A01

Mechanisms of Wnt protein secretion

Funding period: 2017-2025

Project A01

Project Leaders

Prof. Dr. Michael Boutros

Prof. Dr. Michael Boutros

Project Leader A01, A04, Z01, Z03

Prof. Dr. Irmgard Sinning

Project Leader A01, B07

Abstract

Wnt proteins are lipidated glycoproteins which require a specialized secretion machinery for their export. Previously, we identified in genetic screens the Wnt cargo-receptor Evi/Wls as an essential factor for Wnt secretion and studied its role ex vivo and in vivo. Nevertheless, it remains currently unclear how Evi/Wls interacts on a molecular level with different proteins in the secretion and ERAD pathways in order to regulate the secretion of Wnt ligands. To address these questions, we will identify novel Wnt secretion components by a genetic screen in Drosophila, analyze the biochemical interactions and the structure of Evi/Wls with interacting proteins and will further characterize the functions of novel regulators.

Project-related Publications

Superresolution microscopy localizes endogenous Dvl2 to Wnt signaling-responsive biomolecular condensates

Schubert A, Voloshanenko O, Ragaller F, Gmach P, Kranz D, Scheeder C, Miersch T, Schulz M, Trümper L, Binder C, Lampe M, Engel U, Boutros M. Proc Natl Acad Sci U S A. 2022 Jul 26;119(30):e2122476119. doi: 10.1073/pnas.2122476119. Epub 2022 Jul 22. PMID: 35867833

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EVI/WLS function is regulated by ubiquitination and linked to ER-associated degradation by ERLIN2

Wolf LM, Lambert AM, Haenlin J, Boutros M. J Cell Sci. 2021 Jul 19:jcs.257790. doi: 10.1242/jcs.257790. Online ahead of print.
PMID: 3427964

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A spatial vascular transcriptomic, proteomic, and phosphoproteomic atlas unveils an angiocrine Tie–Wnt signaling axis in the liver

Inverso D, Shi J, Lee KH, Jakab M, Ben-Moshe S, Kulkarni SR, Schneider M, Wang G, Komeili M, Vélez PA, Riedel M, Spegg C, Ruppert T, Schaeffer-Reiss C, Helm D, Singh I, Boutros M, Chintharlapalli S, Heikenwalder M, Itzkovitz S, Augustin HG. Dev Cell. 2021 Jun 7;56(11):1677-1693.e10. PMID: 34038707

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Wnt10b GSK3β dependent Wnt/STOP signaling prevents aneuploidy in human somatic cells

Lin YC, Haas A, Bufe A, Parbin S, Hennecke M, Voloshanenko O, Gross J, Boutros M, Acebron SP, Bastians H. Life Sci Alliance. 2020 Nov 30;4(1):e202000855. Print 2021 Jan.
PMID: 33257473

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Extracellular vesicles and oncogenic signaling

Schubert A, Boutros M. Mol Oncol. 2020 Nov 18. doi: 10.1002/1878-0261.12855. PMID: 33207034

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Structural Basis of Tail-Anchored Membrane Protein Biogenesis by the GET Insertase Complex

McDowell, M.A., M. Heimes, F. Fiorentino, S. Mehmood, Á. Farkas, J. Coy-Vergara, D. Wu, J.R. Bolla, V. Schmid, R. Heinze, K. Wild, D. Flemming, S. Pfeffer, B. Schwappach, C.V. Robinson, and I. Sinning. Mol Cell. 2020 Oct 1;80(1):72-86.e7. doi: 10.1016/j.molcel.2020.08.012. Epub 2020 Sep 9. PMID: 32910895

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Multiplexed conditional genome editing with Cas12a in Drosophila

Port F, Starostecka M, Boutros M. Proc Natl Acad Sci U S A. 2020 Aug 25:202004655.

