Identification of soluble WSX-1 not as a dominant-negative but as an alternative functional subunit of a receptor for an anti-Alzheimer’s disease rescue factor Humanin

Hashimoto, Yuichi; Kurita, Megumi; Matsuoka, Masao

doi:10.1016/j.bbrc.2009.08.095

Cited by 26 publications

(23 citation statements)

References 21 publications

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“…This finding suggests that upregulated homodimerization of the intracellular domains of gp130 results in Humanin-like activity. In agreement, Hashimoto et al have recently shown that soluble WSX-1 lacking intracellular signaling modules could behave as a functional subunit for Humanin signaling in the absence of wild-type WSX-1 at least when soluble WSX-1 is overexpressed [71] (Fig. 2).…”

Section: The Humanin Receptor Consisting Of Cntfr/wsx-1/ Gp130 As a Mmentioning

confidence: 70%

Humanin and the Receptors for Humanin

Matsuoka

Hashimoto

2009

Mol Neurobiol

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Alzheimer's disease (AD) is a prevalent dementia-causing neurodegenerative disease. Neuronal death is closely linked to the progression of AD-associated dementia. Accumulating evidence has established that a 24-amino-acid bioactive peptide, Humanin, protects neurons from AD-related neuronal death. A series of studies using various murine AD models including familial AD gene-expressing transgenic mice have shown that Humanin is effective against AD-related neuronal dysfunction in vivo. Most recently, it has been shown that Humanin inhibits neuronal cell death and dysfunction by binding to a novel IL-6-receptor-related receptor(s) on the cell surface involving CNTFRalpha, WSX-1, and gp130. These findings suggest that endogenous Humanin [or a Humanin-like substance(s)] may suppress the onset of AD-related dementia by inhibiting both AD-related neuronal cell death and dysfunction.

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Section: The Humanin Receptor Consisting Of Cntfr/wsx-1/ Gp130 As a Mmentioning

confidence: 70%

Humanin and the Receptors for Humanin

Matsuoka

Hashimoto

2009

Mol Neurobiol

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“…Primary Hippocampal Neurons (PHNs) and Cell Death Assay-Mouse PHNs were prepared from hippocampi of mouse E14 embryos, as shown in earlier studies (1,32). They were seeded in poly-L-lysine-coated 6-well plates (Sumitomo Bakelite) at 5 ϫ 10 5 cells/well in Neuron medium (Sumitomo Bakelite).…”

Section: Methodsmentioning

confidence: 99%

“…Humanin also inhibits AD-related neuronal death via the heterotrimeric Humanin receptor (htHNR) on the cell membrane, which is composed of ciliary neurotrophic factor receptor ␣, WSX-1, and gp130 (31). The loss-of-function of any of the htHNR subunits abolishes Humanin-induced inhibition of ADrelated neuronal death (31,32). The binding of Humanin to htHNR results in oligomerization of the receptor subunits and the activation of JAK2 and STAT3 (22,(31)(32)(33), which is thought to alter expression of target genes of Humanin.…”

Section: Humanin Is a Secreted Bioactive Peptide That Suppresses Cellmentioning

confidence: 99%

“…The loss-of-function of any of the htHNR subunits abolishes Humanin-induced inhibition of ADrelated neuronal death (31,32). The binding of Humanin to htHNR results in oligomerization of the receptor subunits and the activation of JAK2 and STAT3 (22,(31)(32)(33), which is thought to alter expression of target genes of Humanin. However, it remains unknown which target genes of Humanin mediates the neuroprotective effect of Humanin.…”

Section: Humanin Is a Secreted Bioactive Peptide That Suppresses Cellmentioning

confidence: 99%

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SH3-binding Protein 5 Mediates the Neuroprotective Effect of the Secreted Bioactive Peptide Humanin by Inhibiting c-Jun NH2-terminal Kinase

Takeshita

Hashimoto

Nawa

et al. 2013

Journal of Biological Chemistry

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Background: Humanin, a secreted bioactive peptide, suppresses a variety of cell toxicities. Results: An intracellular protein SH3BP5, which directly inhibits JNK activity, is identified as an effector of Humanin. Conclusion: SH3BP5 is a physiological inhibitor of JNK and the firstly identified effector of Humanin. Significance: The discovery provides a novel mechanistic insight into the actions of JNK and Humanin.

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“…Gp130 naturally exists as a soluble form that inhibits IL-6/IL-6R complex signaling (14) but does not inhibit IL-27 signaling (15). Mouse neuronal cells express an alternatively spliced IL-27Ra isoform of 33 kDa, lacking exons [7][8][9][10][11][12][13][14], that encodes part of the extracellular domain (16). This truncated IL-27Ra isoform was reported, not to act as a dominant negative, but to associate with CNTF-R and gp130 similarly to full-length membrane IL-27Ra, to form a tripartite functional receptor for humanin, a neurotrophic peptide (16,17).…”

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confidence: 99%

A Soluble Form of IL-27Rα Is a Natural IL-27 Antagonist

Dietrich

Candon

Ruemmele

et al. 2014

The Journal of Immunology

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IL-27 is a cytokine of the IL-12 family that plays a key role in the regulation of inflammatory and T cell responses. Its receptor is composed of IL-27Rα and gp130 and activates the STAT pathway. We show in this study, using an ELISA that we developed, that a naturally occurring soluble form of IL-27Rα (sIL-27Rα) is produced by human activated CD4+ and CD8+ T cells, B cells, myeloid cells, and various cell lines. sIL-27Rα is present at a mean concentration of 10,344 ± 1,274 pg/ml in the sera from healthy individuals. Biochemical studies showed that sIL-27Rα is released as two N-glycosylated variants of ∼90 and ∼70 kDa. In IL-27Rα–transfected COS7 cells, primary cells, and cell lines, production of sIL-27Rα is inhibited by the metalloprotease inhibitors GM6001 and TAPI-0. Importantly, natural sIL-27Rα binds rIL-27, inhibits IL-27 binding to its cell surface receptor, and is a potent inhibitor of IL-27 signaling, as shown by its ability to specifically block IL-27–mediated STAT activation, at low molar excess over IL-27. Also, we found that serum levels of sIL-27Rα were elevated in patients with Crohn’s disease, a Th1-mediated disease. These findings suggest that sIL-27Rα may play important immunoregulatory functions under normal and pathological conditions.

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Identification of soluble WSX-1 not as a dominant-negative but as an alternative functional subunit of a receptor for an anti-Alzheimer’s disease rescue factor Humanin

Cited by 26 publications

References 21 publications

Humanin and the Receptors for Humanin

Humanin and the Receptors for Humanin

SH3-binding Protein 5 Mediates the Neuroprotective Effect of the Secreted Bioactive Peptide Humanin by Inhibiting c-Jun NH2-terminal Kinase

A Soluble Form of IL-27Rα Is a Natural IL-27 Antagonist

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