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• W2078366752 abstract "Wntless is a sorting receptor required for Wnt secretion. Wntless is retrieved from endosomes to the Golgi by retromer, permitting Wntless reutilization in Wnt transport. In the absence of retromer, Wntless is degraded in lysosomes and Wnt secretion is impaired. Wntless is a sorting receptor required for Wnt secretion. Wntless is retrieved from endosomes to the Golgi by retromer, permitting Wntless reutilization in Wnt transport. In the absence of retromer, Wntless is degraded in lysosomes and Wnt secretion is impaired. The Wnt family of secreted signaling proteins patterns a huge variety of developing tissues throughout metazoa. In this issue, and in an upcoming issue of Nature Cell Biology, work from five different labs addresses the mechanism by which Wntless and the retromer complex work together to promote secretion of Wnt family proteins (Belenkaya et al., 2008Belenkaya T.Y. Wu Y. Tang X. Zhou B. Cheng L. Sharma Y.V. Yan D. Selva E.M. Lin X. Dev. Cell. 2008; 14 (this issue. Published online December 20, 2007): 120-131https://doi.org/10.1016/j.devcel.2007.12.003Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar, Franch-Marro et al., 2008Franch-Marro X. Wendler F. Guidato S. Griffith J. Baena-Lopez A. Itasaki N. Maurice M. Vincent J. Nat. Cell Biol.,. 2008; (in press. Published online January 13, 2008)https://doi.org/10.1038/ncb1678Crossref PubMed Scopus (199) Google Scholar, Pan et al., 2008Pan C.-L. Baum P.D. Gu M. Jorgensen E.M. Clark S.G. Garriga G. Dev. Cell. 2008; 14 (this issue. Published online December 20, 2007): 132-139https://doi.org/10.1016/j.devcel.2007.12.001Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, Port et al., 2008Port F. Kuster M. Herr P. Furger E. Bänziger C. Hausmann G. Basler K. Nat. Cell Biol.,. 2008; (in press. Published online January 13, 2008)https://doi.org/10.1038/ncb1687Crossref PubMed Scopus (196) Google Scholar, Yang et al., 2008Yang P.-T. Lorenowicz M. Silhankova M. Coudreuse D.Y.M. Betist M.C. Korswagen H.C. Dev. Cell. 2008; 14 (this issue. Published online December 20, 2007): 140-147https://doi.org/10.1016/j.devcel.2007.12.004Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar). The conserved requirement for the multiple pass transmembrane protein Wntless in Wnt secretion was first reported in 2006 by multiple groups working with Drosophila melanogaster, Caenorhabditis elegans, and human tissue culture cells (reviewed in Hausmann et al., 2007Hausmann G. Banziger C. Basler K. Nat. Rev. Mol. Cell Biol. 2007; 8: 331-336Crossref PubMed Scopus (96) Google Scholar). Wntless has been variously called Evenness Interrupted (Evi) and Sprinter in Drosophila and MOM-3/MIG-14 in C. elegans; here, I will refer to it as Wntless for the sake of clarity. In Wntless mutants, Wnts accumulate inside the cells that make them and both surface delivery and secretion are impaired. Wnt secretion appears to be the only nonredundant function for Wntless; Drosophila wntless mutants, which do not secrete normal levels of the Drosophila Wnt Wingless (Wg), can be rescued to viability by wntless expression in Wingless-producing cells. Retromer was first identified in yeast as being important for efficient trafficking of lysosomal hydrolases to the vacuole. Its substituents, Vps35, Vps29, Vps26, Vps5, and Vps17, form a multiprotein complex that retrieves the sorting receptor Vps10 from endosomes back to the Golgi. This allows reuse of Vps10 for multiple rounds of lysosomal hydrolase delivery. Retromer function is conserved in mammalian cells, where it mediates endosome-to-Golgi retrieval of the mannose-6-phosphage receptor (reviewed in Seaman, 2005Seaman M.N. Trends Cell Biol. 2005; 15: 68-75Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). Despite the importance of retromer in such a basic aspect of cell biology, manipulations of Vps35 or Vps26 were reported to produce rather restricted phenotypes that suggested loss of Wnt signaling (reviewed in Hausmann et al., 2007Hausmann G. Banziger C. Basler K. Nat. Rev. Mol. Cell Biol. 2007; 8: 331-336Crossref PubMed Scopus (96) Google Scholar). The similarity of the Wntless and Vps35 mutant phenotypes raised the compelling possibility that the proteins they encoded were part of the same machinery for Wnt secretion. With these two pieces of the puzzle available, there has been a race to understand how they are connected. Two of the groups whose work is published this month have focused on Wnt secretion in the nematode worm C. elegans (Pan et al., 2008Pan C.