RT Journal Article
SR Electronic
T1 β-arrestin mediates communication between plasma membrane and intracellular GPCRs to regulate signaling
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.08.031542
DO 10.1101/2020.04.08.031542
A1 Maxwell S. DeNies
A1 Alan Smrcka
A1 Santiago Schnell
A1 Allen P. Liu
YR 2020
UL http://biorxiv.org/content/early/2020/04/08/2020.04.08.031542.abstract
AB It has become increasingly apparent that G protein-coupled receptor (GPCR) localization is a master regulator of cell signaling. However, the molecular mechanisms involved in this process are not well understood. To date, observations of intracellular GPCR activation can be organized into two categories: a dependence on OCT3 cationic channel-permeable ligands or the necessity of endocytic trafficking. Using CXC chemokine receptor 4 (CXCR4) as a model, we identified a third mechanism of intracellular GPCR signaling. We show that independent of membrane permeable ligands and endocytosis, upon stimulation, plasma membrane and internal pools of CXCR4 are post-translationally modified and collectively regulate EGR1 transcription. We found that β-arrestin-1 (arrestin 2) is necessary to mediate communication between plasma membrane and internal pools of CXCR4. Notably, these observations may explain that while CXCR4 overexpression is highly correlated with cancer metastasis and mortality, plasma membrane localization is not. Together these data support a model were a small initial pool of plasma membrane-localized GPCRs are capable of activating internal receptor-dependent signaling events.