RAMP3 determines rapid recycling of atypical chemokine receptor-3 for guided angiogenesis

Abstract

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.

Targeting Adrenomedullin in Oncology: A Feasible Strategy With Potential as Much More Than an Alternative Anti-Angiogenic Therapy

“…Furthermore, it is worth mentioning that, although best studied and characterized, the modulating action of RAMPs is not exclusive to CTR and CLR. In this sense, RAMPs also operate as molecular chaperones and allosteric modulators of several GPCRs and their signaling pathways, including glucagon, growth hormone releasing hormone (GHRH), parathyroid hormone and chemokine receptors among others (82,88,89).…”

Targeting tumor cell-derived CCL2 as a strategy to overcome Bevacizumab resistance in ETV5+ colorectal cancer

“…To explore the potential mechanisms involved in Bevacizumab resistance in CRC, we used TCGA database to perform ETV5-related GSEA analysis. We found that ETV5 expression was significantly associated with the activation of a chemokine signaling pathway, and this could also contribute to angiogenesis in a number of cancers 29,30 . Of the significantly enriched genes, four genes were proangiogenic factors, including CXCL11, CXCL5, CCL2, and CCL13 19 .…”

“…It should be noted that ETV5 was positively related to the activation of a chemokine signaling pathway (Fig. 3a ) that was involved in angiogenesis in cancers 29 , 30 . In this pathway, 26 genes were significantly enriched and are further displayed according to a heatmap (Fig.…”

Targeting tumor cell-derived CCL2 as a strategy to overcome bevacizumab resistance in ETV5+ colorectal cancer

“…In order to explore the potential mechanisms involved in bevacizumab resistance in CRC, we used the TCGA data to performed ETV5-related GSEA analysis. We found that ETV5 expression was signi cantly associated with activation of chemokine signaling pathway, which could also contribute to angiogenesis in many cancers [29,30]. In the signi cantly enriched genes, four genes were also proangiogenic factors, such as CXCL11, CXCL5, CCL2, CCL13 [19].…”

“…It was worth noting that ETV5 positively related to activation of chemokine signaling pathway (Fig. 3a), which was involved in angiogenesis in cancers [29,30]. In this pathway, 26 genes were signi cantly enriched and further displayed by heatmap (Fig.…”