Hippocalcin Promotes Neuronal Differentiation and Inhibits Astrocytic Differentiation in Neural Stem Cells

Summary 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.

• Publication year

  2016

• Venue

  Stem Cell Reports

• Publication date

  2016-12-22

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.stemcr.2016.11.009PMID 28017654PMCID 5233403
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Activation of signal transducer and activator of transcription 3 (STAT3) signaling in EGFR mutant non-small-cell lung cancer (NSCLC)

  2017cited by this paper
• ACTIVATION OF SIGNAL TRANSDUCER AND ACTIVATORS OF TRANSCRIPTION

  2017cited by this paper
• Phospholipase D1 Increases Bcl-2 Expression During Neuronal Differentiation of Rat Neural Stem Cells

  2014cited by this paper
• STAT3 Modulation to Enhance Motor Neuron Differentiation in Human Neural Stem Cells

  2014cited by this paper
• PKCα is required for inflammation-induced trafficking of extrasynaptic AMPA receptors in tonically firing lamina II dorsal horn neurons during the maintenance of persistent inflammatory pain.

  2013cited by this paper
• Induction of nitric oxide synthase expression by lipopolysaccharide is mediated by calcium-dependent PKCα-β1 in alveolar epithelial cells.

  2013cited by this paper
• Hippocalcin mediates calcium-dependent translocation of brain-type creatine kinase (BB-CK) in hippocampal neurons.

  2012cited by this paper
• A novel obatoclax derivative, SC-2001, induces apoptosis in hepatocellular carcinoma cells through SHP-1-dependent STAT3 inactivation.

  2012cited by this paper
• Phospholipase D1 mediates bFGF-induced Bcl-2 expression leading to neurite outgrowth in H19-7 cells.

  2012cited by this paper
• Phospholipase D2 acts as an important regulator in LPS-induced nitric oxide synthesis in Raw 264.7 cells.

  2010cited by this paper
• Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95

  2010cited by this paper
• Conditional deletion of Stat3 promotes neurogenesis and inhibits astrogliogenesis in neural stem cells.

  2010influential reference
• Betulinic acid suppresses STAT3 activation pathway through induction of protein tyrosine phosphatase SHP‐1 in human multiple myeloma cells

  2010cited by this paper
• Activation of Signal Transducer and Activator of Transcription-3 in the Spinal Cord of Sporadic Amyotrophic Lateral Sclerosis Patients

  2009cited by this paper
• A novel role of hippocalcin in bFGF‐induced neurite outgrowth of H19‐7 cells

  2008cited by this paper
• Depolarization‐induced differentiation of PC12 cells is mediated by phospholipase D2 through the transcription factor CREB pathway

  2008cited by this paper
• Nicotine Inhibits bFGF-induced Neurite Outgrowth through Suppression of NO Synthesis in H19-7 Cells

  2007cited by this paper
• Loss of SHP-1 tyrosine phosphatase expression correlates with the advanced stages of cutaneous T-cell lymphoma.

  2007cited by this paper
• Hippocalcin protects hippocampal neurons against excitotoxin damage by enhancing calcium extrusion.

  2007cited by this paper
• Phospholipase D2-generated phosphatidic acid couples EGFR stimulation to Ras activation by Sos

  2007cited by this paper
• Lack of hippocalcin causes impairment in Ras/extracellular signal‐regulated kinase cascade via a Raf‐mediated activation process

  2007cited by this paper
• Timing Is Everything: Making Neurons versus Glia in the Developing Cortex

  2007cited by this paper
• Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large-cell lymphoma.

  2006influential reference
• Binding of Cdc42 to phospholipase D1 is important in neurite outgrowth of neural stem cells.

  2006cited by this paper
• Hippocalcin increases phospholipase D2 expression through extracellular signal‐regulated kinase activation and lysophosphatidic acid potentiates the hippocalcin‐induced phospholipase D2 expression

  2006cited by this paper
• The timing of cortical neurogenesis is encoded within lineages of individual progenitor cells

  2006cited by this paper
• Hippocalcin functions as a calcium sensor in hippocampal LTD.

  2005cited by this paper
• Hippocalcin-deficient mice display a defect in cAMP response element-binding protein activation associated with impaired spatial and associative memory.