-L. Baum P.D. Gu M. Jorgensen E.M. Clark S.G. Garriga G. Dev. Cell. 2008; 14 (this issue. Published online December 20, 2007): 132-139https://doi.org/10.1016/j.devcel.2007.12.001Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, Yang et al., 2008Yang P.-T. Lorenowicz M. Silhankova M. Coudreuse D.Y.M. Betist M.C. Korswagen H.C. Dev. Cell. 2008; 14 (this issue. Published online December 20, 2007): 140-147https://doi.org/10.1016/j.devcel.2007.12.004Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar), and three others have examined secretion of Wingless (Wg), a Drosophila Wnt protein, in developing wing discs (Belenkaya et al., 2008Belenkaya T.Y. Wu Y. Tang X. Zhou B. Cheng L. Sharma Y.V. Yan D. Selva E.M. Lin X. Dev. Cell. 2008; 14 (this issue. Published online December 20, 2007): 120-131https://doi.org/10.1016/j.devcel.2007.12.003Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar, Franch-Marro et al., 2008Franch-Marro X. Wendler F. Guidato S. Griffith J. Baena-Lopez A. Itasaki N. Maurice M. Vincent J. Nat. Cell Biol.,. 2008; (in press. Published online January 13, 2008)https://doi.org/10.1038/ncb1678Crossref PubMed Scopus (199) Google Scholar, Port et al., 2008Port F. Kuster M. Herr P. Furger E. Bänziger C. Hausmann G. Basler K. Nat. Cell Biol.,. 2008; (in press. Published online January 13, 2008)https://doi.org/10.1038/ncb1687Crossref PubMed Scopus (196) Google Scholar). In many cases, human tissue culture cells have also been exploited for the clear visibility of intracellular membrane compartments and accessibility to cell biological manipulations (Belenkaya et al., 2008Belenkaya T.Y. Wu Y. Tang X. Zhou B. Cheng L. Sharma Y.V. Yan D. Selva E.M. Lin X. Dev. Cell. 2008; 14 (this issue. Published online December 20, 2007): 120-131https://doi.org/10.1016/j.devcel.2007.12.003Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar, Franch-Marro et al., 2008Franch-Marro X. Wendler F. Guidato S. Griffith J. Baena-Lopez A. Itasaki N. Maurice M. Vincent J. Nat. Cell Biol.,. 2008; (in press. Published online January 13, 2008)https://doi.org/10.1038/ncb1678Crossref PubMed Scopus (199) Google Scholar, Port et al., 2008Port F. Kuster M. Herr P. Furger E. Bänziger C. Hausmann G. Basler K. Nat. Cell Biol.,. 2008; (in press. Published online January 13, 2008)https://doi.org/10.1038/ncb1687Crossref PubMed Scopus (196) Google Scholar, Yang et al., 2008Yang P.-T. Lorenowicz M. Silhankova M. Coudreuse D.Y.M. Betist M.C. Korswagen H.C. Dev. Cell. 2008; 14 (this issue. Published online December 20, 2007): 140-147https://doi.org/10.1016/j.devcel.2007.12.004Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar). The work reported in these five papers clearly confirms the importance of retromer function in Wnt secretion and shows that this role is conserved for a wide variety of Wnts in Drosophila, C. elegans, and human cells. Each group now conclusively demonstrates that retromer functions primarily to maintain Wntless levels. In all three systems, knockdown or mutation of Vps35 destabilizes Wntless, and Wnt signaling in Vps35 mutants is rescued by Wntless overexpression. To investigate how retromer stabilizes Wntless, all five groups have followed its trafficking in normal cells and in cells in which either the endocytic machinery or retromer function has been perturbed. Taken together, their results show that retromer maintains Wntless protein levels by inhibiting its delivery to the lysosomes and promoting delivery to the Golgi. Wntless is normally found both in the Golgi and in endocytic compartments. Mutation or RNAi-mediated knock-down of Rab5 or dynamin relocalizes Wntless to the plasma membrane (Belenkaya et al., 2008Belenkaya T.Y. Wu Y. Tang X. Zhou B. Cheng L. Sharma Y.V. Yan D. Selva E.M. Lin X. Dev. Cell. 2008; 14 (this issue. Published online December 20, 2007): 120-131https://doi.org/10.1016/j.devcel.2007.12.003Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar, Pan et al., 2008Pan C.-L. Baum P.D. Gu M. Jorgensen E.M. Clark S.G. Garriga G. Dev. Cell. 2008; 14 (this issue. Published online December 20, 2007): 132-139https://doi.org/10.1016/j.devcel.2007.12.001Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar) and increases Wntless protein levels (Yang et al., 2008Yang P.