Wingless secretion requires endosome-to-Golgi retrieval of Wntless/Evi/Sprinter by the retromer complex

Franch-Marro, Xavier; Wendler, Franz; Guidato, Sonia; Griffith, Janice; Baena-Lopez, Alberto; Itasaki, Nobue; Maurice, Madelon M.; Vincent, Jean‐Paul

doi:10.1038/ncb1678

Cited by 238 publications

(269 citation statements)

References 23 publications

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“…Wls (also known as Evi or Sprinter in flies and MIG-14 in Caenorhabditis elegans) is an integral membrane protein found in the Golgi, plasma membrane, and endosomes (Banziger et al 2006;Belenkaya et al 2008;Franch-Marro et al 2008b;Port et al 2008;Yang et al 2008). Retromer is a multiprotein complex that shuttles cargo from endosomes to the trans-Golgi (Seaman 2005).…”

Section: Getting Out and About-wnt Secretion And Transportmentioning

confidence: 99%

Wnt Signaling from Development to Disease: Insights from Model Systems

Cadigan¹,

Peifer²

2009

Cold Spring Harbor Perspectives in Biology

275

259

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One of the early surprises in the study of cell adhesion was the discovery that b-catenin plays dual roles, serving as an essential component of cadherin-based cell -cell adherens junctions and also serving as the key regulated effector of the Wnt signaling pathway. Here, we review our current model of Wnt signaling and discuss how recent work using model organisms has advanced our understanding of the roles Wnt signaling plays in both normal development and in disease. These data help flesh out the mechanisms of signaling from the membrane to the nucleus, revealing new protein players and providing novel information about known components of the pathway.

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Section: Getting Out and About-wnt Secretion And Transportmentioning

confidence: 99%

Wnt Signaling from Development to Disease: Insights from Model Systems

Cadigan¹,

Peifer²

2009

Cold Spring Harbor Perspectives in Biology

275

259

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“…In the Wnt secretory pathway, this lipid modification is important for the interaction between Wnt proteins and the conserved transmembrane protein Evi (Wls, GPR177), which shuttles lipid‐modified Wnt proteins to the plasma membrane and onto exovesicles (Bänziger et al , 2006; Bartscherer et al , 2006; Goodman et al , 2006; Gross et al , 2012; Herr & Basler, 2012). Evi is then recycled via the retromer complex back to the Golgi and ER (Coudreuse, 2006; Belenkaya et al , 2008; Franch‐Marro et al , 2008; Pan et al , 2008; Port et al , 2008; Yang et al , 2008; Yu et al , 2014). The levels of both Wnt and Evi proteins are often aberrantly regulated in cancer (Augustin et al , 2012; Voloshanenko et al , 2013; Stewart et al , 2015), which contributes to high Wnt activity during tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

ERAD‐dependent control of the Wnt secretory factor Evi

et al. 2018

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Active regulation of protein abundance is an essential strategy to modulate cellular signaling pathways. Within the Wnt signaling cascade, regulated degradation of β‐catenin by the ubiquitin‐proteasome system (UPS) affects the outcome of canonical Wnt signaling. Here, we found that abundance of the Wnt cargo receptor Evi (Wls/GPR177), which is required for Wnt protein secretion, is also regulated by the UPS through endoplasmic reticulum (ER)‐associated degradation (ERAD). In the absence of Wnt ligands, Evi is ubiquitinated and targeted for ERAD in a VCP‐dependent manner. Ubiquitination of Evi involves the E2‐conjugating enzyme UBE2J2 and the E3‐ligase CGRRF1. Furthermore, we show that a triaging complex of Porcn and VCP determines whether Evi enters the secretory or the ERAD pathway. In this way, ERAD‐dependent control of Evi availability impacts the scale of Wnt protein secretion by adjusting the amount of Evi to meet the requirement of Wnt protein export. As Wnt and Evi protein levels are often dysregulated in cancer, targeting regulatory ERAD components might be a useful approach for therapeutic interventions.

