The Popeye domain containing (POPDC) gene family consists of POPDC1 (also known as BVES), POPDC2 and POPDC3 and encode a novel class of cyclic adenosine monophosphate (cAMP) effector proteins. Despite first reports of their isolation and initial characterization at the protein level dating back already 20 years, only recently have major advances in defining their biological functions and disease association been made. Loss-of-function experiments in mouse and zebrafish established an important role in skeletal muscle regeneration, heart rhythm control and stress signaling. Patients suffering from muscular dystrophy and atrioventricular block were found to carry missense and nonsense mutations in either of the three POPDC genes, which suggests an important function in the control of striated muscle homeostasis. However, POPDC genes are also expressed in a number of epithelial cells and function as tumor suppressor genes involved in the control of epithelial structure, tight junction formation and signaling. Suppression of POPDC genes enhances tumor cell proliferation, migration, invasion and metastasis in a variety of human cancers, thus promoting a malignant phenotype. Moreover, downregulation of POPDC1 and POPDC3 expression in different cancer types has been associated with poor prognosis. However, high POPDC3 expression has also been correlated to poor clinical prognosis in head and neck squamous
cell carcinoma, suggesting that POPDC3 potentially plays different roles in the progression of different types of cancer. Interestingly, gain of POPDC1 function in tumor cells inhibits cell proliferation, migration and invasion thereby reducing malignancy. Furthermore, POPDC proteins have been implicated in the control of cell cycle genes and epidermal growth factor and Wnt signaling. Work in tumor cell lines suggest that cyclic nucleotide binding may also be important in epithelial cells. Thus, POPDC proteins have a prominent role in tissue homeostasis and cellular signaling in both epithelia and striated muscle.