Article

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.

Download full-text

Full-text

Available from: Magdalena Lorenowicz, May 19, 2015
1 Follower
 · 
198 Views
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Throughout the animal kingdom, Wnt-triggered signal transduction pathways play fundamental roles in embryonic development and tissue homeostasis. Wnt proteins are modified as glycolipoproteins and are secreted into the extracellular environment as morphogens. Recent studies on the intracellular trafficking of Wnt proteins demonstrate multiple layers of regulation along its secretory pathway. These findings have propelled a great deal of interest among researchers to further investigate the molecular mechanisms that control the release of Wnts and hence the level of Wnt signaling. This review is dedicated to Wntless, a putative G-protein coupled receptor that transports Wnts intracellularly for secretion. Here, we highlight the conclusions drawn from the most recent cellular, molecular and genetic studies that affirm the role of Wntless in the secretion of Wnt proteins.
    Frontiers of Biology in China 12/2012; 7(6):587-593. DOI:10.1007/s11515-012-1200-8
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Elevated levels of nuclear β-catenin are associated with higher rates of survival in patients with melanoma, raising questions as to how ß-catenin is regulated in this context. In the present study, we investigated the formal possibility that the secretion of WNT ligands that stabilize ß-catenin may be regulated in melanoma and thus contributes to differences in ß-catenin levels. We find that WLS, a conserved transmembrane protein necessary for WNT secretion, is decreased in both melanoma cell lines and in patient tumours relative to skin and to benign nevi. Unexpectedly, reducing endogenous WLS with shRNAs in human melanoma cell lines promotes spontaneous lung metastasis in xenografts in mice and promotes cell proliferation in vitro. Conversely, overexpression of WLS inhibits cell proliferation in vitro. Activating β-catenin downstream of WNT secretion blocks the increased cell migration and proliferation observed in the presence of WLS shRNAs, while inhibiting WNT signalling rescues the growth defects induced by excess WLS. These data suggest that WLS functions as a negative regulator of melanoma proliferation and spontaneous metastasis by activating WNT/β-catenin signalling.
    EMBO Molecular Medicine 12/2012; 4(12). DOI:10.1002/emmm.201201486 · 8.25 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The WNT signal transduction cascade controls myriad biological phenomena throughout development and adult life of all animals. In parallel, aberrant Wnt signaling underlies a wide range of pathologies in humans. In this Review, we provide an update of the core Wnt/β-catenin signaling pathway, discuss how its various components contribute to disease, and pose outstanding questions to be addressed in the future.
    Cell 06/2012; 149(6):1192-205. DOI:10.1016/j.cell.2012.05.012 · 33.12 Impact Factor
Show more