A neuron-specific EGF family protein, NELL2, promotes survival of neurons through mitogen-activated protein kinases

Aihara, Koutoku; Kuroda, Shinya; Kanayama, Naoyuki; Matsuyama, Shogo; Tanizawa, Katsuyuki; Horie, Masato

doi:10.1016/s0169-328x(03)00256-0

Cited by 53 publications

(65 citation statements)

References 34 publications

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“…The released NELL2 stimulates the intracellular ERK pathway through an unknown receptor (Aihara et al, 2003;Choi et al, 2010). The activated ERK stimulates cell survival and differentiation (Choi et al, 2010;Kim et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Characteristically, NELL2 has Ca 2+ -binding sites in its six EGF-like repeat domains, suggesting a contribution to Ca tion, and protection of neural cells (Choi et al, 2010;Jeong et al, 2008;Nelson et al, 2002). Among its possible functions, a cell survival-promoting effect has been relatively well studied (Aihara et al, 2003;Choi et al, 2010;Jeong et al, 2008;Munemasa et al, 2012) and is mediated by an intracellular mitogen-activated protein kinase (MAPK) pathway (Aihara et al, 2003;Choi et al, 2010).…”

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confidence: 99%

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NELL2 Function in the Protection of Cells against Endoplasmic Reticulum Stress

Kim

et al. 2015

Molecules and Cells

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* Continuous intra-and extracellular stresses induce disorder of Ca2+ homeostasis and accumulation of unfolded protein in the endoplasmic reticulum (ER), which results in ER stress. Severe long-term ER stress triggers apoptosis signaling pathways, resulting in cell death. Neural epidermal growth factor-like like protein 2 (NELL2) has been reported to be important in protection of cells from cell death-inducing environments. In this study, we investigated the cytoprotective effect of NELL2 in the context of ER stress induced by thapsigargin, a strong ER stress inducer, in Cos7 cells. Overexpression of NELL2 prevented ER stress-mediated apoptosis by decreasing expression of ER stress-induced C/EBP homologous protein (CHOP) and increasing ER chaperones. In this context, expression of anti-apoptotic Bcl-xL was increased by NELL2, whereas NELL2 decreased expression of pro-apoptotic proteins, such as cleaved caspases 3 and 7. This antiapoptotic effect of NELL2 is likely mediated by extracellular signal-regulated kinase (ERK) signaling, because its inhibitor, U0126, inhibited effects of NELL2 on the expression of anti-and pro-apoptotic proteins and on the protection from ER stress-induced cell death.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

NELL2 Function in the Protection of Cells against Endoplasmic Reticulum Stress

Kim

et al. 2015

Molecules and Cells

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“…NELL2 appears to promote neuronal survival by modulating MAPKs and consequently is highly expressed in hippocampus and cerebral cortex; its gene product is a thrombospondin-1-like protein exhibiting six epidermal growth factor-like domains, 19 most probably acting as a multi-domain adhesive in the extracellular matrix and participating in cell-cell communication. 20 In the central nervous system, NELL2 is expressed in nascent, postmitotic neurons as they start to differentiate whereas, in the peripheral nervous system, it is also expressed in subsets of progenitor cells.…”

Section: Discussionmentioning

confidence: 99%

Differential gene expression in the peripheral zone compared to the transition zone of the human prostate gland

Noël

Ragavan

James

et al. 2007

Prostate Cancer Prostatic Dis

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“…NELL2 acts on neuronal cells to promote differentiation, proliferation (Kim et al, 2010;Nelson et al, 2004), and survival through mitogen-activated protein kinases (Aihara et al, 2003). NELL2 also supports the survival of retinal ganglion cells after optic nerve injury (Munemasa et al, 2012), and NELL2 is involved in the formation of the sexually dimorphic nucleus of the preoptic area (Jeong et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Secreted NELL2 has been suggested to have a putative function as a trophic factor (Matsuhashi et al, 1995;Watanabe et al, 1996). A study of the effect of recombinant rat NELL2 proteins on primary cultured neurons provided direct evidence that secreted NELL2 promotes the survival of primary neurons by decreasing mitogen-activated protein kinase activities (Aihara et al, 2003). Secreted NELL2 acts in a paracrine manner to stimulate the mitogenesis of adjacent cells within the nascent chick dorsal root ganglia (Nelson et al, 2004), and ectopic expression of NELL2 also promotes differentiation of neuronal progenitor HiB5 cells (Kim et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

The Molecular Mechanism of NELL2 Movement and Secretion in Hippocampal Progenitor HiB5 Cells

Hwang

Kim

et al. 2013

Molecules and Cells

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Neural epidermal growth factor-like protein-like 2 (NELL2) is a secreted glycoprotein that is predominantly expressed in the nervous system, but little is known about the intracellular movement and secretion mechanism of this protein. By monitoring the localization and movements of enhanced green fluorescent protein (EGFP)-labeled NELL2 in living cultured hippocampal neuroprogenitor HiB5 cells, we determined the subcellular localization of NELL2 and its intracellular movement and secretion mechanism. Cterminal EGFP-fused NELL2 showed a typical expression pattern of secreted proteins, especially with respect to its localization in the endoplasmic reticulum, Golgi apparatus, and punctate structures. Vesicles containing NELL2 exhibited bidirectional movement in HiB5 cells. The majority of the vesicles (70.1%) moved in an anterograde direction with an average velocity of 0.454 μm/s, whereas some vesicles (28.7%) showed retrograde movement with an average velocity of 0.302 μm/s. The movement patterns of NELL2 vesicles were dependent upon the presence of microtubules in HiB5 cells. Anterograde movement of NELL2 did not lead to a detectable accumulation of NELL2 in the peripheral region of the cell, indicating that it was secreted into the culture medium. We also showed that the N-terminal 29 amino acids of NELL2 were important for secretion of this protein. Taken together, these results strongly suggest that the N-terminal region of NELL2 determines both the pattern of its intracellular expression and transport of NELL2 vesicles by high-velocity movement. Therefore, NELL2 may affect the cellular activity of cells in a paracrine or autocrine manner.

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A neuron-specific EGF family protein, NELL2, promotes survival of neurons through mitogen-activated protein kinases

Cited by 53 publications

References 34 publications

NELL2 Function in the Protection of Cells against Endoplasmic Reticulum Stress

NELL2 Function in the Protection of Cells against Endoplasmic Reticulum Stress

Differential gene expression in the peripheral zone compared to the transition zone of the human prostate gland

The Molecular Mechanism of NELL2 Movement and Secretion in Hippocampal Progenitor HiB5 Cells

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