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

Area of Science:

• Molecular Biology
• Cell Signaling
• Biochemistry

Background:

• The Wnt pathway is crucial for cell proliferation, differentiation, and cancer.
• Canonical Wnt signaling is tightly regulated by various proteins.
• Carboxypeptidase E (CPE) has been identified as a novel regulator of this pathway.

Purpose of the Study:

• To elucidate the mechanism by which CPE regulates the canonical Wnt signaling pathway.
• To investigate the interaction between CPE and Wnt3a.
• To understand the role of CPE in Wnt3a secretion and activity.

Main Methods:

• Co-secretion assays to study CPE and Wnt3a.
• Analysis of Wnt3a C'-terminal Lys residue activity.
• Investigation of CPE N'-terminal interactions with Wnt3a.
• Assessment of endoplasmic reticulum (ER) stress markers.

Main Results:

• CPE and Wnt3a are co-secreted from cells.
• While the C'-terminal Lys residue of Wnt3a is essential for activity, CPE does not cleave it.
• CPE's N'-terminal sequence induces Wnt3a aggregation and potential ER stress, leading to Wnt pathway dysregulation.

Conclusions:

• CPE regulates Wnt signaling through a novel mechanism involving Wnt3a aggregation and ER stress.
• This interaction impacts Wnt3a function without direct cleavage of its critical C'-terminal residue.
• Provides mechanistic insight into CPE's role in Wnt pathway regulation.