Wnt Signaling Requires Retromer-Dependent Recycling of MIG-14/Wntless in Wnt-Producing Cells

Hubrecht Institute, Developmental Biology and Stem Cell Research, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.
Developmental Cell (Impact Factor: 10.37). 02/2008; 14(1):140-7. DOI: 10.1016/j.devcel.2007.12.004
Source: PubMed

ABSTRACT Wnt proteins are secreted signaling molecules that play a central role in development and adult tissue homeostasis. We have previously shown that Wnt signaling requires retromer function in Wnt-producing cells. The retromer is a multiprotein complex that mediates endosome-to-Golgi transport of specific sorting receptors. MIG-14/Wls is a conserved transmembrane protein that binds Wnt and is required in Wnt-producing cells for Wnt secretion. Here, we demonstrate that in the absence of retromer function, MIG-14/Wls is degraded in lysosomes and becomes limiting for Wnt signaling. We show that retromer-dependent recycling of MIG-14/Wls is part of a trafficking pathway that retrieves MIG-14/Wls from the plasma membrane. We propose that MIG-14/Wls cycles between the Golgi and the plasma membrane to mediate Wnt secretion. Regulation of this transport pathway may enable Wnt-producing cells to control the range of Wnt signaling in the tissue.

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Available from: Magdalena Lorenowicz, May 19, 2015
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    • "From early endosomes, Wntless is carried to the Golgi in a retromer-dependent manner in small vesicles (Belenkaya et al., 2008; Franch-Marro et al., 2008; Port et al., 2008; Silhankova et al., 2010; Yang et al., 2008) (Fig. 2). Retromer is a complex of different protein subcomplexes including a cargo recognition Vps26-Vps29-Vps35 trimer (Seaman, 2005; Attar and Cullen, 2010) and a cargo sorting, SNX-BAR (Sorting Nexin Protein with Carboxyl terminal Bin amphiphysin Rvs) hetero or homodimer (Carlton et al., 2004; Carlton et al., 2005; Wassmer et al., 2007). "
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    • "One of the key components required for WNT ligand secretion is Wntless (WLS), also known as Evi, Sprinter or GPR177. WLS encodes an evolutionarily conserved transmembrane protein that genetically interacts with components involved in specified secretory pathways (Harterink et al, 2011; Silhankova et al, 2010; Yang et al, 2008). Overexpressed WLS physically interacts with WNT3A, and this interaction depends upon the palmitoylation of WNT3A at Serine 209 (Coombs et al, 2010). "
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    • "One of the key functions of the retromer complex involves the retrograde transport of specific endocytosed transmembrane proteins back to the trans-Golgi network. Current evidence indicates that the retromer retrieves endosomal Wls, which is otherwise destined to be degraded in lysosomes, trafficking it to the trans-Golgi network by retrograde transport (Belenkaya et al., 2008; Franch-Marro et al., 2008b; Port et al., 2008; Yang et al., 2008; Figure 1). In Most Contexts, Wnts Signal over a Short Distance In the current literature, it is often taken for granted that Wnt signals are morphogens, molecules that exert their action across a distance in tissues. "
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