The Questions of Developmental Biology

The Wnt pathway
Members of the Wnt family of paracrine factors interact with transmembrane receptors of
the Frizzled family. In most instances, the binding of Wnt by the Frizzled protein causes the
Frizzled protein to activate the Disheveled protein. Once the Disheveled protein is activated, it
inhibits the activity of the glycogen synthase kinase-3 enzyme. GSK-3, if it were active, would
prevent the dissociation of the β-catenin protein from the APC protein, which targets β-catenin
for degradation. However, when the Wnt signal is given and GSK-3 is inhibited, β-catenin can
dissociate from the APC protein and enter the nucleus. Once inside the nucleus, it can form a
heterodimer with an LEF or TCF DNA-binding protein, becoming a transcription factor. This
complex binds to and activates the Wnt-responsive genes (Figure 6.23A; Behrens et al. 1996;
Cadigan and Nusse 1997).
This model is undoubtedly an oversimplification, because different cells use this pathway
in different ways (see Cox and Peifer 1998). Moreover, its components can have more than one
function in the cell. In addition to being part of the Wnt signal transduction cascade, GSK-3 is
also a metabolic enzyme regulating glycogen metabolism. The β-catenin protein was first
recognized as being part of the cell adhesion complex on the cell surface before it was also found
to be a transcription factor. The APC protein also functions as a tumor suppressor in adults. The
transformation of normal colon cells into colon cancer is thought to occur when the APC gene is