Affinage

ACKR2

Atypical chemokine receptor 2 · UniProt O00590

Round 2 corrected
Length
384 aa
Mass
43.4 kDa
Annotated
2026-04-28
130 papers in source corpus 32 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACKR2 is an atypical chemokine receptor that scavenges inflammatory CC chemokines (and CXCL10) through constitutive β-arrestin-dependent, clathrin-mediated internalization and lysosomal degradation, without activating G-protein signaling or calcium flux (PMID:9405404, PMID:12594248, PMID:15084596). Expressed predominantly on lymphatic endothelial cells and hematopoietic precursors, ACKR2 constitutively recycles via Rab4/Rab11 pathways and upregulates its surface abundance in response to chemokine engagement through a β-arrestin1→Rac1→PAK1→LIMK1→cofilin signaling cascade that optimizes scavenging capacity (PMID:18480427, PMID:23633677). In vivo, ACKR2-mediated chemokine clearance by non-hematopoietic cells is essential for resolution of cutaneous inflammation, prevention of adverse cardiac remodeling after myocardial infarction, regulation of lymphatic vessel density via control of pro-lymphangiogenic macrophage positioning, and modulation of neutrophil release from bone marrow (PMID:15750596, PMID:22796582, PMID:25271254, PMID:29445158). In cancer contexts, ACKR2 can also serve as a receptor for CXCL14, activating NOS1- or PLCβ3-PKCα-NF-κB-dependent signaling that promotes epithelial-mesenchymal transition and metastasis (PMID:30850359, PMID:37056937).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1997 High

    Cloning of ACKR2 revealed a promiscuous CC chemokine-binding receptor that, unlike classical chemokine receptors, failed to signal through calcium flux, establishing it as functionally atypical.

    Evidence cDNA cloning with radioligand binding and calcium flux assays in HEK293/CHO transfectants

    PMID:9139699 PMID:9405404

    Open questions at the time
    • Mechanism of ligand engagement without signaling was unknown
    • In vivo function not addressed
    • Selectivity for inflammatory vs. homeostatic chemokines not yet mapped
  2. 1999 High

    N-terminal residues of CC chemokines (specifically a proline at position 2) were identified as critical determinants of ACKR2 binding affinity, providing early structural insight into ligand recognition.

    Evidence Radioligand competition assays and proline-2 mutagenesis on D6 transfectants

    PMID:10364178

    Open questions at the time
    • Full structural basis of ligand selectivity unresolved
    • No crystal or cryo-EM structure of ACKR2-chemokine complex
  3. 2001 High

    Identification of lymphatic endothelium as the primary site of ACKR2 expression provided the anatomical context for its function as a chemokine gatekeeper at tissue-lymph interfaces.

    Evidence Monoclonal antibody immunohistochemistry and in situ hybridization on human dermis, intestinal mucosa, and lymph node sections co-stained with podoplanin

    PMID:11238036

    Open questions at the time
    • Expression on hematopoietic cells not yet appreciated
    • Whether ACKR2 functions identically in all lymphatic beds remained untested
  4. 2003 High

    Demonstration that ACKR2 internalizes and degrades CC chemokines without triggering signaling or transcytosis established the chemokine-scavenging/decoy receptor paradigm.

    Evidence Calcium flux, chemotaxis, internalization, and degradation assays in transfectants and primary lymphatic endothelial cells

    PMID:12594248

    Open questions at the time
    • Molecular machinery of constitutive internalization uncharacterized
    • Whether ligand engagement alters receptor trafficking unknown
  5. 2004 High

    The trafficking and scavenging mechanism was dissected: ACKR2 constitutively internalizes via β-arrestin-dependent clathrin-coated pits, with an acidic C-terminal motif (not phosphorylation) driving β-arrestin association, and most receptor resides in intracellular vesicles.

    Evidence β-arrestin co-IP, clathrin inhibition, C-terminal mutagenesis, subcellular fractionation, and metabolic labeling in HEK293 transfectants

    PMID:14723600 PMID:15084596

    Open questions at the time
    • Which Rab GTPases govern vesicular recycling not yet known
    • How ligand binding feeds back on trafficking unclear
  6. 2004 High

    Systematic ligand profiling confirmed ACKR2 selectively scavenges inflammatory (CCR1–CCR5 agonists) but not homeostatic CC chemokines, with N-terminal integrity required for recognition, defining the functional ligand spectrum.

    Evidence Radioligand binding, scavenging assays, and CD26-processing experiments in D6 transfectants

    PMID:15067078

    Open questions at the time
    • Whether any non-CC chemokine could serve as ligand was unexplored
    • In vivo chemokine selectivity not validated
  7. 2005 High

    ACKR2-deficient mice revealed that in vivo chemokine scavenging is essential for resolution of cutaneous inflammation, as knockouts accumulated excess β-chemokines and developed psoriasis-like pathology.

