Wnt-ligand-dependent interaction of TAK1 (TGF-beta-activated kinase-1) with the receptor tyrosine kinase Ror2 modulates canonical Wnt-signalling.
Wnt-ligand-dependent interaction of TAK1 (TGF-beta-activated kinase-1) with the receptor tyrosine kinase Ror2 modulates canonical Wnt-signalling.
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TAK1（TGF-β 激活激酶-1）与受体酪氨酸激酶 Ror2 的 Wnt 配体依赖性相互作用可调节典型的 Wnt 信号传导。
DOI：
10.1016/j.cellsig.2008.08.009
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发表时间：
2008
影响因子：
4.8
通讯作者：
A. Hoffmann
中科院分区：
文献类型：
--
作者：
A. Winkel;S. Stricker;P. Tylzanowski;Virginia Seiffart;S. Mundlos;G. Gross;A. Hoffmann
受体酪氨酸激酶Ror 2的突变导致B型短趾畸形和Robinow综合征。我们已经确定了两个新的因子与Ror 2细胞内结构域相互作用。TAK 1（TGF-β激活激酶1）是一种MAP 3 K，与Ror 2相互作用并磷酸化其细胞内羧基末端丝氨酸/苏氨酸/脯氨酸富集（STP）结构域。这种Ror 2的TAK 1依赖性磷酸化诱导酪氨酸残基的磷酸化，包括MAPK样TGY基序。TAK 1依赖性磷酸化被第二种胞质因子PRTB增强，PRTB与Ror 2和TAK 1相互作用。Ror 2的TAK 1依赖性酪氨酸磷酸化不受Ror 2酪氨酸激酶结构域介导，似乎主要由胞质激酶触发。Wnt-配体结合差异控制Ror 2/TAK 1相互作用。Wnt 1结合从Ror 2置换TAK 1，而Wnt 3a和Wnt 5a不能这样做，从而改变TAK 1引起Ror 2磷酸化的能力。Ror 2似乎作为Wnt共受体增强Wnt依赖的经典途径，而Ror 2的Tyr-和Ser/Thr-磷酸化负控制这些途径的效率。我们建议，由胞质因子调节的Wnt配体磷酸化水平决定了Ror 2是否作为典型Wnt信号传导的刺激剂或抑制剂。
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-β 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.