  2005cited by this paper
• Suppression of Stat3 promotes neurogenesis in cultured neural stem cells

  2005cited by this paper
• Novel Functions of the Phospholipase D2-Phox Homology Domain in Protein Kinase Cζ Activation

  2005cited by this paper
• Role of phospholipase D1 in neurite outgrowth of neural stem cells.

  2005cited by this paper
• Calcium handler mishandles heart

  2004cited by this paper
• Dysmyelination and reduced myelin basic protein gene expression by oligodendrocytes of SHP‐1‐deficient mice

  2004cited by this paper
• Neuronal Ca2+-sensor proteins: multitalented regulators of neuronal function.

  2004influential reference
• Phospholipase D2 functions as a downstream signaling molecule of MAP kinase pathway in L1‐stimulated neurite outgrowth of cerebellar granule neurons

  2004cited by this paper
• Dynamics and calcium sensitivity of the Ca2+/myristoyl switch protein hippocalcin in living cells

  2003cited by this paper
• Regulation of phospholipase D

  2002cited by this paper
• Neurotrophic factors and axonal growth.

  2002cited by this paper
• Differential Use of Myristoyl Groups on Neuronal Calcium Sensor Proteins as a Determinant of Spatio-temporal Aspects of Ca2+ Signal Transduction*

  2002cited by this paper
• Neuronal apoptosis inhibitory protein: Structural requirements for hippocalcin binding and effects on survival of NGF-dependent sympathetic neurons.

  2002cited by this paper
• Purification of a pluripotent neural stem cell from the adult mouse brain

  2001cited by this paper
• Neural bHLH genes control the neuronal versus glial fate decision in cortical progenitors.

  2001cited by this paper
• Differential Binding of Traffic-related Proteins to Phosphatidic Acid- or Phosphatidylinositol (4,5)- Bisphosphate-coupled Affinity Reagents*

  2001cited by this paper
• The Stat family in cytokine signaling.

  2001cited by this paper
• Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms.

  2001cited by this paper
• Allosteric effects of Pit-1 DNA sites on long-term repression in cell type specification.

  2000cited by this paper
• Timing of CNS cell generation: a programmed sequence of neuron and glial cell production from isolated murine cortical stem cells.

  2000cited by this paper
• The neuronal calcium sensor family of Ca2+-binding proteins.

  2000cited by this paper
• Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR.

  2000cited by this paper
• Role of Hippocalcin in Ca2+-induced Activation of Phospholipase D

  2000cited by this paper
• The role of 3-phosphoinositide-dependent protein kinase 1 in activating AGC kinases defined in embryonic stem cells.

  2000cited by this paper
• Regulation of phospholipase D.

  1999cited by this paper
• Binding of phosphatidic acid to the protein-tyrosine phosphatase SHP-1 as a basis for activity modulation.

  1999cited by this paper
• Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300.

  1999cited by this paper
• Progression from extrinsic to intrinsic signaling in cell fate specification: a view from the nervous system.

  1999cited by this paper
• The MAP kinase kinase kinase MLK2 co‐localizes with activated JNK along microtubules and associates with kinesin superfamily motor KIF3

  1998cited by this paper
• Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK-1).

  1998cited by this paper
• Phospholipase D: enzymology, mechanisms of regulation, and function.

  1997cited by this paper
• Muscle progenitor cells failing to respond to positional cues adopt non-myogenic fates in myf-5 null mice

  1996cited by this paper
• Distinct roles for bFGF and NT-3 in the regulation of cortical neurogenesis.

  1995cited by this paper
• Isolation, characterization, and use of stem cells from the CNS.

  1995cited by this paper
• Expression of hippocalcin in the developing rat brain.

  1994cited by this paper
• Myristoylation of hippocalcin is linked to its calcium-dependent membrane association properties.

  1993cited by this paper

• Hybridization Reveals Cell Type-Specific Regulatory Variation Driving Brain Transcriptomic Divergence

  2025cites this paper
• MiR-125b suppresses bladder Cancer cell growth and triggers apoptosis by regulating IL-6/IL-6R/STAT3 axis in vitro and in vivo.

