Editors' ChoiceReceptors

Complexity at the Receptor Complex

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Science Signaling  19 Jan 2010:
Vol. 3, Issue 105, pp. ec20
DOI: 10.1126/scisignal.3105ec20

The Wnt ligands of the wingless signaling pathway regulate diverse biological processes from development to cancer. Mammals have 19 such ligands, and there are 10 members of the Frizzled (Fz) family of Wnt receptors. Furthermore, the Wnt proteins can interact with associated signaling proteins, including the low-density lipoprotein receptor–related protein 5 (LRP5) and LRP6, and receptor tyrosine kinase–like orphan receptor 1 (Ror1) and Ror2, so there are many ways that distinct signals can be generated. In fact, Sato et al. show that a single Wnt ligand (Wnt5a) can differentially regulate signaling from the Fz2 receptor protein. Binding of Wnts to Fz proteins can initiate (i) a pathway that depends on stabilization of β-catenin protein and consequent changes in gene expression or (ii) a β-catenin–independent pathway that results in activation of the small guanosine triphosphatase Rac. Sato et al. explored the differential effects of Wnt3a, which activates the β-catenin pathway, and Wnt5a, which activates a β-catenin–independent pathway and also inhibits the β-catenin pathway. They used protein depletion by siRNA to show that in HeLaS3 cells (a cell line derived from a human epithelial carcinoma) the receptor protein Fz2 acted with LRP6 to cause stabilization of β-catenin in response to Wnt3a, and with Ror1 and with Ror2 to cause β-catenin–independent activation of Rac in response to Wnt5a. The activation of Rac by Wnt5a appeared to require clathrin-dependent internalization of the receptor. However, the inhibitory effect of Wnt5a was not affected by treatments that affected clathrin-dependent internalization of the receptor. Rather, various experiments indicated that Wnt5a acted at the receptor to compete with Wnt3a for binding to Fz2 and that receptor internalized in response to Wnt3 was associated mainly with caveolin rather than clathrin. Thus, the authors propose that the abundance of Wnt5a can have multiple effects on Fz signaling by influencing ligand binding and receptor internalization, and thus its coupling to distinct signaling pathways.

A. Sato, H. Yamamoto, H. Sakane, H. Koyama, A. Kikuchi, Wnt5a regulates distinct signalling pathways by binding to Frizzled 2. EMBO J. 29, 41–54 (2010). [Online Journal]

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