CXCR7: a β-arrestin-biased receptor that potentiates cell migration and recruits β-arrestin2 exclusively through Gβγ subunits and GRK2

Nguyen, Huyen Thi; Reyes‐Alcaraz, Arfaxad; Yong, Hyo Jeong; Nguyen, Lan Phuong; Park, Hee Kyung; Inoue, Asuka; Lee, Cheol Soon; Seong, Jae Young; Hwang, Jong Ik

doi:10.1186/s13578-020-00497-x

Cited by 48 publications

(53 citation statements)

References 58 publications

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“…Enhanced co-internalization of both ACKR3 and GRK5 in early endosomes could be an explanation for these observations. As recently reported, CMPD101 hampers β-arrestin2 recruitment via inhibiting GRK2 and 3 activity [10,53]. Here, we confirm their data, and furthermore demonstrate that those GRKs are also involved in the recruitment mechanism of β-arrestin1 and β-arrestin2.…”

Section: Discussionsupporting

confidence: 91%

Differential Involvement of ACKR3 C-Tail in β-Arrestin Recruitment, Trafficking and Internalization

Zarca

Pérez

Bor

et al. 2021

Cells

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Background: The atypical chemokine receptor 3 (ACKR3) belongs to the superfamily of G protein-coupled receptors (GPCRs). Unlike classical GPCRs, this receptor does not activate G proteins in most cell types but recruits β-arrestins upon activation. ACKR3 plays an important role in cancer and vascular diseases. As recruitment of β-arrestins is triggered by phosphorylation of the C-terminal tail of GPCRs, we studied the role of different potential phosphorylation sites within the ACKR3 C-tail to further delineate the molecular mechanism of internalization and trafficking of this GPCR. Methods: We used various bioluminescence and fluorescence resonance energy transfer-based sensors and techniques in Human Embryonic Kidney (HEK) 293T cells expressing WT or phosphorylation site mutants of ACKR3 to measure CXCL12-induced recruitment of β-arrestins and G-protein-coupled receptor kinases (GRKs), receptor internalization and trafficking. Results: Upon CXCL12 stimulation, ACKR3 recruits both β-arrestin 1 and 2 with equivalent kinetic profiles. We identified interactions with GRK2, 3 and 5, with GRK2 and 3 being important for β-arrestin recruitment. Upon activation, ACKR3 internalizes and recycles back to the cell membrane. We demonstrate that β-arrestin recruitment to the receptor is mainly determined by a single cluster of phosphorylated residues on the C-tail of ACKR3, and that residue T352 and in part S355 are important residues for β-arrestin1 recruitment. Phosphorylation of the C-tail appears essential for ligand-induced internalization and important for differential β-arrestin recruitment. GRK2 and 3 play a key role in receptor internalization. Moreover, ACKR3 can still internalize when β-arrestin recruitment is impaired or in the absence of β-arrestins, using alternative internalization pathways. Our data indicate that distinct residues within the C-tail of ACKR3 differentially regulate CXCL12-induced β-arrestin recruitment, ACKR3 trafficking and internalization.

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Section: Discussionsupporting

confidence: 91%

Differential Involvement of ACKR3 C-Tail in β-Arrestin Recruitment, Trafficking and Internalization

Zarca

Pérez

Bor

et al. 2021

Cells

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“…As can be seen in Fig. 1 C, D and Additional file 1 : Figure S1B, C, none of the G proteins could be activated by ACKR3, confirming previous studies reporting lack of G protein engagement by the atypical chemokine receptor [ 12 , 13 , 15 , 37 ]. Cells transfected with the delta opioid receptor (DOR) were used as a positive control for the assay and indeed showed robust G protein activation for the Gi/Go family members upon treatment with Met-Enkephalin (Fig.…”

