Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 48, Pages 24093-24099Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1905561116
Keywords
receptor-activity-modifying proteins; G-protein-coupled receptors; chemokine receptors; guided cell migration; endosomal sorting
Categories
Funding
- NIH [RO1-DK099156, RO1-HD060860, RO1-HL129086, F32-HL134279, F31-HL143836]
- American Heart Association [16IRG27260077, 15POST25270006]
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/M00015X/2]
- BBSRC [BB/JO14540/1]
- BBSRC [1643678, BB/M00015X/2] Funding Source: UKRI
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Receptor-activity-modifying proteins (RAMPs) are single transmembrane-spanning proteins which serve as molecular chaperones and allosteric modulators of G-protein-coupled receptors (GPCRs) and their signaling pathways. Although RAMPs have been previously studied in the context of their effects on Family B GPCRs, the coevolution of RAMPs with many GPCR families suggests an expanded repertoire of potential interactions. Using bioluminescence resonance energy transfer-based and cell-surface expression approaches, we comprehensively screen for RAMP interactions within the chemokine receptor family and identify robust interactions between RAMPs and nearly all chemokine receptors. Most notably, we identify robust RAMP interaction with atypical chemokine receptors (ACKRs), which function to establish chemotactic gradients for directed cell migration. Specifically, RAMP3 association with atypical chemokine receptor 3 (ACKR3) diminishes adrenomedullin (AM) ligand availability without changing G-protein coupling. Instead, RAMP3 is required for the rapid recycling of ACKR3 to the plasma membrane through Rab4-positive vesicles following either AM or SDF-1/CXCL12 binding, thereby enabling formation of dynamic spatiotemporal chemotactic gradients. Consequently, genetic deletion of either ACKR3 or RAMP3 in mice abolishes directed cell migration of retinal angiogenesis. Thus, RAMP association with chemokine receptor family members represents a molecular interaction to control receptor signaling and trafficking properties.
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