Calcitonin Receptor-Zonula Occludens-1 Interaction Is Critical for Calcitonin-Stimulated Prostate Cancer Metastasis. PLoS One 2016;11(3):e0150090
Date
03/05/2016Pubmed ID
26934365Pubmed Central ID
PMC4775073DOI
10.1371/journal.pone.0150090Scopus ID
2-s2.0-84961112396 (requires institutional sign-in at Scopus site) 19 CitationsAbstract
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.
Author List
Aljameeli A, Thakkar A, Thomas S, Lakshmikanthan V, Iczkowski KA, Shah GVMESH terms used to index this publication - Major topics in bold
AnimalsCalcitonin
Cell Line, Tumor
Humans
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Metastasis
PDZ Domains
Prostatic Neoplasms
Protein Binding
Protein Interaction Domains and Motifs
Receptors, Calcitonin
Signal Transduction
Tight Junctions
Zonula Occludens-1 Protein
