Abstract
Wnts are small secreted glycoproteins that are highly conserved among species. To date, 19 Wnts have been described, which initiate a signal transduction cascade that is either β-catenin dependent or independent, culminating in the regulation of hundreds of target genes. Extracellular release of Wnts is dependent on lipidation of Wnts by porcupine, a membrane-bound-O-acyltransferase protein in the endoplasmic reticulum. Studies demonstrating the requirement of porcupine for Wnts production are based on cell line and non-human primary cells. We evaluated the requirement for porcupine for Wnts production in human primary astrocytes and CD8+ T cells. Using IWP-2, an inhibitor of porcupine, or siRNA targeting porcupine, we demonstrate that porcupine is not required for the release of Wnt 1, 3, 5b, 6,7a, 10b, and 16a. While IWP had no effect on Wnt 2b release, knockdown of porcupine by siRNA reduced Wnt 2b release by 60%. These data indicate that porcupine-mediated production of Wnts is context dependent and is not required for all Wnts production, suggesting that alternative mechanisms exist for Wnts production.
Highlights
Wnts are evolutionarily conserved small glycoproteins that initiate the Wnt signaling transduction cascade
Because many of the studies detailing the complex process of Wnts production are largely based on human cell lines, drosophila, Zebra fish, and mice, we evaluated the requirement for porcupine in Wnts production and efficacy of Inhibitors of Wnt Production (IWP)-2 to inhibit Wnt production and activity in human primary-progenitor-derived astrocytes (PDAs), Human Fetal Astrocytes (HFAs), a human astrocytic cell line (U138), and primary human CD8+ T cells
Previous studies indicated that porcupine is required for Wnt production in drosophila, mouse, and human cells including HEK293, mouse fibroblast L cells, and NIH3T3 cells [1]. To determine whether this requirement is context dependent, we evaluated the efficacy of IWP-2 in inhibiting Wnt production in human primary astrocyte and CD8+ T cells
Summary
Wnts are evolutionarily conserved small glycoproteins that initiate the Wnt signaling transduction cascade. The Wnt pathway is involved in many cellular processes including development, proliferation, survival, regeneration, wound healing, and stress responses [1,2,3]. It is initiated by binding of Wnts to frizzled receptors (Fz) initiating either the b-catenin-dependent or bcatenin-independent (calmodulin/Ca2+ and planar polarity) pathway of signal transduction, which culminates in target gene regulation [1,3]. Wnts are translated and targeted into the endoplasmic reticulum (ER) where they are bound and modified with lipids by the membrane-bound Oacyltransferase Porcupine [4]. The lipidated Wnts are transported to the Golgi where they are bound by the transmembrane protein Wntless. Findings in mouse and Drosophila, indicate that Wnts require lipidation by porcupine in order to be recognized by WLS [8,9]
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