The LRP5 high-bone-mass G171V mutation disrupts LRP5 interaction with mesd
The LRP5 high-bone-mass G171V mutation disrupts LRP5 interaction with mesd
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DOI：
10.1128/mcb.24.11.4677-4684.2004
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发表时间：
2004-06-01
影响因子：
5.3
通讯作者：
Wu, DQ
中科院分区：
文献类型：
--
作者：
Zhang, YH;Wang, Y;Wu, DQ
研究了Wnt共受体LRP5的高骨量（HBM）突变（G171V）调控典型Wnt信号的机制。该突变先前被证明可以降低dkk1介导的拮抗作用，这表明G171所在的第一个YWTD重复结构域可能与dkk介导的拮抗作用有关。然而，我们发现dkk1介导的拮抗需要第三个YWTD重复结构域，而不是第一个重复结构域。相反，我们发现G171V突变破坏了LRP5与Mesd的相互作用，导致细胞表面的LRP5分子减少。Mesd是LRP5/6的伴侣蛋白，是将辅助受体运输到细胞表面所必需的。虽然细胞表面LRP5分子数量的减少导致旁分泌模式下Wnt信号的减少，但突变似乎不会影响自分泌模式下共表达Wnt的活性。结合观察到成骨细胞产生自分泌典型Wnt， Wnt7b，以及骨细胞产生旁分泌DKK1，我们认为G171V突变可能通过减少旁分泌DKK1拮抗的靶标数量而不影响自分泌Wnt的活性，从而导致成骨细胞中Wnt活性的增加。
dThe mechanism by which the high-bone-mass (HBM) mutation (G171V) of the Wnt coreceptor LRP5 regulates canonical Wnt signaling was investigated. The mutation was previously shown to reduce DKK1-mediated antagonism, suggesting that the first YWTD repeat domain where G171 is located may be responsible for DKK-mediated antagonism. However, we found that the third YWTD repeat, but not the first repeat domain, is required for DKK1-mediated antagonism. Instead, we found that the G171V mutation disrupted the interaction of LRP5 with Mesd, a chaperone protein for LRP5/6 that is required for transport of the coreceptors to cell surfaces, resulting in fewer LRP5 molecules on the cell surface. Although the reduction in the number of cell surface LRP5 molecules led to a reduction in Wnt signaling in a paracrine paradigm, the mutation did not appear to affect the activity of coexpressed Wnt in an autocrine paradigm. Together with the observation that osteoblast cells produce autocrine canonical Wnt, Wnt7b, and that osteocytes produce paracrine DKK1, we think that the G171V mutation may cause an increase in Wnt activity in osteoblasts by reducing the number of targets for paracrine DKK1 to antagonize without affecting the activity of autocrine Wnt.