Project B01

Role of DDX56 in GSK3β regulation during Wnt signaling

Project leader: Christof Niehrs

Abstract

DDX RNA helicases are ATPases that promote RNA folding and processing in numerous biological processes and in disease. The function of most DDX helicases is still unknown. We have previously identified the DEAD-box RNA helicase DDX3 as a regulator of the Wnt/β-catenin network in embryonic development, where it acts as a regulatory subunit of Casein kinase 1 epsilon (CK1e). In the last funding period we have finalized a study (with I. Sinning (B07) and J. Krijgsveld (Z04) as coauthors), which indicates that unexpectedly, DDX proteins stimulate protein kinase activity by accelerating the exchange of ADP for ATP, commonly the rate-limiting step in protein phosphorylation. These findings reveal a novel, fundamental principle in kinase regulation. We have evidence that another kinase-DDX pair is engaged in Wnt signaling, namely GSK3b and DDX56. The three main aims of the project are to i) validate the interaction between DDX56 and GSK3b biochemically in the context of Wnt signaling in mammalian cultured cells; ii) demonstrate that DDX56 acts as NEF for GSK3b in vitro; iii) validate the interaction between DDX56 and GSK3b in the context of Wnt signaling during Xenopus development. This project will once again be carried out with I. Sinning (B07) and J. Krijgsveld (Z04) as close collaborators.

Project-related publications

  • Sun R, He L, Lee H, Glinka A, Andresen C, Hübschmann D, Jeremias I, Müller-Decker K, Pabst C, Niehrs C. RSPO2 inhibits BMP signaling to promote self-renewal in acute myeloid leukemia. Cell Rep. 2021 Aug 17;36(7):109559. PMID: 34407399
  • Lee, H., C. Seidl, R. Sun, A. Glinka, and C. Niehrs. 2020. R-spondins are BMP receptor antagonists in early embryonic development. Nat Commun. 11:5570. PMID: 33149137
  • Chang, L.S., M. Kim, A. Glinka, C. Reinhard, and C. Niehrs. 2020. The tumor suppressor PTPRK promotes ZNRF3 internalization and is required for Wnt inhibition in the Spemann organizer. Elife. 51248. PMID:
    31934854
  • Kirsch, N., L.S. Chang, S. Koch, A. Glinka, C. Dolde, G. Colozza, M.D.J. Benitez, E.M. De Robertis, and C. Niehrs. 2017. Angiopoietin-like 4 Is a Wnt Signaling Antagonist that Promotes LRP6 Turnover. Dev Cell. 43: 71-82. PMID:29017031
  • Koch, S., S.P. Acebron, J. Herbst, G. Hatiboglu, and C. Niehrs. 2015. Posttranscriptional Wnt signaling governs epididymal sperm maturation. Cell. 163:1225-1236. PMID:26590424
  • Huang, Y.L., Z. Anvarian, G. Doderlein, S.P. Acebron, and C. Niehrs. 2015. Maternal Wnt/STOP signaling promotes cell division during early Xenopus embryogenesis. Proceedings of the National Academy of Sciences of the United States of America. 112:5732-5737. PMID:25901317
  • Acebron, S.P., E. Karaulanov, B.S. Berger, Y.L. Huang, and C. Niehrs. 2014. Mitotic wnt signaling promotes protein stabilization and regulates cell size. Mol Cell. 54:663-674. PMID:24837680
  • Cruciat, C.M., C. Dolde, R.E. de Groot, B. Ohkawara, C. Reinhard, H.C. Korswagen, and C. Niehrs. 2013. RNA helicase DDX3 is a regulatory subunit of casein kinase 1 in Wnt-beta-catenin signaling. Science. 339:1436-1441. PMID:23413191
  • Davidson, G., J. Shen, Y.L. Huang, Y. Su, E. Karaulanov, K. Bartscherer, C. Hassler, P. Stannek, M. Boutros, and C. Niehrs. 2009. Cell cycle control of wnt receptor activation. Dev Cell. 17:788-799. PMID:20059949.
  • Bilic, J., Y.L. Huang, G. Davidson, T. Zimmermann, C.M. Cruciat, M. Bienz, and C. Niehrs. 2007. Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation. Science. 316:1619-1622. PMID:17569865
  • Davidson, G., W. Wu, J. Shen, J. Bilic, U. Fenger, P. Stannek, A. Glinka, and C. Niehrs. 2005. Casein kinase 1 gamma couples Wnt receptor activation to cytoplasmic signal transduction. Nature. 438:867-872. PMID:16341016.