Several somatic mutations in -catenin have been associated with colorectal, liver, and hair follicle cancer. These mutations often occur at sites subject to phosphorylation by CK1a and GSK3 . Mutations are also found in armadillo repeats (see Figure 14.7): mutations in the 3rd and 4th repeat affect binding to APC or axin, mutations in the 12th

enhance transcriptional activity. All these are so-called activation mutations because they enhance the output of-catenin, either through an increase in protein content or by an increase in its transcriptional activity.

box or they prevent its binding to the axin/APC complex.

They are therefore considered as ‘activating’ mutations (even though they do not actually activate the protein). In some patients having familial gastric cancer, the gene for E-cadherin expresses a truncated product103 which

is unable to participate in junctional complexes. As a result, the adherent junctions are improperly formed so that over time, the cells detach and become invasive.

Non-canonical signal transduction pathways

A number of developmental processes require Wnt (in particular, Wnts 5a, 7a, or 11), Fz, and Dsh, but not -catenin. They are responsible for cell polarization, e.g. during gastrulation of X. laevis embryos, cell movement

during ovarian morphogenesis, and planar cell polarity during gastrulation of zebrafish. These processes involve the Rho-related GTPases, Rho, Rac, and Cdc42 and their effectors, amongst which, mDia, Rho kinase (ROCK), and the MAP kinase JNK (reviewed in Veeman et al.29 and Strutt;104 see Figure 14.15). A non-canonical Wnt pathway also operates in muscle development in chick and mouse embryos. This requires Wnt1, generated by the neural tube, and Wnt7A, generated by the surface ectoderm tissue. Wnt serves to differentiate mesoderm into muscle cells. Initiation of this process requires the Fz receptor, but in this case it is coupled to a heterotrimeric GTP-binding protein that activates adenylyl cyclase. A classical PKA to CREB signal

transduction pathway ensues (see page 248) that leads to the induction of the differentiation markers such as Pax3, MyoD and Lyf5.105

A role for cadherin in contact inhibition

Contact inhibition is the term used to describe the abrupt arrest of the cell cycle that occurs in cultures of rapidly proliferating epithelial cells at the point when a confluent monolayer forms. The phenomenon has been recognized for many years, but even now a full description remains elusive. It was clear from the start that the arrest is not due to the accumulation

of inhibitory factors, but is mediated by an adhesion molecule.106 Cadherin plays an important role. As the density of the cells increases and multiple contacts are established, the forming adherent junctions sequester the free -catenin and in this way reduce the proliferation promoting action of TCF/ -catenin.107

Regulation may also occur directly at the receptor level. Clustering of VE-cadherin at intercellular junctions blocks the proliferative response of endothelial cells to VEGF. This is reflected in the inhibition of tyrosine

phosphorylation of the VEGF-R2.108 Dephosphorylation of the VEGF receptor is by the receptor tyrosine phosphatase DEP1/CD148109 which binds the cadherin associated protein p120-catenin (p120ctn).110