PMID: 32843348

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eGFP-tagged Wnt-3a enables functional analysis of Wnt trafficking and signaling and kinetic assessment of Wnt binding to full-length Frizzled

Wesslowski J, Kozielewicz P, Wang X, Cui H, Schihada H, Kranz D, Karuna M P, Levkin P, Gross JC, Boutros M, Schulte G, Davidson G. J Biol Chem. 2020 May 7. pii: jbc.RA120.012892. PMID:32381507

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The ribosome-associated complex RAC serves in a relay that directs nascent chains to Ssb

Zhang Y, Valentín Gesé G, Conz C, Lapouge K, Kopp J, Wölfle T, Rospert S, Sinning I. Nat Commun. 2020 Mar 20;11(1):1504. doi: 10.1038/s41467-020-15313-w. PMID: 32198371

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A Large-Scale Resource for Tissue-Specific CRISPR Mutagenesis in Drosophila

Port F, Strein C, Stricker M, Rauscher B, Heigwer F, Zhou J, Beyersdörffer C, Frei J, Hess A, Kern K, Lange L, Langner N, Malamud R, Pavlović B, Rädecke K, Schmitt L, Voos L, Valentini E, Boutros M. Elife. 2020 Feb 13;9:e53865.

PMID: 32053108

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MetAP-like Ebp1 occupies the human ribosomal tunnel exit and recruits flexible rRNA expansion segments

Wild K, Aleksić M, Lapouge K, Juaire KD, Flemming D, Pfeffer S, Sinning I. Nat Commun. 2020 Feb 7;11(1):776. doi: 10.1038/s41467-020-14603-7. PMID: 32034140

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Exocyst-mediated apical Wg secretion activates signaling in the Drosophila wing epithelium

Chaudhary V, Boutros M. PLoS Genet. 2019 Sep 17;15(9):e1008351. PMID: 31527874

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Robust Wnt signaling is maintained by a Wg protein gradient and Fz2 receptor activity in the developing Drosophila wing

Chaudhary V, Hingole S, Frei J, Port F, Strutt D, Boutros M. Development. 2019 Aug 9;146(15). PMID: 31399474

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β-catenin-independent regulation of Wnt target genes by RoR2 and ATF2/ATF4 in colon cancer cells

Voloshanenko O, Schwartz U, Kranz D, Rauscher B, Linnebacher M, Augustin I, Boutros M. Sci Rep. 2018 Feb 16;8(1):3178. PMID:29453334

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ERAD-dependent control of the Wnt secretory factor Evi

Glaeser K, Urban M, Fenech E, Voloshanenko O, Kranz D, Lari F, Christianson JC, Boutros M. EMBO J. 2018 Feb 15;37(4). PMID:29378775  

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Mapping of Wnt-Frizzled interactions by multiplex CRISPR targeting of receptor gene families

Voloshanenko O, Gmach P, Winter J, Kranz D, Boutros M. FASEB J. 2017 Nov;31(11):4832-4844. doi: 10.1096/fj.201700144R. Epub 2017 Jul 21. PMID: 28733458

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Structural insights into a unique Hsp70-Hsp40 interaction in the eukaryotic ribosome-associated complex

Weyer FA, Gumiero A, Gesé GV, Lapouge K, Sinning I. Nat Struct Mol Biol. 2017 Feb;24(2):144-151. doi: 10.1038/nsmb.3349. Epub 2017 Jan 9.
PMID: 28067917

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Structural basis for tail-anchored membrane protein biogenesis by the Get3-receptor complex

Stefer S, Reitz S, Wang F, Wild K, Pang YY, Schwarz D, Bomke J, Hein C, Löhr F, Bernhard F, Denic V, Dötsch V, Sinning I. Science. 2011 Aug 5;333(6043):758-62. doi: 10.1126/science.1207125. Epub 2011 Jun 30. PMID: 21719644

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Secretion of Wnt ligands requires Evi, a conserved transmembrane protein

Bartscherer K, Pelte N, Ingelfinger D, Boutros M. Cell. 2006 May 5;125(3):523-33. doi: 10.1016/j.cell.2006.04.009. PMID: 16678096

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