Wnt proteins

Abstract

Wnt proteins comprise a major family of signaling molecules that orchestrate and influence a myriad of cell biological and developmental processes. Although our understanding of the role of Wnt signaling in regulating development and affecting disease, such as cancer, has been ever increasing, the study of the Wnt proteins themselves has been painstaking and slow moving. Despite advances in the biochemical characterization of Wnt proteins, many mysteries remain unsolved. In contrast to other developmental signaling molecules, such as fibroblast growth factors (FGF), transforming growth factors (TGFβ), and Sonic hedgehog (Shh), Wnt proteins have not conformed to many standard methods of protein production, such as bacterial overexpression, and analysis, such as ligand-receptor binding assays. The reasons for their recalcitrant nature are likely a consequence of the complex set of posttranslational modifications involving several highly specialized and poorly characterized processing enzymes. With the recent description of the first Wnt protein structure, the time is ripe to uncover and possibly resolve many of the remaining issues surrounding Wnt proteins and their interactions. Here we describe the process of maturation of Wnt from its initial translation to its eventual release from a cell and interactions in the extracellular environment.

Figure 1.

Structure of Wnt. (A) Space-filling model of XWnt8. The Frizzled CRD structure has been removed. (Yellow clusters) The N-linked glycosylations in XWnt8. (B) Secondary structure for Wnt. (Orange) The conserved 22 cysteine residues are numbered to indicate the pairs that form disulfide bridges. N-linked glycosylations are not shown because the numbers and positions of N-linked glycosylations are highly variable among Wnts. (Dashed line) The approximate position of the linker region where Wg carries an insert of about 80 amino acids. (Figures were generated with the kind assistance of C. Janda and C. Garcia, Stanford University.)

Figure 2.

Wnt secretion. Upon translation, Wnt proteins (yellow ovals) undergo a series of modifications as they transit through the secretory pathway and associate with several proteins, including Porcn in the endoplasmic reticulum and Wls in the Golgi apparatus. Efficient secretion of Wnt also requires the recycling of Wls via the retromer complex.