title: Hippocalcin Promotes Neuronal Differentiation and Inhibits Astrocytic Differentiation in Neural Stem Cells.
abstract: Hippocalcin (HPCA) is a calcium-binding protein that is restricted to nervous tissue and contributes to neuronal activity. Here we report that, in addition to inducing neurogenesis, HPCA inhibits astrocytic differentiation of neural stem cells. It promotes neurogenesis by regulating protein kinase Cα (PKCα) activation by translocating to the membrane and binding to phosphoinositide-dependent protein kinase 1 (PDK1), which induces PKCα phosphorylation. We also found that phospholipase D1 (PLD1) is implicated in the HPCA-mediated neurogenesis pathway; this enzyme promotes dephosphorylation of signal transducer and activator of transcription 3 (STAT3[Y705]), which is necessary for astrocytic differentiation. Moreover, we found that the SH2-domain-containing tyrosine phosphatase 1 (SHP-1) acts upstream of STAT3. Importantly, this SHP-1-dependent STAT3-inhibitory mechanism is closely involved in neurogenesis and suppression of gliogenesis by HPCA. Taken together, these observations suggest that HPCA promotes neuronal differentiation through activation of the PKCα/PLD1 cascade followed by activation of SHP-1, which dephosphorylates STAT3(Y705), leading to inhibition of astrocytic differentiation.
authors.affiliation: Department of Biochemistry and Molecular Biology, Biomedical Research Institute, College of Medicine, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea.
authors.forename: Shin-Young
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Molecular Biology, Biomedical Research Institute, College of Medicine, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea.
authors.forename: Sung Nyo
authors.initials: SN
authors.lastname: Yoon
authors.affiliation: Department of Biochemistry and Molecular Biology, Biomedical Research Institute, College of Medicine, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea.
authors.forename: Min-Jeong
authors.initials: MJ
authors.lastname: Kang
authors.affiliation: Department of Biochemistry and Molecular Biology, Biomedical Research Institute, College of Medicine, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea.
authors.forename: YunYoung
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Physiology, College of Medicine, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea.
authors.forename: Sung Jun
authors.initials: SJ
authors.lastname: Jung
authors.affiliation: Department of Biochemistry and Molecular Biology, Biomedical Research Institute, College of Medicine, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea. Electronic address: jshan@hanyang.ac.kr.
authors.forename: Joong-Soo
authors.initials: JS
authors.lastname: Han
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D015870:Gene Expression; D051597:Hippocalcin / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010739:Phospholipase D / Q000378:metabolism; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D051381:Rats; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D014404:Tubulin / Q000235:genetics
chemical_list: D050796:STAT3 Transcription Factor; D014404:Tubulin; D051597:Hippocalcin; D051571:Protein Kinase C-alpha; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D010739:Phospholipase D; C106801:phospholipase D1; D002118:Calcium
keywords: SH2-domain-containing tyrosine phosphatase-1 (SHP-1); gliogenesis; hippocalcin (HPCA); neural stem cells; neurogenesis; phosphoinositide-dependent protein kinase-1 (PDK1); phospholipase D1 (PLD1); signal transducers and activator of transcription 3 (STAT3)