Abstract
The role of neuroendocrine peptide calcitonin (CT) and its receptor (CTR) in epithelial cancer progression is an emerging concept with great clinical potential. Expression of CT and CTR is frequently elevated in prostate cancers (PCs) and activation of CT–CTR axis in non-invasive PC cells induces an invasive phenotype. Here we show by yeast-two hybrid screens that CTR associates with the tight junction protein Zonula Occludens-1 (ZO-1) via the interaction between the type 1 PDZ motif at the carboxy-terminus of CTR and the PDZ3 domain of ZO-1. Mutation of either the CTR C-PDZ-binding motif or the ZO-1-PDZ3 domain did not affect binding of CTR with its ligand or G-protein-mediated signaling but abrogated destabilizing actions of CT on tight junctions and formation of distant metastases by orthotopically implanted PC cells in nude mice, indicating that these PDZ domain interactions were pathologically relevant. Further, we observed CTR-ZO-1 interactions in PC specimens by proximity ligation immunohistochemistry, and identified that the number of interactions in metastatic PC specimens was several-fold larger than in non-metastatic PC. Our results for the first time demonstrate a mechanism by which PDZ-mediated interaction between CTR and ZO1 is required for CT-stimulated metastasis of prostate cancer. Since many receptors contain PDZ-binding motifs, this would suggest that PDZ-binding motif-adaptor protein interactions constitute a common mechanism for cancer metastasis.
Highlights
Calcitonin receptor (CTR) is a member of the class B family of G protein-coupled receptors (GPCRs), which contain numerous drug targets
Since the disruption of intercellular junctions and acquisition of invasive phenotype are obligate steps in tumor progression, we examined the action of CTR on tight junctions (TJs) and its importance in CTR-stimulated metastasis of prostate cancers (PCs) cells
In this report we show that the cytoplasmic (C) tail of CTR associates with tight junction (TJ) protein Zonula Occludens-1 (ZO-1) via the interaction between the type 1 PDZ-binding motif in the carboxy-terminus of CTR and PDZ3 domain of ZO-1
Summary
Calcitonin receptor (CTR) is a member of the class B family of G protein-coupled receptors (GPCRs), which contain numerous drug targets. CTR binds neuroendocrine peptide CT to maintain calcium homeostasis in bone and kidney [1]. Its expression in multiple organs and its actions in development, cell growth and differentiation suggest that CTR may have more diverse role Tolcos et al [2],[3,4]. The abundance of CT and CTR transcripts is increased in malignant prostates, and correlates positively with Gleason grade of prostate cancer (PC). Activation of CT-CTR autocrine axis stimulates several processes.
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