Dataset Information

Upregulation of the Wnt co-receptor LRP6 promotes hepatocarcinogenesis and enhances cell invasion.

ABSTRACT:

Background

Activation of the Wnt/?-catenin signaling pathway plays a crucial role in hepatocellular carcinoma (HCC). Low-density lipoprotein (LDL) receptor-related protein-6 (LRP6) is one of the co-receptors of the Wnt/?-catenin pathway and forms a signaling complex with Wnt ligand and Frizzled receptor to activate downstream signaling. However, the role of LRP6 in hepatocarcinogenesis is unclear. In this study, we examined its expression and roles in human HCC.

Methodology/principal findings

Using real-time quantitative RT-PCR, we found that LRP6 was frequently (45%) overexpressed in human HCCs (P = 0.003). In vitro studies showed that ectopic expression of LRP6 increased the protein level of ?-catenin. Moreover, overexpression of the full-length and constitutively active LRP6, respectively, activated the WNT/?-catenin signaling pathway, as shown by the TCF/?-catenin reporter assay. With regard to the effects of LRP6 overexpression in HCC cells, stable overexpression of the constitutively active LRP6 in BEL-7402 HCC cells enhanced cell proliferation, cell migration, and invasion in vitro as well as tumorigenicity in nude mice.

Conclusions/significance

Our findings indicate that overexpression of LRP6 contributes to the hyperactivation of the Wnt/?-catenin signaling pathway in human HCCs and suggest it may play a role in hepatocarcinogenesis.

SUBMITTER: Tung EK

PROVIDER: S-EPMC3343020 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

Upregulation of the Wnt co-receptor LRP6 promotes hepatocarcinogenesis and enhances cell invasion.

Tung Edmund Kwok-Kwan EK Wong Betty Yin-Chi BY Yau Tai-On TO Ng Irene Oi-Lin IO

PloS one 20120503 5

<h4>Background</h4>Activation of the Wnt/β-catenin signaling pathway plays a crucial role in hepatocellular carcinoma (HCC). Low-density lipoprotein (LDL) receptor-related protein-6 (LRP6) is one of the co-receptors of the Wnt/β-catenin pathway and forms a signaling complex with Wnt ligand and Frizzled receptor to activate downstream signaling. However, the role of LRP6 in hepatocarcinogenesis is unclear. In this study, we examined its expression and roles in human HCC.<h4>Methodology/principal ...[more]

PMID: 22570728

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Project description:Low density lipoprotein receptor-related protein 6 (LRP6) and its homologue LRP5 serve as Wnt co-receptors that are essential for the Wnt/beta-catenin pathway. Wnt activation of LRP6 leads to recruitment of the scaffolding protein Axin and inhibition of Axin-mediated phosphorylation/destruction of beta-catenin. We showed that five conserved PPPSP motifs in the LRP6 intracellular domain are required for LRP6 function, and mutation of these motifs together abolishes LRP6 signaling activity. We further showed that Wnt induces the phosphorylation of a prototypic PPPSP motif, which provides a docking site for Axin and is sufficient to transfer signaling activity to a heterologous receptor. However, the activity, regulation, and functionality of multiple PPPSP motifs in LRP6 have not been characterized. Here we provide a comprehensive analysis of all five PPPSP motifs in LRP6. We define the core amino acid residues of a prototypic PPPSP motif via alanine scanning mutagenesis and demonstrate that each of the five PPPSP motifs exhibits signaling and Axin binding activity in isolation. We generated two novel phosphorylation-specific antibodies to additional PPPSP motifs and show that Wnt induces phosphorylation of these motifs in the endogenous LRP6 through glycogen synthase kinase 3. Finally, we uncover the critical cooperativity of PPPSP motifs in the full-length LRP6 by demonstrating that LRP6 mutants lacking a single PPPSP motif display compromised function, whereas LRP6 mutants lacking two of the five PPPSP motifs are mostly inactive. This cooperativity appears to reflect the ability of PPPSP motifs to promote the phosphorylation of one another and to interact with Axin synergistically. These results establish the critical role and a common phosphorylation/activation mechanism for the PPPSP motifs in LRP6 and suggest that the conserved multiplicity and cooperativity of the PPPSP motifs represents a built-in amplifier for Wnt signaling by the LRP6 family of receptors.

Dataset Information

Upregulation of the Wnt co-receptor LRP6 promotes hepatocarcinogenesis and enhances cell invasion.

Background

Methodology/principal findings

Conclusions/significance

Publications

Upregulation of the Wnt co-receptor LRP6 promotes hepatocarcinogenesis and enhances cell invasion.

Similar Datasets

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