Structural Features of Glypicans and Their Impact on Wnt Signaling in Cancer

Glypicans (GPCs) are a family of cell surface proteoglycans involved in multiple signaling pathways that regulate cell fate and proliferation. They share a characteristic structure composed of a core protein with two or more heparan sulfate chains and a glycosyl-phosphatidylinositol anchor that attaches them to the cell membrane. Aberrant expression of certain glypicans such as GPC1, GPC2, and GPC3 has been found in multiple types of cancer and causes the dysregulation of Wnt, hedgehog, and other signaling pathways, making them emerging targets for cancer immunotherapy. The molecular mechanism by which glypicans interact with signaling factors will provide insights for the development of cancer therapeutics. However, the structural complexes of human glypicans with Wnt and other key signaling factors remain unsolved. In this brief review, we analyze the current protein structural evidence for glypicans, with an emphasis on their interaction with Wnt, in an effort to provide insights to understand the molecular mechanisms by which glypicans play positive or negative roles in Wnt signaling in cancer and to discuss their translational potentials.