Frizzled Receptors

Wnt constitutes a family of genes encoding ligands essential for signaling in early development.93 These secreted glycoproteins, which resemble other secreted glycoprotein ligands such as gonadotropins, act via members of the Frizzled gene family. The Wnt signaling transduction pathway is essentially a network of a number of separate but interacting pathways. Aberrant activation and upregulation of the Wnt pathway is a key feature of many cancers. Despite extensive investigation of the role of Wnt genes in human cancer,94 no documentation has been made to date of any mutations or amplifications of genes encoding Wnt ligands or receptors. In contrast, several components of the Wnt pathway have been implicated in carcinogenesis, especially APC and p-catenin.

Mutations that lead to the stabilization of p-catenin have been documented in melanoma cell lines and may be implicated in tumor progression.95 Aberrant Wnt pathway signaling occurs through mutations mainly of APC and, although less often, of the genes encoding p-catenin or axin-2 (also known as conductin).96 The nuclear/cytoplasmic localization of p-catenin, rather than at the plasma membrane, is an indicator of possible involvement of the activation of Wnt/Frizzled pathways in melanoma tumors.97 For example, aberrant Wnt pathway signaling is thought to be an early progression event in 90% of colorectal cancers.96

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