Carboxypeptidase E (NF-α1): a new trophic factor in neuroprotection

Cheng, Yong; Cawley, Niamh X.; Loh, Y. Peng

doi:10.1007/s12264-013-1430-z

Cited by 26 publications

(30 citation statements)

References 32 publications

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“…Sortilin, which is an important intracellular sorting receptor, plays a role in targeting some neurotrophins to the regulated secretory vesicles via interaction with a specific sequence of the pro-domain of neurotrophins 15-17. In addition, to sequence information in the pro-region of neurotrophins, the mature neurotrophin has a sequence signal that is recognized by the sorting receptor carboxypeptidase E (CPE) and results in targeting the neurotrophins to the regulated pathway of secretion 18,19. Finally, the importance of these sorting motifs in targeting neurotrophins to the secretory vesicles has been confirmed by experiments, which showed that swapping of these motifs between different neurotrophins might alter the sorting of neurotrophins to either of the secretory pathways 9…”

Section: General Conceptmentioning

confidence: 99%

Mechanisms and regulation of neurotrophin synthesis and secretion

Qudah

Al‐Dwairi

2016

NSJ

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Neurotrophins are secreted proteins that are synthesized as pre-pro-neurotrophins on the rough endoplasmic reticulum, which are subsequently processed and then secreted as mature proteins. During synthesis, neurotrophins are sorted in the trans-Golgi apparatus into 2 pathways of secretion; the constitutive and the regulated pathways. Neurotrophins in the constitutive pathway are secreted cautiously without any trigger, while in the regulated pathway of secretion an external stimulus elevates the calcium concentration intracellularly leading to neurotrophin release. The regulation of sorting and secretion of neurotrophins is critical for several processes in the body, such as synaptic plasticity, neurodegenerative disorders, demyelination disease, and inflammation. The purpose of this review is to summarize the current mechanisms of neurotrophin sorting and secretion.

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Section: General Conceptmentioning

confidence: 99%

Mechanisms and regulation of neurotrophin synthesis and secretion

Qudah

Al‐Dwairi

2016

NSJ

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“…Since CPE has been shown to be a survival and neuroprotective factor[10,11,20], we tested whether the T to C mutation at 980 sitein CPE gene would affect these properties. We first analyzed the transcript expression of WT-CPE and TC-CPE.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, a person who bears homozygosity for a truncating mutation of the CPE gene displayed intellectual disability[19]. The hypothesis that CPE mutation would contribute to neurological disorders is also supported by the animal studies showing that CPE-KO mice had the neuronal loss of the CA3 region of hippocampus, displayed memory deficits and depressive-like behaviors[12,13,20]. …”

Section: Discussionmentioning

confidence: 99%

A Novel Single Nucleotide T980C Polymorphism in the Human Carboxypeptidase E Gene Results in Loss of Neuroprotective Function

et al. 2017

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Report of a human with a homozygous truncating null mutation of the Carboxypeptidase E (CPE) gene with endocrinological and neurological deficits prompted us to search for other mutations in the human CPE gene that might be linked to disease. We searched an EST database and identified from a small population of patients, a novel T to C single nucleotide polymorphism (SNP) in the CPE gene at bp980 of exon 4, herein called TC-CPE. This introduces a tryptophan to arginine (W235R) mutation in the catalytic domain of human CPE protein. Over-expression of TC-CPE in N2A cells, a neuroendocrine cell line, showed that it was synthesized, but was found in lesser amounts compared to over-expressed WT-CPE in these cells. Furthermore, TC-CPE was secreted poorly from these N2A cells. The levels of TC-CPE were significantly increased after the N2A cells were treated with MG132 (a proteasome inhibitor), suggesting that TC-CPE was targeted to proteasomes for degradation in N2A cells. In addition, TC-CPE induced ER stress as demonstrated by the increased expression of CHOP in N2A cells. Double labeling of CPE and calnexin (and ER marker) suggested the accumulation of TC-CPE in the ER, and the accumulation appears to be enhanced by the treatment of MG132 in the cells. Moreover, the secreted levels of TC-CPE were not affected by the treatment of MG132 in the cells. Over-expression studies revealed that while N2A cells transfected with WT-CPE showed reduced cytotoxicity when challenged with H2O2 compared to cells expressing an empty vector, cells transfected with TC-CPE had no effect. Furthermore, WT-CPE condition medium showed protective effect against oxidative stress, but not TC-CPE condition medium. Although co-expression of WT-CPE and TC-CPE in N2A cells resulted in the reduction in secretion of WT-CPE, co-expression of WT-CPE and TC-CPE did not significantly affect the protective effect of WT-CPE. Taken together, we have identified a novel SNP in the CPE gene which results in the loss of its neuroprotective function in cells and may confer neurological disorders in humans.

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“…17,8 CPE has also been implicated in cancer progression [18][19][20][21] and as a neuro-trophic factor regulating brain functions. [22][23][24][25][26] Lately, it was found that CPE is also involved in other biological processes such as bone homeostasis 27 and bowel disease. 28 We have previously shown that CPE negatively regulates the oncogenic canonical Wnt signaling pathway by interacting with Wnt3a leading to decreased β-catenin protein levels and reduced Wnt signaling levels.…”

Section: Discussionmentioning

confidence: 99%

Carboxypeptidase E (CPE) inhibits the secretion and activity of Wnt3a

et al. 2016

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The Wnt pathway has essential roles in cell proliferation, cell fate determination and tumorigenesis by regulating the expression of a wide range of target genes. As a core signaling cascade, the canonical Wnt pathway is regulated at different levels by numerous proteins. We have previously shown that carboxypeptidase E (CPE) is a novel regulator of the canonical Wnt signaling pathway. Here, we show that CPE and the Wnt3a ligand are co-secreted from cells. We show that although the C'-terminal Lys residue of Wnt3a is critical for its activity and is important for the effect of CPE on the Wnt pathway, CPE does not execute its effect by removing this Wnt3a residue. Interestingly, CPE through its N'-terminal sequence, forms aggregates with Wnt3a and possible endoplasmic reticulum (ER) stress leading to its loss of function. Together, our current results provide a mechanistic insight into the way CPE regulates the canonical Wnt signaling pathway.

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Carboxypeptidase E (NF-α1): a new trophic factor in neuroprotection

Cited by 26 publications

References 32 publications

Mechanisms and regulation of neurotrophin synthesis and secretion

Mechanisms and regulation of neurotrophin synthesis and secretion

A Novel Single Nucleotide T980C Polymorphism in the Human Carboxypeptidase E Gene Results in Loss of Neuroprotective Function

Carboxypeptidase E (CPE) inhibits the secretion and activity of Wnt3a

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