  2025cites this paper
• Intranasal delivery of extracellular vesicles: A promising new approach for treating neurological and respiratory disorders.

  2025cites this paper
• Epigallocatechin gallate improves neuronal damage in animal model of ischemic stroke and glutamate-exposed neurons via modulation of hippocalcin expression

  2024cites this paper
• Real‐Time, Non‐Invasive Monitoring of Neuronal Differentiation Using Intein‐Enabled Fluorescence Signal Translocation in Genetically Encoded Stem Cell‐Based Biosensors

  2024cites this paper
• SUICA: Learning Super-high Dimensional Sparse Implicit Neural Representations for Spatial Transcriptomics

  2024cites this paper
• MFGE8 promotes adult hippocampal neurogenesis in rats following experimental subarachnoid hemorrhage via modifying the integrin β3/Akt signaling pathway

  2024cites this paper
• Mesenchymal Stem Cell-Extracellular Vesicle Therapy for Stroke: Scalable Production and Imaging Biomarker Studies

  2023cites this paper
• Phospholipase D1 promotes astrocytic differentiation through the FAK/AURKA/STAT3 signaling pathway in hippocampal neural stem/progenitor cells.

  2022cites this paper
• Brain Homogenate of a Rat Model of Alzheimer's Disease Modifies the Secretome of 3D Cultured Periodontal Ligament Stem Cells: A Potential Neuroregenerative Therapy

  2022cites this paper
• Kinase inhibit region of SOCS3 attenuates IL6‐induced proliferation and astrocytic differentiation of neural stem cells via cross talk between signaling pathways

  2022cites this paper
• Neuroprotective Effect of Bcl-2 on Lipopolysaccharide-Induced Neuroinflammation in Cortical Neural Stem Cells

  2022cites this paper
• The Normal Human Adult Hypothalamus Proteomic Landscape: Rise of Neuroproteomics in Biological Psychiatry and Systems Biology

  2021cites this paper
• Restoring Oat Nanoparticles Mediated Brain Memory Function of Mice Fed Alcohol by Sorting Inflammatory Dectin-1 Complex Into Microglial Exosomes

  2021cites this paper
• Effects of Physical Exercise on Autophagy and Apoptosis in Aged Brain: Human and Animal Studies

  2020cites this paper
• The transcriptome of anterior regeneration in earthworm Eudrilus eugeniae

  2020cites this paper
• Promotive effects of tetrahydroxystilbene glucoside on the differentiation of neural stem cells from the mesencephalon into dopaminergic neurons.

  2020cites this paper
• MSC spheroids-loaded collagen hydrogels simultaneously promote neuronal differentiation and suppress inflammatory reaction through PI3K-Akt signaling pathway.

  2020cites this paper
• Calcium Sensors in Neuronal Function and Dysfunction.

  2019cites this paper
• Yokukansan, a Kampo medicine, enhances the level of neuronal lineage markers in differentiated P19 embryonic carcinoma cells

  2019cites this paper
• MicroRNA-24-3p regulates neuronal differentiation by controlling hippocalcin expression

  2019cites this paper
• Phospholipase D1 Signaling: Essential Roles in Neural Stem Cell Differentiation

  2018influential citation
• Activation of signal transducer and activator of transcription 3 signaling attenuates neurogenesis in a rat model of intracerebral hemorrhage.

  2018cites this paper
• Methyl 3,4-Dihydroxybenzoate Induces Neural Stem Cells to Differentiate Into Cholinergic Neurons in vitro

  2018cites this paper
• Moderate-Intensity Exercise Induces Neurogenesis and Improves Cognition in Old Mice by Upregulating Hippocampal Hippocalcin, Otub1, and Spectrin-α

  2018cites this paper
• Therapeutic potential of a phospholipase D1 inhibitory peptide fused with a cell-penetrating peptide as a novel anti-asthmatic drug in a Der f 2-induced airway inflammation model

  2018cites this paper
• The construction of the multifunctional targeting ursolic acids liposomes and its apoptosis effects to C6 glioma stem cells

  2017cites this paper
• Interleukin-6-Mediated Induced Pluripotent Stem Cell (iPSC)-Derived Neural Differentiation

  2017cites this paper