Wnt pathways are crucial for embryonic development and adult tissue homeostasis in all multicellular animals. Our understanding of Wnt signaling networks has grown increasingly complex. Recent studies have revealed many regulatory proteins that function at the proximal membrane level to fine-tune signaling output and enhance signaling specificity. These proteins regulate crucial points in Wnt signaling, including post-translational modification of Wnt proteins, regulation of Wnt receptor degradation, internalization of Wnt receptor complex, and specific ligand-receptor complex formation. Such regulators not only provide us with molecular details of Wnt regulation but also serve as potential targets for therapeutic intervention. In this review we highlight new insights into Wnt regulation at the plasma membrane, especially newly identified feedback regulators.
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