DUSP4 regulates neuronal differentiation and calcium homeostasis by modulating ERK1/2 phosphorylation.
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.
1 Department of Biological Sciences, Center for Stem Cell Differentiation, KAIST , Daejeon, Republic of Korea.
Sun Young
SY
Kim
Yong-Mahn
YM
Han
Mihee
M
Oh
Won-Kon
WK
Kim
Kyoung-Jin
KJ
Oh
Sang Chul
SC
Lee
Kwang-Hee
KH
Bae
Baek-Soo
BS
Han
D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*
C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C522186:Dusp4 protein, mouse; D017027:Protein Tyrosine Phosphatases