The LRP5 high-bone-mass G171V mutation disrupts LRP5 interaction with Mesd

Yazhou Zhang, Yang Wang, Xiaofeng Li, Jianhong Zhang, Junhao Mao, Zhong Li, Jie Zheng, Lin Li, Stephen E Harris, Dianqing Wu

Research output: Contribution to journalArticle

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Abstract

The 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.

Original languageEnglish (US)
Pages (from-to)4677-4684
Number of pages8
JournalMolecular and Cellular Biology
Volume24
Issue number11
DOIs
StatePublished - Jun 2004
Externally publishedYes

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Bone and Bones
Mutation
Osteoblasts
Osteocytes
Cell Count
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

The LRP5 high-bone-mass G171V mutation disrupts LRP5 interaction with Mesd. / Zhang, Yazhou; Wang, Yang; Li, Xiaofeng; Zhang, Jianhong; Mao, Junhao; Li, Zhong; Zheng, Jie; Li, Lin; Harris, Stephen E; Wu, Dianqing.

In: Molecular and Cellular Biology, Vol. 24, No. 11, 06.2004, p. 4677-4684.

Research output: Contribution to journalArticle

Zhang, Y, Wang, Y, Li, X, Zhang, J, Mao, J, Li, Z, Zheng, J, Li, L, Harris, SE & Wu, D 2004, 'The LRP5 high-bone-mass G171V mutation disrupts LRP5 interaction with Mesd', Molecular and Cellular Biology, vol. 24, no. 11, pp. 4677-4684. https://doi.org/10.1128/MCB.24.11.4677-4684.2004
Zhang, Yazhou ; Wang, Yang ; Li, Xiaofeng ; Zhang, Jianhong ; Mao, Junhao ; Li, Zhong ; Zheng, Jie ; Li, Lin ; Harris, Stephen E ; Wu, Dianqing. / The LRP5 high-bone-mass G171V mutation disrupts LRP5 interaction with Mesd. In: Molecular and Cellular Biology. 2004 ; Vol. 24, No. 11. pp. 4677-4684.
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