Project B07

Project leaders: Irmgard Sinning and Suat Özbek

Uncovering novel molecular mechanisms within Wnt signaling

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.

Analyse neuer molekularer Mechanismen im Wnt-Signalweg

Dieses Projekt zielt auf die Analyse und Identifizierung neuer molekulare Mechanismen im Wnt-Signalweg durch die Integration von struktur-, zell- und molekularbiologischen Ansätzen ab. Wir werden uns dabei auf spezifische Interaktionen im Wnt-Signalweg konzentrieren. Zum einen werden wir die Interaktion von DEAD-Box-Helikasen und Casein-Kinasen zur Regulation von Dishevelled untersuchen. Weiterhin werden wir eine Analyse von Evi/Wls-Interaktionen mit Wnt, Porcupine and anderen Bindungspartnern durchführen. Außerdem werden wir die strukturelle Grundlage der Spaltung von Wnt-Liganden durch eine konservierte Proteinase als neuen Mechanismus zur Inhibierung des Wnt-Signalwegs untersuchen.

Project-related publications

  • Ziegler, B., I. Yiallouros, B. Trageser, S. Kumar, M. Mercker, S. Kling, M. Fath, U. Warnken, M. Schnölzer, T.W. Holstein, M. Hartl, A. Marciniak-Czochra, J. Stetefeld, W. Stöcker, and S. Özbek. 2021. The Wnt-specific
    astacin proteinase controls head formation in Hydra. BMC Biol., 19(1):120. PMID: 34107975
  • 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.
    2020. Structural Basis of Tail-Anchored Membrane Protein Biogenesis by the GET Insertase Complex.
    Mol Cell. 80:72-86. PMID: 32910895
  • Wild, K., M. Aleksić, K. Lapouge, K.D. Juaire, D. Flemming, S. Pfeffer, and I. Sinning. 2020. MetAP-like
    Ebp1 occupies the human ribosomal tunnel exit and recruits flexible rRNA expansion segments. Nat
    Commun. 11:776. PMID: 32034140
  • Zhang, Y., G. Valentín Gesé, C. Conz, K. Lapouge, J. Kopp, T. Wölfle, S. Rospert, and I. Sinning. 2020. The
    ribosome-associated complex RAC serves in a relay that directs nascent chains to Ssb. Nat Commun.
    11:1504. PMID: 32198371.
  • Mattes, B., Y. Dang, G. Greicius, L.T. Kaufmann, B. Prunsche, J. Rosenbauer, J. Stegmaier, R. Mikut, S.
    Ozbek, G.U. Nienhaus, A. Schug, D.M. Virshup, and S. Scholpp. 2018. Wnt/PCP controls spreading of
    Wnt/beta-catenin signals by cytonemes in vertebrates. Elife. 7. PMID: 30863851
  • Lommel, M., J. Strompen, A.L. Hellewell, G.P. Balasubramanian, E.D. Christofidou, A.R. Thomson, A.L.
    Boyle, D.N. Woolfson, K. Puglisi, M. Hartl, T.W. Holstein, J.C. Adams, and S. Ozbek. 2018. Hydra
    Mesoglea Proteome Identifies Thrombospondin as a Conserved Component Active in Head Organizer
    Restriction. Sci Rep. 8:11753. PMID: 30082916
  • Brinkmann, E.M., B. Mattes, R. Kumar, A.I. Hagemann, D. Gradl, S. Scholpp, H. Steinbeisser, L.T. Kaufmann,
    and S. Ozbek. 2016. Secreted Frizzled-related Protein 2 (sFRP2) Redirects Non-canonical Wnt
    Signaling from Fz7 to Ror2 during Vertebrate Gastrulation. J Biol Chem. 291:13730-13742. PMID:
  • Watanabe, H., H.A. Schmidt, A. Kuhn, S.K. Hoger, Y. Kocagoz, N. Laumann-Lipp, S. Ozbek, and T.W.
    Holstein. 2014. Nodal signalling determines biradial asymmetry in Hydra. Nature. PMID: 25156256
  • Kumar, S., M. Zigman, T.R. Patel, B. Trageser, J.C. Gross, K. Rahm, M. Boutros, D. Gradl, H. Steinbeisser, T.
    Holstein, J. Stetefeld, and S. Ozbek. 2014. Molecular dissection of Wnt3a-Frizzled8 interaction reveals
    essential and modulatory determinants of Wnt signaling activity. BMC Biol. 12:44. PMID: 24885675
  • Stefer, S., S. Reitz, F. Wang, K. Wild, Y.Y. Pang, D. Schwarz, J. Bomke, C. Hein, F. Löhr, F. Bernhard, V.
    Denic, V. Dötsch, and I. Sinning. 2011. Structural basis for tail-anchored membrane protein biogenesis
    by the Get3-receptor complex. Science. 333:758-762. PMID: 21719644