    Evidence D6 knockout mice in phorbol ester-induced cutaneous inflammation model with chemokine quantification and histopathology

    PMID:15750596

    Open questions at the time
    • Whether non-hematopoietic or hematopoietic ACKR2 is responsible not determined in this context
    • Mechanism of inflammation resolution vs. prevention not distinguished
  8. 2007 High

    Bidirectional genetic evidence (knockout susceptibility, transgenic protection) established ACKR2 as a tumor suppressor in chemically induced skin carcinogenesis by limiting pro-tumorigenic inflammatory cell recruitment.

    Evidence D6-KO and keratinocyte-specific D6 transgenic mice in DMBA/TPA carcinogenesis model; immune cell quantification

    PMID:17607362

    Open questions at the time
    • Whether ACKR2 suppresses tumors in non-cutaneous tissues via same mechanism unknown
    • Cell-autonomous effects on tumor cells not addressed
  9. 2008 High

    Ligand-induced Rab11-dependent redistribution of ACKR2 to the plasma membrane was identified as the mechanism by which scavenging capacity scales with chemokine concentration, and the C-terminal serine cluster was shown to be essential for sustained scavenging.

    Evidence Rab4/Rab11 dominant-negative constructs, wortmannin/brefeldin A inhibition, C-terminal deletion and serine mutagenesis with chemokine degradation assays

    PMID:18201974 PMID:18480427

    Open questions at the time
    • How Rab11 pathway is activated by ligand engagement unknown
    • No link yet to actin cytoskeleton remodeling
  10. 2008 High

    Discovery of ACKR2 expression on hematopoietic cells (B cells, DCs, mast cells) under GATA1 control expanded the expression domain beyond lymphatic endothelium and identified TGF-β and LPS as dynamic regulators.

    Evidence Flow cytometry, RT-PCR, chemokine uptake in D6-null vs. WT leukocytes, GATA1 knockout experiments

    PMID:18714007

    Open questions at the time
    • Relative contribution of hematopoietic vs. non-hematopoietic ACKR2 to systemic chemokine homeostasis unclear
    • Whether GATA1 directly or indirectly activates the D6 promoter not resolved
  11. 2012 High

    Bone marrow chimera experiments in myocardial infarction and monocyte trafficking models localized the critical in vivo scavenging function to non-hematopoietic ACKR2, operating via control of CCR2-dependent Ly6C-hi monocyte recruitment.

    Evidence D6-KO and CCR2-KO bone marrow chimeras; MI model with echocardiography, MMP assays; GVHD model with T-cell suppression assays

    PMID:22504926 PMID:22796582

    Open questions at the time
    • Which non-hematopoietic cell types express functionally relevant ACKR2 in heart was not pinpointed
    • Whether ACKR2 regulates monocyte function beyond recruitment unclear
  12. 2013 High

    Identification of the β-arrestin1→Rac1→PAK1→LIMK1→cofilin signaling cascade downstream of ACKR2 overturned the 'silent receptor' paradigm, showing that ACKR2 activates actin remodeling to drive its own surface redistribution and scavenging.

    Evidence β-arrestin1 co-IP, Rac1/PAK1/LIMK1 inhibitors and dominant-negatives, cofilin phosphorylation assays, D6 surface quantification

    PMID:23633677

    Open questions at the time
    • Whether this pathway operates in all ACKR2-expressing cell types unknown
    • Whether other actin regulators participate not tested
    • Link to Rab11-dependent recycling not formally demonstrated
  13. 2014 High

    ACKR2 was shown to regulate lymphatic vessel density by controlling the proximity of CCR2-dependent pro-lymphangiogenic macrophages to developing lymphatic vessels, revealing a developmental morphogenetic role.

    Evidence ACKR2-KO and CCR2-KO mice; lymphatic vessel quantification; embryonic skin analysis; macrophage proximity measurements; blood pressure assessment

    PMID:25271254

    Open questions at the time
    • Which VEGF family members mediate macrophage-driven lymphangiogenesis downstream of ACKR2 not identified
    • Whether increased lymphatic density has functional consequences beyond fluid drainage
  14. 2018 High

    ACKR2 was found to act as a checkpoint of myeloid differentiation in bone marrow, with its loss increasing neutrophil release and anti-metastatic neutrophil activity, while also promoting pulmonary fibrosis via regulation of CCR2+/CCR5+ IFNγ-producing γδT cell influx.

    Evidence ACKR2-KO mice in NeuT mammary carcinoma, 4T1/B16F10 metastasis models, and bleomycin fibrosis model; bone marrow chimeras; γδT cell depletion; CCR2-KO/CCR5-KO mice

    PMID:29445158 PMID:29469612

    Open questions at the time
    • How ACKR2 is downregulated during myeloid differentiation mechanistically unclear
    • Whether neutrophil anti-metastatic activity is direct or requires other immune cell cooperation
  15. 2019 Medium

    ACKR2 was identified as a functional receptor for the orphan chemokine CXCL14, mediating EMT and metastasis through NOS1 in breast cancer, revealing a signaling role distinct from classical scavenging.