-T. Lorenowicz M. Silhankova M. Coudreuse D.Y.M. Betist M.C. Korswagen H.C. Dev. Cell. 2008; 14 (this issue. Published online December 20, 2007): 140-147https://doi.org/10.1016/j.devcel.2007.12.004Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar), suggesting that a fraction of internalized Wntless is normally degraded after internalization. However, some Wntless escapes this fate and is returned to the Golgi apparatus by a mechanism that depends on Vps35. Two groups have shown that incubation of tissue culture cells with antibodies to tagged Wntless results in delivery of the antibodies to the Golgi apparatus; this Golgi delivery can be blocked by RNAi-mediated knockdown of Vps35 (Belenkaya et al., 2008Belenkaya T.Y. Wu Y. Tang X. Zhou B. Cheng L. Sharma Y.V. Yan D. Selva E.M. Lin X. Dev. Cell. 2008; 14 (this issue. Published online December 20, 2007): 120-131https://doi.org/10.1016/j.devcel.2007.12.003Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar, Franch-Marro et al., 2008Franch-Marro X. Wendler F. Guidato S. Griffith J. Baena-Lopez A. Itasaki N. Maurice M. Vincent J. Nat. Cell Biol.,. 2008; (in press. Published online January 13, 2008)https://doi.org/10.1038/ncb1678Crossref PubMed Scopus (199) Google Scholar). Loss of Vps35 causes a corresponding increase in Wntless accumulation in lysosomes (Franch-Marro et al., 2008Franch-Marro X. Wendler F. Guidato S. Griffith J. Baena-Lopez A. Itasaki N. Maurice M. Vincent J. Nat. Cell Biol.,. 2008; (in press. Published online January 13, 2008)https://doi.org/10.1038/ncb1678Crossref PubMed Scopus (199) Google Scholar, Pan et al., 2008Pan C.-L. Baum P.D. Gu M. Jorgensen E.M. Clark S.G. Garriga G. Dev. Cell. 2008; 14 (this issue. Published online December 20, 2007): 132-139https://doi.org/10.1016/j.devcel.2007.12.001Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, Yang et al., 2008Yang P.-T. Lorenowicz M. Silhankova M. Coudreuse D.Y.M. Betist M.C. Korswagen H.C. Dev. Cell. 2008; 14 (this issue. Published online December 20, 2007): 140-147https://doi.org/10.1016/j.devcel.2007.12.004Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar). Interestingly, Wntless protein stability is most sensitive to the loss of Vps35 in Wg-expressing cells (Port et al., 2008Port F. Kuster M. Herr P. Furger E. Bänziger C. Hausmann G. Basler K. Nat. Cell Biol.,. 2008; (in press. Published online January 13, 2008)https://doi.org/10.1038/ncb1687Crossref PubMed Scopus (196) Google Scholar). This suggests that Wntless cycles through endosomes more frequently in these cells and may indicate that Wntless moves with Wg to the plasma membrane. The finding that Wntless and Vps35 can be coimmunoprecipitated (Belenkaya et al., 2008Belenkaya T.Y. Wu Y. Tang X. Zhou B. Cheng L. Sharma Y.V. Yan D. Selva E.M. Lin X. Dev. Cell. 2008; 14 (this issue. Published online December 20, 2007): 120-131https://doi.org/10.1016/j.devcel.2007.12.003Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar, Franch-Marro et al., 2008Franch-Marro X. Wendler F. Guidato S. Griffith J. Baena-Lopez A. Itasaki N. Maurice M. Vincent J. Nat. Cell Biol.,. 2008; (in press. Published online January 13, 2008)https://doi.org/10.1038/ncb1678Crossref PubMed Scopus (199) Google Scholar) suggests that Vps35 may act directly to promote incorporation of Wntless into vesicles destined for the Golgi. Thus, the function of retromer in Wntless trafficking is similar to its function in trafficking of sorting receptors for lysosomal hydrolases; it retrieves Wntless from endosomes before they mature into lysosomes and delivers it to the Golgi. In sum, the work of these five groups provides strong support for the idea that retromer promotes Wnt secretion by ensuring the retrieval and reutilization of its sorting receptor, Wntless (Figure 1). Is Wntless/retromer-dependent secretion the only mechanism by which Wnt proteins can leave the cell? It was originally suggested that long-range Wnt signaling was more sensitive to loss of retromer function than was short-range signaling, raising the possibility that Wnt proteins might be released by different mechanisms (Coudreuse et al., 2006Coudreuse D.Y. Roel G. Betist M.C. Destree O. Korswagen H.C. Science. 2006; 312: 921-924Crossref PubMed Scopus (189) Google Scholar). However, further studies in C. elegans clearly show a role for retromer in short-range Wnt signaling as well (Pan et al., 2008Pan C.