The Role of the Popeye Domain Containing Gene Family in Organ Homeostasis

Abstract

The Popeye domain containing (POPDC) gene family consists of POPDC1 (also known as BVES), POPDC2 and POPDC3 and encodes 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 20 years, only recently major advances in defining their biological functions and disease association have been made. Loss-of-function experiments in mice 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, a 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.

An interaction of heart disease-associated proteins POPDC1/2 with XIRP1 in transverse tubules and intercalated discs

“…In addition to the essential roles that POPDC proteins play in the maintenance of structure and function of skeletal muscles and in cardiac pacemaking and conduction, POPDC1 may play a role in tumor formation [ 19 ]. POPDC1 is thought to have a tumor suppressor function and decreased POPDC1 expression due to DNA methylation occurs in the early stages of a number of cancers [reviewed: [ 20 , 21 ]].…”

The role of Popeye domain‐containing protein 1 (POPDC1) in the progression of the malignant phenotype

“…The POPDC protein family is one of the five downstream targets of cAMP, the other four being PKA, exchange protein directly activated by cAMP (Epac), hyperpolarisation-activated cyclic nucleotide-gated channel (HCN), and cyclic nucleotide receptor involved in sperm function (CRIS) (Schindler & Brand, 2016 Amunjela et al, 2019;Jayagopal et al, 2011;Russ et al, 2010Russ et al, , 2011 Occludin Unknown sequence on CTD HCE, uveal melanoma Maintenance of tight junction formation Amunjela et al, 2019;Jayagopal et al, 2011;Russ et al, 2010Russ et al, , 2011 Parang et al, 2017 Note: The POPDC1 protein interacts with many downstream including TREK1, CAV-3, VAMP3, GEFT, GEFH, ZO-1, occludin, Bnip3, LRP6, and PR61α. This interaction has mainly been shown in cardiac and skeletal muscle cells; however, an increasing body of evidence is emerging that demonstrates POPDC1 interaction with these targets in cancer cells.…”

“…binds to the PBC of the POPEYE domain (discussed above) and leads to increased protein expression, stabilisation, and activation (Amunjela et al, 2019). In cancer cells, increased cellular levels of cAMP correlate with increased apoptosis and reduced proliferation, invasion, and metastasis.…”

Special Issue on “New Advances in Cyclic AMP Signalling”—An Editorial Overview

“…POPDCs are recently discovered membrane bound cyclic AMP receptors that interact with the two-pore domain potassium channel, TREK-1 [ 32 ], and Caveolin-3 [ 33 ], in order to regulate pacemaker activity. Indeed, a comprehensive review in this Special Edition by the Brand laboratory describes a central role for the POPDC family in organ homeostasis and describes their role in different cellular pathways that are involved in membrane trafficking, cardiac arrhythmia, muscular dystrophy, cell proliferation, migration and invasion [ 34 ]. Indeed, deletion of POPDCs produces pronounced cardiac arrhythmia, suggesting that they have a vital role in cardiac function consistent with their targeted expression within cardiomyocytes [ 29 ].…”