Glypicans, 35 years later

Abstract Glypicans are a family of proteoglycans that are bound to the cell surface by a glycosylphosphatidylinositol anchor. These proteoglycans are highly conserved during evolution, and the mammalian genome contains six members of the family. Glypicans carry two to four heparan sulfate chains that are inserted near the carboxy terminus. The crystal structure reveals a densely packed cylindrical shape that is parallel to the cell surface. The functions of glypicans are mediated by the heparan sulfate chains and/or the core protein. One of the main functions of these proteoglycans is the regulation of the signaling pathways triggered by hedgehogs, Wnts, fibroblast growth factors, and bone morphogenetic proteins. Glypicans can either stimulate or inhibit the interaction of these growth factors with their signaling receptors. Studies in Drosophila have also shown that glypicans can regulate hedgehog, Wnt, and bone morphogenetic factor gradient formation. In addition, glypicans play important roles in the establishment of synapses and in neuron guidance and migration. Glypican mutations cause several developmental syndromes, and overexpression of these proteins contribute to the progression of various cancer types. In particular, glypican‐3 is currently being used as a marker for the diagnosis of hepatocellular carcinomas, and it is being targeted by several immunotherapeutic approaches for the treatment of this malignancy.