title: 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.
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Skalka
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Caspi
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: L
authors.initials: L
authors.lastname: Lahav-Ariel
authors.affiliation: Section on Cellular Neurobiology, Program on Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Y P
authors.initials: YP
authors.lastname: Loh
authors.affiliation: Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: K
authors.initials: K
authors.lastname: Hirschberg
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Rosin-Arbesfeld
mesh_terms: D000818:Animals; D019556:COS Cells; D043423:Carboxypeptidase H / Q000502:physiology*; D002522:Chlorocebus aethiops; D059865:Endoplasmic Reticulum Stress; D057809:HEK293 Cells; D006801:Humans; D066329:Protein Aggregates; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000378:metabolism*
chemical_list: D066329:Protein Aggregates; D060509:Wnt3A Protein; D043423:Carboxypeptidase H