-L. Baum P.D. Gu M. Jorgensen E.M. Clark S.G. Garriga G. Dev. Cell. 2008; 14 (this issue. Published online December 20, 2007): 132-139https://doi.org/10.1016/j.devcel.2007.12.001Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar). In fact, in the Drosophila wing disc, it is short-range Wg signaling that is most strongly affected by loss of retromer function. Transcription of the long-range target Distalless is not affected by mutation of either Wntless or retromer (Franch-Marro et al., 2008Franch-Marro X. Wendler F. Guidato S. Griffith J. Baena-Lopez A. Itasaki N. Maurice M. Vincent J. Nat. Cell Biol.,. 2008; (in press. Published online January 13, 2008)https://doi.org/10.1038/ncb1678Crossref PubMed Scopus (199) Google Scholar, Port et al., 2008Port F. Kuster M. Herr P. Furger E. Bänziger C. Hausmann G. Basler K. Nat. Cell Biol.,. 2008; (in press. Published online January 13, 2008)https://doi.org/10.1038/ncb1687Crossref PubMed Scopus (196) Google Scholar). This might suggest that an alternative pathway exists for secreting Wg with long-range activity. But it is equally plausible that residual, maternally contributed retromer proteins allow secretion of small amounts of Wg that suffice for Distalless transcription. Further experiments will be necessary to resolve this issue. While these five papers have focused on the role of retromer in Wnt secretion, another recently published study of Drosophila vps35 has shown that it also regulates Rac1-dependent actin polymerization, promotes endocytosis of a subset of membrane receptors, and downregulates both BMP signaling and signaling through MAP kinases (Korolchuk et al., 2007Korolchuk V.I. Schutz M.M. Gomez-Llorente C. Rocha J. Lansu N.R. Collins S.M. Wairkar Y.P. Robinson I.M. O'Kane C.J. J. Cell Sci. 2007; 120: 4367-4376Crossref PubMed Scopus (69) Google Scholar). Clearly, Vps35 influences cellular functions at many levels. Interestingly, however, there is no evidence that lysosomal degradation is weakened in Vps35 mutant animals. When endosome-to-Golgi retrieval of MPR is blocked by dominant-negative Rab9 expression, cells compensate by elevating the production of lysosomal hydrolases and by internalization of secreted hydrolases (Riederer et al., 1994Riederer M.A. Soldati T. Shapiro A.D. Lin J. Pfeffer S.R. J. Cell Biol. 1994; 125: 573-582Crossref PubMed Scopus (240) Google Scholar). Similarly, these robust and redundant mechanisms probably insure that lysosomal function is unaffected by the mutation of retromer components. Trafficking of signaling molecules and their receptors appears to be more sensitive to perturbed retromer function. While no data yet suggests that cells normally modulate retromer-dependent trafficking to control cellular signaling pathways, this is an intriguing subject for future investigations. C. elegans AP-2 and Retromer Control Wnt Signaling by Regulating MIG-14/WntlessPan et al.Developmental CellJanuary, 2008In BriefWhile endocytosis can regulate morphogen distribution, its precise role in shaping these gradients is unclear. Even more enigmatic is the role of retromer, a complex that shuttles proteins between endosomes and the Golgi apparatus, in Wnt gradient formation. Here we report that DPY-23, the C. elegans μ subunit of the clathrin adaptor AP-2 that mediates the endocytosis of membrane proteins, regulates Wnt function. dpy-23 mutants display Wnt phenotypes, including defects in neuronal migration, neuronal polarity, and asymmetric cell division. Full-Text PDF Open ArchiveThe Retromer Complex Influences Wnt Secretion by Recycling Wntless from Endosomes to the Trans-Golgi NetworkBelenkaya et al.Developmental CellJanuary, 2008In BriefSecreted Wnt proteins play essential roles in many biological processes during development and diseases. However, little is known about the mechanism(s) controlling Wnt secretion. Recent studies have identified Wntless (Wls) and the retromer complex as essential components involved in Wnt signaling. While Wls has been shown to be essential for Wnt secretion, the function(s) of the retromer complex in Wnt signaling is unknown. Here, we have examined a role of Vps35, an essential retromer subunit, in Wnt signaling in Drosophila and mammalian cells. Full-Text PDF Open Archive" @default.
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