B07

Uncovering novel molecular mechanisms within Wnt signaling

Funding period: 2017-2025

Project B07

Project Leaders

Prof. Dr. Irmgard Sinning

Project Leader A01, B07
Apl. Prof. Dr. Suat Özbek

Apl. Prof. Dr. Suat Özbek

Project Leader B07

Abstract

The project aims at unraveling molecular mechanisms of Wnt signaling by integration of structural, cell and molecular biology approaches. We will study key interactions in Wnt signaling focusing on selected interactions. We will continue dissecting the interplay between DEAD-box helicases and Casein kinases for regulation of Dishevelled, and perform a detailed analysis of Evi/Wls interaction with Wnt, Porcupine and novel protein partners. In addition, we will unravel the structural basis of Wnt cleavage by a conserved proteinase as a novel mechanism of Wnt signal inhibition. To this end, we will study Wnt inhibition at the ligand level by a recently identified member of the astacin proteinase family (HAS-7) as a Wnt3 processing factor.

Project-related Publications

The Wnt-specific astacin proteinase HAS-7 restricts head organizer formation in Hydra

Ziegler B, Yiallouros I, Trageser B, Kumar S, Mercker M, Kling S, Fath M, Warnken U, Schnölzer M, Holstein TW, Hartl M, Marciniak-Czochra A, Stetefeld J, Stöcker W, Özbek S. BMC Biol. 2021 Jun 9;19(1):120. 
PMID: 34107975

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Wnt/β-Catenin Signaling Controls Spatio-Temporal Elasticity Patterns in Extracellular Matrix during Hydra Morphogenesis

Veschgini, M., H.O. Petersen, F. Rossetti, W. Abuillan, S. Kaufmann, R. Suzuki, M. Burghammer, S. Özbek, T.W. Holstein, and M. Tanaka. 2020. bioRxiv, preprint.

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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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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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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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Hydra Mesoglea Proteome Identifies Thrombospondin as a Conserved Component Active in Head Organizer Restriction

Lommel M, Strompen J, Hellewell AL, Balasubramanian GP, Christofidou ED, Thomson AR, Boyle AL, Woolfson DN, Puglisi K, Hartl M, Holstein TW, Adams JC, Özbek S. Sci Rep. 2018 Aug 6;8(1):11753. PMID:30082916

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Wnt/PCP controls spreading of Wnt/β-catenin signals by cytonemes in vertebrates

Mattes B, Dang Y, Greicius G, Kaufmann LT, Prunsche B, Rosenbauer J, Stegmaier J, Mikut R, Özbek S, Nienhaus GU, Schug A, Virshup DM, Scholpp S. Elife. 2018 Jul 31;7. PMID:30060804

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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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Secreted Frizzled-related Protein 2 (sFRP2) Redirects Non-canonical Wnt Signaling from Fz7 to Ror2 during Vertebrate Gastrulation

Brinkmann EM, Mattes B, Kumar R, Hagemann AI, Gradl D, Scholpp S, Steinbeisser H, Kaufmann LT, Özbek S. J Biol Chem. 2016 Jun 24;291(26):13730-42. doi: 10.1074/jbc.M116.733766. Epub 2016 Apr 29. PMID: 27129770

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A Comprehensive Transcriptomic and Proteomic Analysis of Hydra Head Regeneration.

Petersen, H.O., S.K. Hoger, M. Looso, T. Lengfeld, A. Kuhn, U. Warnken, C. Nishimiya-Fujisawa, M. Schnolzer, M. Kruger, S. Ozbek, O. Simakov, and T.W. Holstein. Mol Biol Evol. 2015 Aug;32(8):1928-47. doi: 10.1093/molbev/msv079. Epub 2015 Apr 3. PMID: 25841488

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Nodal signalling determines biradial asymmetry in Hydra

Watanabe H, Schmidt HA, Kuhn A, Höger SK, Kocagöz Y, Laumann-Lipp N, Ozbek S, Holstein TW. Nature. 2014 Nov 6;515(7525):112-5. doi: 10.1038/nature13666. Epub 2014 Aug 24.
PMID: 25156256

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Molecular dissection of Wnt3a-Frizzled8 interaction reveals essential and modulatory determinants of Wnt signaling activity

Kumar S, Žigman M, Patel TR, Trageser B, Gross JC, Rahm K, Boutros M, Gradl D, Steinbeisser H, Holstein T, Stetefeld J, Özbek S. BMC Biol. 2014 May 30;12:44. doi: 10.1186/1741-7007-12-44. PMID: 24885675

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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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Autoregulatory and repressive inputs localize Hydra Wnt3 to the head organizer

Nakamura Y, Tsiairis CD, Özbek S, Holstein TW. Proc Natl Acad Sci U S A. 2011 May 31;108(22):9137-42. doi: 10.1073/pnas.1018109108. Epub 2011 May 16. PMID: 21576458

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