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Negative regulation of Wnt signaling mediated by CK1‐phosphorylated Dishevelled via Ror2
Author(s) -
Witte Florian,
Bernatik Ondrej,
Kirchner Katharina,
Masek Jan,
Mahl Annika,
Krejci Pavel,
Mundlos Stefan,
Schambony Alexandra,
Bryja Vitezslav,
Stricker Sigmar
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.09-150615
Subject(s) - dishevelled , wnt signaling pathway , casein kinase 1 , phosphorylation , microbiology and biotechnology , lrp5 , wnt3a , beta catenin , frizzled , lrp6 , chemistry , tyrosine phosphorylation , signal transduction , biology , protein kinase a
Dishevelled (Dvl) is a multifunctional effector of different Wnt cascades. Both canonical Wnt3a and noncanonical Wnt5a stimulate casein‐kinase‐1 (CK1) ‐mediated phosphorylation of Dvl, visualized as electrophoretic mobility shift [phosphorylated and shifted Dvl (ps‐Dvl)]. However, the role of this phosphorylation remains obscure. Here we report the functional interaction of ps‐Dvl with the receptor tyrosine kinase Ror2, which is an alternative Wnt receptor and is able to inhibit canonical Wnt signaling. We demonstrate interaction between Ror2 and ps‐Dvl at the cell membrane after Wnt3a or Wnt5a stimulus dependent on CK1. Ps‐Dvl interacts with the C‐terminal proline‐serine‐threonine‐rich domain of Ror2, which is required for efficient inhibition of canonical Wnt signaling. We further show that the Dvl C terminus, which seems to be exposed in ps‐Dvl and efficiently binds Ror2, is an intrinsic negative regulator of the canonical Wnt pathway downstream of ß‐catenin. The Dvl C terminus is necessary and sufficient to inhibit canonical Wnt/ß‐catenin signaling, which is dependent on the presence of Ror2. Furthermore, both the Dvl C terminus and CK 1 E can inhibit the Wnt5a/Ror2/ATF2 pathway in mammalian cells and Xenopus explant cultures. This suggests that phosphorylation of Dvl triggers negative feedback regulation for different branches of Wnt signaling in a Ror2‐dependent manner.—Witte, F., Bernatik, O., Kirchner, K., Masek, J., Mahl, A., Krejci, P., Mundlos, S., Schambony, A, Bryja, V., Stricker, S. Negative regulation of Wnt signaling mediated by CK1‐phosphorylated Dishevelled via Ror2. FASEB J. 24, 2417–2426 (2010). www.fasebj.org