A role of plakophilins in the regulation of translation.

Plakophilins 1-3 are members of the p120(ctn)-family of armadillo related proteins. They have been characterized as desmosomal plaque proteins, stabilizing desmosomal cadherins at the plasma membrane and interacting with the cytoskeletal linker protein desmoplakin. Loss of cell adhesion contributes to cancerogenesis. In agreement with this, some tumors were found to lack plakophilin expression. Surprisingly, in other tumors, plakophilins 1 and 3 are overexpressed. We have recently identified a function of plakophilins 1 and 3 in the regulation of protein synthesis. Plakophilin 1 was characterized as a component of the cap-binding translation initiation complex where it associates directly with the initiation factor eIF4A1. Plakophilin 1 not only stimulated the recruitment of eIF4A1 into the cap complex but also its helicase activity. This pointed to a role of plakophilin 1 in the stimulation of proliferation. Given the importance of mRNA translation and protein synthesis in the development of cancer, we speculate that overexpressed plakophilin 1 could contribute to tumor formation. Thus, plakophilin's function in cancerogenesis could go both ways: while an increase of plakophilin could support cancerogenesis via the stimulation of translation and proliferation, loss of plakophilin could contribute to cancerogenesis and/or metastasis via loss of contact inhibition and increased motility. Elucidating the regulation of plakophilin's function in adhesion versus translation will help to understand this context-dependent phenomenon.