Low-Density Lipoprotein Receptor-Related Protein-5 Binds to Axin and Regulates the Canonical Wnt Signaling Pathway

Mao, Junhao; Wang, Jiyong; Liu, Bo; Pan, Weijun; Farr, Gist H.; Flynn, Christopher; Yuan, Huidong; Takada, Shinji; Kimelman, David; Lin, Li; Wu, Dianqing

doi:10.1016/s1097-2765(01)00224-6

Cited by 760 publications

(744 citation statements)

References 30 publications

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“…Similar to what has been reported for LRP5/6, (7,46) we found that LRP8 interacted with endogenous Axin when cells were challenged with Wnt3a (Fig. 3C).…”

Section: Discussionsupporting

confidence: 89%

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LRP8 mediates Wnt/β-catenin signaling and controls osteoblast differentiation

Zhang

et al. 2012

Journal of Bone and Mineral Research

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The Wnt/b-catenin signaling pathway plays a pivotal role in regulating osteoblast differentiation and bone formation. Here, we identify low-density lipoprotein (LDL) receptor-related protein 8 (LRP8) as a positive regulator of Wnt/b-catenin signaling. In a small interfering RNA (siRNA) screen, LRP8 was shown to be required for Wnt/b-catenin-induced transcriptional reporter activity. We found that ectopic expression of LRP8 increased Wnt-induced transcriptional responses, and promoted Wnt-induced b-catenin accumulation. Moreover, knockdown of LRP8 resulted in a decrease in b-catenin levels and suppression of Wnt/b-catenin-induced Axin2 transcription. Functional studies in KS483 osteoprogenitor cells showed that LRP8 depletion resulted in impaired activation of endogenous Wnt-induced genes and decreased osteoblast differentiation and mineralization, whereas LRP8 ectopic expression had the opposite effect. These results identify LRP8 as a novel positive factor of canonical Wnt signaling pathway and show its involvement in Wnt-induced osteoblast differentiation. ß

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“…Similar to what has been reported for LRP5/6, (7,46) we found that LRP8 interacted with endogenous Axin when cells were challenged with Wnt3a (Fig. 3C).…”

Section: Discussionsupporting

confidence: 89%

“…Previously, LRP5 was also found to interact with Axin via its intracellular domain. (46) To map the region in LRP8 involved in Axin binding, LRP8-with and without its intracellular domain-was analyzed for its ability to coprecipitate with Axin1 and Axin2. As shown in Fig.…”

Section: Lrp8 Positively Regulates Wnt/b-catenin Signalingmentioning

confidence: 99%

LRP8 mediates Wnt/β-catenin signaling and controls osteoblast differentiation

Zhang

et al. 2012

Journal of Bone and Mineral Research

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“…The co-receptor, LRP, may also contact a cytoplasmic component of the pathway, as it has been reported that Axin can interact with the cytoplasmic tail of LRP [6,9]. This suggests that Wnt signaling can lead to the formation of a complex including the two receptors, plus Axin and Dsh.…”

Section: How Do the Wnt Receptors Signal?mentioning

confidence: 97%

Wnt signaling in disease and in development

2005

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ABSCTACTThe highly conserved Wnt secreted proteins are critical mediators of cell-to-cell signaling during development of animals. Recent biochemical and genetic analyses have led to significant insight into understanding how Wnt signals work. The catalogue of Wnt signaling components has exploded. We now realize that multiple extracellular, cytoplasmic, and nuclear components modulate Wnt signaling. Moreover, receptor-ligand specificity and multiple feedback loops determine Wnt signaling outputs. It is also clear that Wnt signals are required for adult tissue maintenance. Perturbations in Wnt signaling cause human degenerative diseases as well as cancer.

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“…Why the recruitment of Axin to the membrane should alter the activity of the destruction complex is far from clear. Moreover, at least in certain overexpression assays, LRP5/6 can activate the canonical Wnt pathway independently of Frizzled and Dishevelled (Mao et al, 2001;Cong et al, 2004a, b). While normal Wnt signaling requires Frizzled, LRP6 and Dishevelled (Mao et al, 2001;Schweizer and Varmus, 2003;Cong et al, 2004b), the overexpression assays show that LRP5/6 can function without Frizzled or Dishevelled.…”

Section: How Does Dishevelled Affect the Destruction Complex?mentioning

confidence: 99%

β-Catenin destruction complex: insights and questions from a structural perspective

2006

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At the heart of the canonical Wnt signaling pathway is the b-catenin destruction complex, which functions in the absence of Wnt signaling to keep the cytosolic and nuclear levels of b-catenin very low by promoting the phosphorylation and ubiquitination of b-catenin. Structural studies, combined with other experimental approaches, have begun to provide important insights into the mechanism of the destruction complex. We suggest a working model for the destruction complex based on the existing structural and experimental data, and focus on the questions that this model and other studies have raised about the function of the complex in both the normal and Wnt-inhibited states.

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Low-Density Lipoprotein Receptor-Related Protein-5 Binds to Axin and Regulates the Canonical Wnt Signaling Pathway

Cited by 760 publications

References 30 publications

LRP8 mediates Wnt/β-catenin signaling and controls osteoblast differentiation

LRP8 mediates Wnt/β-catenin signaling and controls osteoblast differentiation

Wnt signaling in disease and in development

β-Catenin destruction complex: insights and questions from a structural perspective

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