G Protein-Coupled Receptor GPR19 Regulates E-cadherin Expression and Invasion of Breast Cancer Cells

Biochim Biophys Acta Mol Cell Res. 2017 Jul;1864(7):1318-1327. doi: 10.1016/j.bbamcr.2017.05.001. Epub 2017 May 2.

Abstract

Dysregulation of G protein-coupled receptors (GPCRs) is known to be involved in the pathogenesis of a variety of diseases, including cancer initiation and progression. Within this family, approximately 140 GPCRs have no known endogenous ligands and these "orphan" GPCRs remain poorly characterized. The orphan GPCR GPR19 was identified and cloned 2 decades ago, but relatively little is known about its physio-pathological relevance. We observed its expression to be elevated in breast cancers and therefore sought to investigate its potential role in breast cancer pathology. In this work, we show that overexpression of GPR19 drives mesenchymal-like breast cancer cells to adopt an epithelial-like phenotype, as demonstrated by the upregulation in E-cadherin expression and changes in functional behavior. We confirm a previous report that a peptide, adropin, is an endogenous ligand for GPR19. We further show that adropin-mediated activation of GPR19 activates the MAPK/ERK1/2 pathway, which is essential for the observed upregulation in E-cadherin and accompanying phenotypic changes. The recapitulation of epithelial characteristics at the secondary tumor sites is now understood to be an essential step in the colonization process. Taken together our work shows for the first time that GPR19 plays a potential role in metastasis by promoting the mesenchymal-epithelial transition (MET) through the ERK/MAPK pathway, thus facilitating colonization of metastatic breast tumor cells.

Keywords: Adropin; E-cadherin; GPR19; MAPK/ERK; Mesenchymal-epithelial transition (MET); Orphan GPCR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Proteins / metabolism
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Cell Adhesion
  • Cell Movement*
  • Epithelial-Mesenchymal Transition
  • Gene Expression Regulation, Neoplastic*
  • HEK293 Cells
  • Humans
  • MAP Kinase Signaling System
  • MCF-7 Cells
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Peptides / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Neurotransmitter / genetics
  • Receptors, Neurotransmitter / metabolism*
  • Up-Regulation

Substances

  • Blood Proteins
  • Cadherins
  • Enho protein, human
  • GPR19 protein, human
  • Nerve Tissue Proteins
  • Peptides
  • Receptors, G-Protein-Coupled
  • Receptors, Neurotransmitter