Dear Colleagues and Students,
You are cordially invited to attend the seminar organized by the Department of MBG.
Title: “Plasma membrane content is critical for regulation of Wnt/beta-catenin signaling”
Speaker: Assoc. Prof. Güneş Özhan (iBG-izmir)
Time: April 17th, Wednesday at 15:40
Host: Bahar Değirmenci Uzun
Abstract: Little is known about the molecular mechanisms involved in binding of canonical Wnt ligand to its receptors at the plasma membrane, a key step underlying initiation of the pathway. The plasma membrane contains ordered membrane nanodomains, conventionally referred to as membrane (lipid) rafts, that are highly dynamic membrane regions characterized by selective recruitment of saturated lipids, sterols and specific lipid-anchored proteins. These ordered structures generate compact transient platforms for ligand-receptor interaction and receptor clustering, and are critical in signal transduction pathways including the canonical Wnt signaling. While the receptor Fz8 and the coreceptor Lrp6 of canonical pathway are distributed throughout the membrane, the membrane-bound Wnt pathway modulator Lypd6 becomes localized to ordered membrane nanodomains and ensures via direct physical interaction that Lrp6 is phosphorylated in these domains to activate signaling. Our recent work has unraveled the influence of the immediate plasma membrane environment on the canonical Wnt–receptor interaction by showing that canonical Wnt selectively binds to its pool of receptors in the ordered nanodomains and this domain-specific binding is necessary for downstream signaling activity. Next, we addressed the influence of the lipid modification on the ability of canonical Wnt ligand in binding the plasma membrane and activating signaling. Specifically, we investigated the effect of palmitoylation in zebrafish Wnt3 by generating a point mutation in a conserved serine residue. Our data support that this specific palmitoylation of Wnt ligand is necessary for its proper localization to the ordered membrane nanodomains. Moreover, mutant protein is unable to activate Wnt signaling as shown by reporter activity measurement, qPCR and in situ hybridization for Wnt reporter and target genes, indicating that proper acylation of Wnt is critical for its activity. Finally, our recent findings indicate that modification of the membrane cholesterol content alters Wnt signaling activity in a variety of liver cancer cell lines. Thus we believe that lipids are involved in regulation of Wnt signaling pathway not only as a posttranslational modification of the ligand and the receptors but also for controlling their physical interactions and ability to activate signaling at the plasma membrane, and may therefore be exploited as key regulators in development of new drugs that interfere with signaling activity.
All interested are cordially invited.