Regulation of Wnt Receptor Activation by the Tumor Suppressor APC

Abstract

The Wnt pathway is a highly-conserved pathway that controls many developmental processes and is mutated in many human diseases (e.g., cancer). The tumor suppressor adenomatous polyposis coli (APC) is a critical negative regulator of Wnt signal transduction. Mutations in the APC gene resulting in constitutive activation of the Wnt pathway occur in over 80% of human colorectal cancers (CRC). Despite its critical role in the Wnt pathway, the exact mechanism of APC function in Wnt signal transduction is not clear. The lab developed a monoclonal antibody (mAb7E5) that targets the co-receptor LRP6 and inhibits Wnt signaling in APC-mutant CRC cells. Using the antibody mAb7E5, I found that APC regulates Wnt receptor activation. Furthermore, I found that, in APC-depleted cells, the co-receptor LRP6 is constitutively active in a manner independent of Wnt ligands and that LRP6 is internalized by the clathrin-dependent endocytic machinery. Finally, I demonstrate that APC, clathrin, and the AP-2 adaptor protein interact as a complex. Thus, my studies reveal a new role for APC function in Wnt signal transduction and provide insight into the development of therapeutic agents targeting APC-mutant tumors.