Disabled‐2 (Dab2) inhibits Wnt/β‐catenin signalling by binding LRP6 and promoting its internalization through clathrin
- Authors
- Jiang, Y., He, X., and Howe, P.H.
- ID
- ZDB-PUB-120412-7
- Date
- 2012
- Source
- The EMBO journal 31(10): 2336-2349 (Journal)
- Registered Authors
- Howe, Philip H.
- Keywords
- CK2 kinase, disabled-2, LRP6, tumourigenesis, Wnt signalling
- MeSH Terms
-
- Adaptor Proteins, Vesicular Transport/metabolism*
- Animals
- Clathrin/metabolism*
- Low Density Lipoprotein Receptor-Related Protein-6/metabolism*
- Mice
- Wnt Proteins/antagonists & inhibitors*
- Wnt Signaling Pathway*
- Zebrafish
- beta Catenin/antagonists & inhibitors*
- PubMed
- 22491013 Full text @ EMBO J.
Canonical Wnt signalling requires caveolin-dependent internalization of low-density lipoprotein receptor-related protein 6 (LRP6). Here we report that the tumour suppressor and endocytic adaptor disabled-2 (Dab2), previously described as an inhibitor of Wnt/β-catenin signalling, selectively recruits LRP6 to the clathrin-dependent endocytic route, thereby sequestering it from caveolin-mediated endocytosis. Wnt stimulation induces the casein kinase 2 (CK2)-dependent phosphorylation of LRP6 at S1579, promoting its binding to Dab2 and internalization with clathrin. LRP6 receptor mutant (S1579A), deficient in CK2-mediated phosphorylation and Dab2 binding, fails to associate with clathrin, and thus escapes the inhibitory effects of Dab2 on Wnt/β-catenin signalling. Our data suggest that the S1579 site of LRP6 is a negative regulatory point during LRP6-mediated dorsoventral patterning in zebrafish and in allograft mouse tumour models. We conclude that the tumour suppressor functions of Dab2 involve modulation of canonical Wnt signalling by regulating the endocytic fate of the LRP6 receptor.