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

Abstract

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.

Carboxypeptidase E transmits its anti-migratory function in glioma cells via transcriptional regulation of cell architecture and motility regulating factors

“…One possible mechanism how CPE might also mitigate glioma cell migration beside downregulating SLUG is the effect of CPE on the wNT-pathway as described by Skalka et al (43). wNT regulates the architecture of the cytoskeleton and in this regard is responsible for cell shape, cell adhesion and cell motility.…”

Synaptic Vesicles Dynamics in Neocortical Epilepsy

“…However, we did not find any statistical differences in the number of DCV present in the three experimental groups. We focussed our study on CPE, a protein that is involved in many different pathways, including neuropeptides' synthesis and WNT/BDNF signaling, that was also hypothesized to regulate synaptic vesicles trafficking and positioning (Bamji et al, 2006;Staras et al, 2010;Skalka et al, 2016). Although the exact role of CPE is not completely clear, we reported a reduced hyperexcitability of acute epileptic mice after the administration of its inhibitor (Figure 4).…”

Synaptic vesicles dynamics in neocortical epilepsy

“…However, we did not find any statistical differences in the number of DCV present in the three experimental groups. We focussed our study on CPE, a protein that is involved in many different pathways, including neuropeptides’ synthesis and WNT/BDNF signalling, that was also hypothesized to regulate synaptic vesicles trafficking and positioning (Bamji et al, 2006; Staras et al, 2010; Skalka et al, 2016). Although the exact role of CPE is not completely clear, we reported a reduced hyperexcitability of acute epileptic mice after the administration of its inhibitor ( Fig.…”

“…We focussed our study on CPE and its effects on vesicular organization (Park, Cawley and Loh, 2008;Lou et al, 2010). CPE is involved in many different pathways, including neuropeptides' synthesis and WNT/BDNF signalling, and it is known that regulates synaptic vesicles trafficking and positioning (Bamji et al, 2006;Staras et al, 2010;Skalka et al, 2016). Interestingly, Lou et al (2010) showed that hypothalamic synapses of CPE-KO mice have a marked reduction in docked vesicles and that the entire vesicular cluster is at a greater distance from the active zone; however, their readout did not allow discrimination between released and non-released vesicles.…”