Section: Resultssupporting

confidence: 86%

Ackr3-Venus knock-in mouse lights up brain vasculature

et al. 2021

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The atypical chemokine receptor 3, ACKR3, is a G protein-coupled receptor, which does not couple to G proteins but recruits βarrestins. At present, ACKR3 is considered a target for cancer and cardiovascular disorders, but less is known about the potential of ACKR3 as a target for brain disease. Further, mouse lines have been created to identify cells expressing the receptor, but there is no tool to visualize and study the receptor itself under physiological conditions. Here, we engineered a knock-in (KI) mouse expressing a functional ACKR3-Venus fusion protein to directly detect the receptor, particularly in the adult brain. In HEK-293 cells, native and fused receptors showed similar membrane expression, ligand induced trafficking and signaling profiles, indicating that the Venus fusion does not alter receptor signaling. We also found that ACKR3-Venus enables direct real-time monitoring of receptor trafficking using resonance energy transfer. In ACKR3-Venus knock-in mice, we found normal ACKR3 mRNA levels in the brain, suggesting intact gene transcription. We fully mapped receptor expression across 14 peripheral organs and 112 brain areas and found that ACKR3 is primarily localized to the vasculature in these tissues. In the periphery, receptor distribution aligns with previous reports. In the brain there is notable ACKR3 expression in endothelial vascular cells, hippocampal GABAergic interneurons and neuroblast neighboring cells. In conclusion, we have generated Ackr3-Venus knock-in mice with a traceable ACKR3 receptor, which will be a useful tool to the research community for interrogations about ACKR3 biology and related diseases.

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“…It is known that, as an atypical GPCR, targeting ACKR3 does not lead to typical G-protein-coupled receptor-mediated calcium mobilization and chemotaxis, but rather the recruitment of β-arrestins and the internalization of GPCR (Nguyen et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Atypical chemokine receptor 3 (ACKR3) induces the perturbation of rRNA biogenesis: a novel mechanism of colorectal tumorigenesis

Yang

et al. 2021

Preprint

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Atypical chemokine receptor 3 (ACKR3) has emerged as a key player in several biologic processes. However, much less is known the underlying mechanisms of ACKR3 in promoting tumorigenesis. We found, in human and animal model, that activation of ACKR3 promotes colorectal tumorigenesis through the NOLC1-induced perturbations of rRNA biogenesis. As compared with non-neoplastic tissue, human colonic cancer tissues demonstrated higher expression of ACKR3, and high ACKR3 expression was associated with increased severity of colonic cancer. Villin-ACKR3 transgenic mice demonstrated the characteristics of ACKR3-induced colorectal cancer, showing nuclear β-arrestin-1-activated perturbation of rRNA biogenesis. Activation of ACKR3 induced nuclear translocation of β-arrestin-1 (β-arr1), leading to the interaction of β-arr1 with nucleolar and coiled-body phosphoprotein 1 (NOLC1). As the highly phosphorylated protein in the nucleolus, NOLC1 further interacted with Fibrillarin, a highly conserved nucleolar methyltransferase responsible for ribosomal RNA methylation, leading to the increase of methylation in Histone H2A, resulting in the promotion of rRNA transcription of ribosome biogenesis. Conclusion: ACKR3 promotes colorectal tumorigenesis through the perturbation of rRNA biogenesis by nuclear β-arr1-induced interaction of NOLC1 with Fibrillarin.

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CXCR7: a β-arrestin-biased receptor that potentiates cell migration and recruits β-arrestin2 exclusively through Gβγ subunits and GRK2

Cited by 48 publications

References 58 publications

Differential Involvement of ACKR3 C-Tail in β-Arrestin Recruitment, Trafficking and Internalization

Differential Involvement of ACKR3 C-Tail in β-Arrestin Recruitment, Trafficking and Internalization

Ackr3-Venus knock-in mouse lights up brain vasculature

Atypical chemokine receptor 3 (ACKR3) induces the perturbation of rRNA biogenesis: a novel mechanism of colorectal tumorigenesis

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