Wnt-ligand-dependent interaction of TAK1 (TGF-beta-activated kinase-1) with the receptor tyrosine kinase Ror2 modulates canonical Wnt-signalling.

Abstract

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.

• Authors: Andreas Winkel, Sigmar Stricker, Przemko Tylzanowski, Virginia Seiffart, Stefan Mundlos, Gerhard Gross, Andrea Hoffmann
• Journal: Cellular signalling (Cell Signal) Vol. 20 Issue 11 Pg. 2134-44 (Nov 2008) ISSN: 0898-6568 [Print] England
• PMID: 18762249 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ligands
• Wnt Proteins
• Tyrosine
• Receptor Protein-Tyrosine Kinases
• Receptor Tyrosine Kinase-like Orphan Receptors
• Ror2 protein, mouse
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7

Topics

• Animals
• Cell Line
• Enzyme Activation
• Humans
• Ligands
• MAP Kinase Kinase Kinases (chemistry, metabolism)
• Mice
• Models, Biological
• Phosphorylation
• Protein Binding
• Protein Structure, Tertiary
• Receptor Protein-Tyrosine Kinases (chemistry, metabolism)
• Receptor Tyrosine Kinase-like Orphan Receptors
• Sequence Deletion
• Signal Transduction
• Tyrosine (metabolism)
• Wnt Proteins (metabolism)