptional Changes in Rabies Virus-Infected Neurons and Their Impact on Neuronal Functions.

Kim S, Larrous F, Varet H, Legendre R, Feige L, Dumas G Front Microbiol. 2021; 12:730892.

PMID: 34970230 PMC: 8713068. DOI: 10.3389/fmicb.2021.730892.

Depletion of Janus kinase-2 promotes neuronal differentiation of mouse embryonic stem cells.

Oh M, Kim S, Byun J, Lee S, Kim W, Oh K BMB Rep. 2021; 54(12):626-631.

PMID: 34847985 PMC: 8728538.

ERK1/2: An Integrator of Signals That Alters Cardiac Homeostasis and Growth.

Gilbert C, Longenecker J, Accornero F Biology (Basel). 2021; 10(4).

PMID: 33923899 PMC: 8072600. DOI: 10.3390/biology10040346.

Dedifferentiation and neuronal repression define familial Alzheimer's disease.

Caldwell A, Liu Q, Schroth G, Galasko D, Yuan S, Wagner S Sci Adv. 2020; 6(46).

PMID: 33188013 PMC: 7673760. DOI: 10.1126/sciadv.aba5933.

References

Rosenberg S, Spitzer N . Calcium signaling in neuronal development. Cold Spring Harb Perspect Biol. 2011; 3(10):a004259. PMC: 3179332. DOI: 10.1101/cshperspect.a004259. View

Malmersjo S, Liste I, Dyachok O, Tengholm A, Arenas E, Uhlen P . Ca2+ and cAMP signaling in human embryonic stem cell-derived dopamine neurons. Stem Cells Dev. 2010; 19(9):1355-64. DOI: 10.1089/scd.2009.0436. View

Barkovich A, Guerrini R, Kuzniecky R, Jackson G, Dobyns W . A developmental and genetic classification for malformations of cortical development: update 2012. Brain. 2012; 135(Pt 5):1348-69. PMC: 3338922. DOI: 10.1093/brain/aws019. View

Mor M, Beharier O, Levy S, Kahn J, Dror S, Blumenthal D . ZnT-1 enhances the activity and surface expression of T-type calcium channels through activation of Ras-ERK signaling. Am J Physiol Cell Physiol. 2012; 303(2):C192-203. DOI: 10.1152/ajpcell.00427.2011. View

Mortensen O . MKP3 eliminates depolarization-dependent neurotransmitter release through downregulation of L-type calcium channel Cav1.2 expression. Cell Calcium. 2013; 53(3):224-30. DOI: 10.1016/j.ceca.2012.12.004. View

Clegg J, Gillott A, Jones J . Conceptual issues in neurodevelopmental disorders: lives out of synch. Curr Opin Psychiatry. 2013; 26(3):289-94. DOI: 10.1097/YCO.0b013e32835f6771. View

Finelli M, Murphy K, Chen L, Zou H . Differential phosphorylation of Smad1 integrates BMP and neurotrophin pathways through Erk/Dusp in axon development. Cell Rep. 2013; 3(5):1592-606. PMC: 3677165. DOI: 10.1016/j.celrep.2013.04.011. View

Arregui C, Balsamo J, Lilien J . Regulation of signaling by protein-tyrosine phosphatases: potential roles in the nervous system. Neurochem Res. 2000; 25(1):95-105. DOI: 10.1023/a:1007595617447. View

Kasahara J, Fukunaga K, Miyamoto E . Activation of CA(2+)/calmodulin-dependent protein kinase IV in cultured rat hippocampal neurons. J Neurosci Res. 2000; 59(5):594-600. DOI: 10.1002/(SICI)1097-4547(20000301)59:5<594::AID-JNR2>3.0.CO;2-Q. View

10.

Dwivedi Y, Rizavi H, Roberts R, Conley R, Tamminga C, Pandey G . Reduced activation and expression of ERK1/2 MAP kinase in the post-mortem brain of depressed suicide subjects. J Neurochem. 2001; 77(3):916-28. DOI: 10.1046/j.1471-4159.2001.00300.x. View

11.

Chen P, Hutter D, Yang X, Gorospe M, Davis R, Liu Y . Discordance between the binding affinity of mitogen-activated protein kinase subfamily members for MAP kinase phosphatase-2 and their ability to activate the phosphatase catalytically. J Biol Chem. 2001; 276(31):29440-9. DOI: 10.1074/jbc.M103463200. View

12.

Zhang T, Wolfe M, Roberson M . An early growth response protein (Egr) 1 cis-element is required for gonadotropin-releasing hormone-induced mitogen-activated protein kinase phosphatase 2 gene expression. J Biol Chem. 2001; 276(49):45604-13. DOI: 10.1074/jbc.M107075200. View

13.

Soderling T, Stull J . Structure and regulation of calcium/calmodulin-dependent protein kinases. Chem Rev. 2001; 101(8):2341-52. DOI: 10.1021/cr0002386. View

14.

Torres C, Francis M, Lorenzini A, Tresini M, Cristofalo V . Metabolic stabilization of MAP kinase phosphatase-2 in senescence of human fibroblasts. Exp Cell Res. 2003; 290(2):195-206. DOI: 10.1016/s0014-4827(03)00309-4. View

15.

Guan K, Butch E . Isolation and characterization of a novel dual specific phosphatase, HVH2, which selectively dephosphorylates the mitogen-activated protein kinase. J Biol Chem. 1995; 270(13):7197-203. DOI: 10.1074/jbc.270.13.7197. View

16.

Rim C, Yao H, Roberson M, Stork P . A novel mitogen-activated protein kinase phosphatase. Structure, expression, and regulation. J Biol Chem. 1995; 270(24):14587-96. DOI: 10.1074/jbc.270.24.14587. View

17.

Chu Y, Solski P, Khosravi-Far R, Der C, Kelly K . The mitogen-activated protein kinase phosphatases PAC1, MKP-1, and MKP-2 have unique substrate specificities and reduced activity in vivo toward the ERK2 sevenmaker mutation. J Biol Chem. 1996; 271(11):6497-501. DOI: 10.1074/jbc.271.11.6497. View

18.

Bito H, Deisseroth K, Tsien R . Ca2+-dependent regulation in neuronal gene expression. Curr Opin Neurobiol. 1997; 7(3):419-29. DOI: 10.1016/s0959-4388(97)80072-4. View

19.

Naito Y, Watanabe Y, Yokokura H, Sugita R, Nishio M, Hidaka H . Isoform-specific activation and structural diversity of calmodulin kinase I. J Biol Chem. 1998; 272(51):32704-8. DOI: 10.1074/jbc.272.51.32704. View

20.

Splawski I, Timothy K, Decher N, Kumar P, Sachse F, Beggs A . Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc Natl Acad Sci U S A. 2005; 102(23):8089-96. PMC: 1149428. DOI: 10.1073/pnas.0502506102. View