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Disabled-2 (Dab2) inhibits Wnt/β-catenin signalling by binding LRP6 and promoting its internalization through

Yong Jiang1, Xi He, Philip H Howe

  • 1Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.

The EMBO Journal
|April 12, 2012
PubMed

Insights

Disabled-2 (Dab2) regulates Wnt signalling by controlling LRP6 receptor internalization. Dab2 recruits LRP6 to clathrin-dependent endocytosis, inhibiting Wnt/β-catenin signalling and impacting tumour growth.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Biology

Background:

  • Canonical Wnt signalling is crucial for development and disease.
  • Low-density lipoprotein receptor-related protein 6 (LRP6) is essential for Wnt signalling.
  • Caveolin-mediated endocytosis is a known route for LRP6 internalization.

Purpose of the Study:

  • To investigate the role of disabled-2 (Dab2) in regulating LRP6 endocytosis and Wnt signalling.
  • To elucidate the mechanism by which Dab2 modulates LRP6 receptor trafficking.
  • To determine the impact of Dab2-mediated LRP6 regulation on Wnt signalling and tumour suppressor functions.

Main Methods:

  • Investigated LRP6 recruitment to clathrin-dependent endocytosis mediated by Dab2.
  • Utilized Wnt stimulation and casein kinase 2 (CK2) phosphorylation of LRP6 at S1579.
  • Employed LRP6 receptor mutants (S1579A) to assess the role of phosphorylation and Dab2 binding.
  • Examined LRP6 endocytic fate and Wnt/β-catenin signalling activity.
  • Assessed effects in zebrafish dorsoventral patterning and mouse allograft tumour models.

Main Results:

  • Dab2 selectively recruits LRP6 to clathrin-dependent endocytosis, sequestering it from caveolin-mediated pathways.
  • Wnt stimulation triggers CK2-dependent phosphorylation of LRP6 at S1579, promoting Dab2 binding and clathrin co-internalization.
  • LRP6 S1579A mutants, unable to be phosphorylated or bind Dab2, escape Dab2's inhibitory effects on Wnt/β-catenin signalling.
  • The LRP6 S1579 site acts as a negative regulatory point in zebrafish and mouse tumour models.
  • Dab2's tumour suppressor functions are linked to its modulation of canonical Wnt signalling via LRP6 endocytic regulation.

Conclusions:

  • Dab2 regulates canonical Wnt signalling by controlling the endocytic route of LRP6.
  • Phosphorylation of LRP6 at S1579 by CK2 is a key event for Dab2-mediated inhibition.
  • Dab2's tumour suppressor activity involves fine-tuning Wnt signalling through LRP6 receptor trafficking.

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