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“…Retromer was originally identified as essential in yeast for the proper retrieval of the vacuolar hydrolase receptor Vps10 from late endosomes back to the trans-Golgi network (Horazdovsky et al, 1997;Seaman et al, 1997) and was later shown to function in an analogous manner in mammalian cells in regard to retrieval of the cation-independent mannose-6-phosphate receptor (Arighi et al, 2004;Seaman, 2004). Since then, retromer has been implicated in a broad range of protein-sorting pathways and has most recently been shown to be required for the maintenance of proper Wnt secretion in the development of both Caenorhabditis elegans and Drosophila melanogaster (Belenkaya et al, 2008;Franch-Marro et al, 2008;Pan et al, 2008;Port et al, 2008;Yang et al, 2008), underscoring its importance in retrograde transport. In yeast retromer is composed of five proteins that assemble into two subcomplexes: Vps5 and Vps17 (Snx1/ Snx2 and Snx5/Snx6 in mammals) and Vps26, Vps29, and Vps35 (and the homologous proteins in metazoans; Seaman et al, 1998;Haft et al, 2000;Wassmer et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Opposing Activities of the Snx3-Retromer Complex and ESCRT Proteins Mediate Regulated Cargo Sorting at a Common Endosome

Strochlic

Schmiedekamp

Lee

et al. 2008

MBoC

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Endocytosed proteins are either delivered to the lysosome to be degraded or are exported from the endosomal system and delivered to other organelles. Sorting of the Saccharomyces cerevisiae reductive iron transporter, composed of the Fet3 and Ftr1 proteins, in the endosomal system is regulated by available iron; in iron-starved cells, Fet3-Ftr1 is sorted by Snx3/Grd19 and retromer into a recycling pathway that delivers it back to the plasma membrane, but when starved cells are exposed to iron, Fet3-Ftr1 is targeted to the lysosome-like vacuole and is degraded. We report that iron-induced endocytosis of Fet3-Ftr1 is independent of Fet3-Ftr1 ubiquitylation, and after endocytosis, degradation of Fet3-Ftr1 is mediated by the multivesicular body (MVB) sorting pathway. In mutant cells lacking any component of the ESCRT protein-dependent MVB sorting machinery, the Rsp5 ubiquitin ligase, or in wild-type cells expressing Fet3-Ftr1 lacking cytosolic lysyl ubiquitin acceptor sites, Fet3-Ftr1 is constitutively sorted into the recycling pathway independent of iron status. In the presence and absence of iron, Fet3-Ftr1 transits an endosomal compartment where a subunit of the MVB sorting receptor (Vps27), Snx3/Grd19, and retromer proteins colocalize. We propose that this endosome is where Rsp5 ubiquitylates Fet3-Ftr1 and where the recycling and degradative pathways diverge. INTRODUCTIONThe endocytic pathway is initiated with the internalization of protein and lipid cargo from the plasma membrane. After endocytosis, internalized molecules transit through the endosomal system, a network of interconnected organelles that process and sort cargo molecules back to the plasma membrane, to other organelles, or to lysosomes for degradation. In mammalian cells, early endosomes are pleiomorphic organelles composed of vacuolar domains that contain lumenal vesicles and tubular domains that lead into and emanate from the vacuolar portion. This distinct architecture has functional significance. The tubular elements of the organelle are regions where the majority of internalized plasma membrane proteins and lipids are exported and recycled from the endosomal system via bulk flow and cargo-specific processes (Mayor et al., 1993;Maxfield and McGraw, 2004;Bonifacino and Rojas, 2006). Cargo proteins that are not exported are delivered to lysosomes and many of these are degraded. This occurs via an active, signal-mediated event in which these proteins are targeted to the vacuolar region of the endosome where they are incorporated into vesicles that bud from the limiting membrane into the lumen of the organelle (Piper and Katzmann, 2007). During endosome maturation lumenal vesicles accrue until fusion of the late endosome with the lysosome results in degradation of these vesicles and their contents. A central sorting function of the endosomal system is thus to segregate cargo to be exported from the endosome from cargo to be degraded via lysosomal proteolysis.The core components of the recycling (retrograde) and degradative sorting pathways have be...

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Wingless secretion requires endosome-to-Golgi retrieval of Wntless/Evi/Sprinter by the retromer complex

Cited by 238 publications

References 23 publications

Wnt Signaling from Development to Disease: Insights from Model Systems

Wnt Signaling from Development to Disease: Insights from Model Systems

ERAD‐dependent control of the Wnt secretory factor Evi

Opposing Activities of the Snx3-Retromer Complex and ESCRT Proteins Mediate Regulated Cargo Sorting at a Common Endosome

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