Dysregulation of G Protein-Coupled Receptor Signaling in Cancer

Abstract

G protein-coupled receptors (GPCRs) are the largest family of signaling receptors in the mammalian genome and elicit responses to a plethora of extracellular stimuli. Moreover, nearly half the drugs currently in use for the treatment of a variety of human diseases target GPCRs either directly or indirectly. A role for dysregulated GPCR signaling in tumor progression is supported by a substantial amount of literature. GPCRs are overexpressed in various types of malignant cancers. In certain endocrine tissues, mutations in specific GPCRs and G proteins result in aberrant signaling, which contributes to cancer progression. In other tissue types, GPCR overexpression coupled with the abundance of activating ligands generated in the tumor microenvironment drives tumor progression. Desensitization and receptor trafficking control the magnitude, duration and spatial aspects of GPCR signaling. Most GPCRs are internalized through clathrin-coated pits and recycled back to the plasma membrane or sorted to lysosomes and degraded. Recent studies suggest that defects in GPCR trafficking contribute to receptor overexpression and aberrant signaling. Recent work also indicates that dysregulation of the trafficking machinery, due in part to aberrant ubiquitination, alters GPCR trafficking and signaling, and thereby contributes to tumor progression.