Wnt-ligand-dependent interaction of TAK1 (TGF-beta-activated kinase-1) with the receptor tyrosine kinase Ror2 modulates canonical Wnt-signalling.
Mutations in the receptor tyrosine kinase Ror2 account for Brachydactyly type B and Robinow Syndrome. We have identified two novel factors interacting with the Ror2 intracellular domain. TAK1 (TGF-beta activated kinase 1), a MAP3K, interacts with Ror2 and phosphorylates its intracellular carboxyterminal serine/thronine/proline-rich (STP) domain. This TAK1-dependent phosphorylation of Ror2 ... induces phosphorylation of tyrosine-residues including a MAPK-like TGY-motif. The TAK1-dependent phosphorylation is enhanced by a second cytosolic factor, PRTB, which interacts with Ror2 and with TAK1 as well. The TAK1-dependent Tyr-phosphorylation of Ror2 is not mediated by the Ror2 tyrosine kinase domain and seems predominantly triggered by cytosolic kinases. Wnt-ligand binding differentially controls the Ror2/TAK1 interaction. Wnt1-binding displaces TAK1 from Ror2 while Wnt3a and Wnt5a are unable to do so thus modifying TAK1's capacity to cause phosphorylation of Ror2. Ror2 seems to act as a Wnt co-receptor enhancing Wnt-dependent canonical pathways while Tyr- and Ser/Thr-phosphorylation of Ror2 negatively controls the efficiency of these pathways. We propose that the level of the Wnt-ligand-regulated phosphorylation by cytosolic factors determines whether Ror2 acts as a stimulator or as an inhibitor of canonical Wnt-signalling.
Mesh Terms:
Animals, Cell Line, Enzyme Activation, Humans, Ligands, MAP Kinase Kinase Kinases, Mice, Models, Biological, Phosphorylation, Protein Binding, Protein Structure, Tertiary, Receptor Protein-Tyrosine Kinases, Receptor Tyrosine Kinase-like Orphan Receptors, Sequence Deletion, Signal Transduction, Tyrosine, Wnt Proteins
Animals, Cell Line, Enzyme Activation, Humans, Ligands, MAP Kinase Kinase Kinases, Mice, Models, Biological, Phosphorylation, Protein Binding, Protein Structure, Tertiary, Receptor Protein-Tyrosine Kinases, Receptor Tyrosine Kinase-like Orphan Receptors, Sequence Deletion, Signal Transduction, Tyrosine, Wnt Proteins
Cell. Signal.
Date: Nov. 01, 2008
PubMed ID: 18762249
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