Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • Hippocalcin HPCA is a high affinity calcium

    2018-10-20

    Hippocalcin (HPCA) is a high-affinity calcium-binding protein restricted to the CNS and is most abundant in pyramidal cells of the hippocampus CA1 region (Kobayashi et al., 2012). During brain development HPCA expression increases sharply, concurrent with synapse formation (Saitoh et al., 1994). HPCA belongs to the family of EF-hand-containing neuronal calcium sensor proteins, which possess a Ca2+/myristoyl switch that allows translocation to membranes in response to increased cytosolic Ca2+ concentrations. It also regulates mixed-lineage kinase 2, phospholipase D (PLD), and neuronal apoptosis inhibitory protein (Burgoyne and Weiss, 2001; Kobayashi et al., 1993; Lindholm et al., 2002; Nagata et al., 1998; O\'Callaghan et al., 2002; O\'Callaghan et al., 2003). We have reported that HPCA is a major regulatory protein in the Ca2+-mediated PLD signaling pathway (Oh et al., 2006) and that it induces expression of Neuro-D, leading to neurite outgrowth in H19-7 cells during differentiation (Oh et al., 2008). It is possible that HPCA regulates neurogenesis through these molecules; however, molecular mechanisms by which HPCA affects neuronal/astrocyte cell-fate decision have not been studied. PLD is a ubiquitous enzyme that catalyzes the hydrolysis of phosphatidylcholine (PC) to phosphatidic buy 3-Deazaneplanocin A and choline (Exton, 1997). Phosphatidic acid (PA) itself acts as a cellular messenger or can be transformed by PA phosphohydrolase into diacylglycerol, which is essential for activation of protein kinase C (PKC) (Manifava et al., 2001; Zhao et al., 2007). PKCα regulates Ca2+-dependent differentiation in several cell lines and primary cells (Kopach et al., 2013; Park et al., 2015) and plays an essential role in synaptic plasticity by raising intracellular Ca2+ levels in neurons (Kopach et al., 2013). Activation and phosphorylation of PLD1 are regulated by PKCα in phorbol myristate acetate-treated COS-7 cells, and a similar interrelationship between PLD and PKC isoforms is seen in a variety of cell types (Kim et al., 2005). Recent studies have reported that PLD plays a key role in neuronal differentiation of cells such as PC12 cells (Banno et al., 2008) and cerebellar granule neurons (Watanabe et al., 2004). We have also reported that it has a critical role in the neuronal differentiation of rat NSCs (Yoon et al., 2005) and H19-7 cells (Yoon et al., 2012). However, the relevance of PLD1 signaling in neuronal differentiation remains unclear. The signal transducer and activator of transcription (STAT) family participates in the regulation of genes involved in the acute phase of inflammatory response, cell growth, and cell differentiation (Park et al., 2010). Among them, STAT3 is an important transcription factor for the regulation of glial fibrillary acidic protein (GFAP) expression, and the DNA binding of STAT3 was shown to be affected by phosphorylation of the Ser727 or/and Tyr705 site (Yokogami et al., 2000). STAT3 binds to different domains of CBP/p300, and the STAT/p300/Smad complex, acting at the STAT-binding element in the astrocyte-specific GFAP promoter, is particularly effective at inducing astrocyte differentiation in NSCs (Nakashima et al., 1999). Moreover, STAT3 signaling is upregulated in certain neurodegenerative diseases (Shibata et al., 2009), and in vitro suppression of Stat3 or its conditional deletion in vivo promoted neurogenesis and inhibited astrogliogenesis (Cao et al., 2010; Gu et al., 2005). Thus, STAT3 is considered an attractive target for promoting neurogenesis. In our previous study, STAT3 activation is associated with PLD2 through the S6K1-ERK pathway in lipopolysaccharide (LPS)-induced inflammation mechanism (Park et al., 2010), but the relationship between PLD1 signaling and STAT3 function is not yet defined. Thus, the present study showed that PLD1 is required for HPCA-mediated STAT3 activation of neuronal differentiation. In addition, a number of protein tyrosine phosphatases negatively regulate STAT3 signaling through direct dephosphorylation of p-STAT3(Y705); these include members of the SH2-domain-containing tyrosine phosphatase family (SHP-1 and SHP-2) and protein tyrosine phosphatase 1B (PTP-1B) (Han et al., 2006). More specifically, SHP-1 regulates STAT3(Y705) phosphorylation in Huh-7 HCC, PLC5, and HepG2 cells (Chen et al., 2012). Thus, activity of SHP-1 may be critical for regulating STAT3 phosphorylation in neuronal differentiation.