    Evidence siRNA/shRNA ACKR2 knockdown; in vitro EMT, migration, invasion assays; xenograft and tail-vein metastasis models; NOS1 inhibition

    PMID:30850359

    Open questions at the time
    • Direct CXCL14-ACKR2 binding not demonstrated biochemically
    • How ACKR2 activates NOS1 is mechanistically undefined
    • Whether this operates outside breast cancer unknown
  16. 2021 Medium

    CXCL10 was identified as the first non-CC chemokine agonist of ACKR2, with DPP4 processing abolishing CXCL10 activity at ACKR2, broadening the receptor's ligand repertoire beyond CC chemokines.

    Evidence NanoBiT and NanoBRET β-arrestin recruitment assays; ACKR2 internalization assays; DPP4 processing experiments

    PMID:33801414

    Open questions at the time
    • In vivo relevance of CXCL10 scavenging by ACKR2 not established
    • Whether other CXC chemokines are also agonists not systematically tested
  17. 2023 Medium

    A PLCβ3→PKCα→c-Src→NF-κB signaling cascade was mapped downstream of ACKR2 in lung cancer cells stimulated by CXCL14, defining a second cancer-specific signaling pathway through ACKR2.

    Evidence ACKR2 siRNA knockdown; phosphorylation western blots for PLCβ3/PKCα/c-Src; NF-κB luciferase reporter; orthotopic lung cancer metastasis model

    PMID:37056937

    Open questions at the time
    • Relationship between PLCβ3-NF-κB and β-arrestin-cofilin pathways unexplored
    • Whether this pathway operates in non-cancer cells unknown
    • Single lab finding awaiting independent replication
  18. 2024 Medium

    ACKR2 upregulation in chemoradiotherapy-resistant cervical cancer cells was shown to drive CD8+ T cell senescence via TGF-β production, linking ACKR2 to immune evasion in the tumor microenvironment.

    Evidence Single-cell RNA-seq of human cervical cancer tissues; in vitro tumor-T cell co-cultures; TGF-β blocking experiments

    PMID:38723624

    Open questions at the time
    • Whether TGF-β induction is a direct ACKR2 signaling output or indirect consequence of chemokine clearance is unresolved
    • Generalizability to other tumor types not tested
    • No in vivo intervention blocking ACKR2 to rescue T cell function

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of ACKR2's promiscuous CC/CXC chemokine recognition (no high-resolution structure exists), the mechanistic link between β-arrestin-cofilin signaling and Rab11-dependent recycling, and whether ACKR2's cancer-context signaling functions (CXCL14/NOS1, PLCβ3-NF-κB, TGF-β) are physiologically relevant outside tumors.
  • No structural model of ACKR2 alone or in complex with any ligand
  • Connection between actin remodeling and vesicular recycling pathways not formally demonstrated
  • Cancer-associated signaling pathways not validated in non-malignant contexts

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0038024 cargo receptor activity 4 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3 GO:0120274 virus coreceptor activity 1
Localization
GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 2 GO:0005768 endosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 8 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-1266738 Developmental Biology 2
Partners
ARRB1CFL1CXCL10CXCL14LIMK1PAK1RAB11ARAC1

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 ACKR2 (D6) was cloned as a novel promiscuous beta-chemokine receptor that binds most inflammatory CC chemokines (MIP-1α, MIP-1β, RANTES, JE, MCP-3) but not alpha-chemokines or C/CXXXC chemokines, and unlike conventional chemokine receptors, failed to elicit calcium flux upon ligand binding in transfected cells, suggesting it is not a classical signaling receptor. cDNA cloning, radioligand binding assays (125I-MIP-1α competition), calcium flux assays in HEK293 and CHO transfectants The Journal of biological chemistry High 9139699 9405404
2001 ACKR2 (D6) is selectively expressed on lymphatic endothelial cells (LECs) lining afferent lymphatics in human dermis, intestinal mucosa, and lymph node sinuses, but not on blood vessel endothelium or peripheral blood cells, establishing lymphatic endothelium as the primary anatomical site for D6 function. Monoclonal antibody generation, immunohistochemistry on serial human skin sections with lymphatic marker podoplanin, in situ hybridization The American journal of pathology High 11238036
2003 Engagement of ACKR2 (D6) by inflammatory CC chemokines elicits no calcium response or chemotaxis in transfected cells or lymphatic endothelium, but results in efficient ligand internalization and degradation. D6 does not mediate transcytosis of chemokines in either direction. This established D6 as a chemokine-scavenging decoy receptor acting as a 'gatekeeper' on lymphatic endothelium. D6 transfectants in multiple cell types; calcium flux assays; chemotaxis assays; internalization/degradation assays; lymphatic endothelial cell experiments Journal of immunology (Baltimore, Md. : 1950) High 12594248
2004 ACKR2 (D6) constitutively internalizes via clathrin-coated pits through a β-arrestin-dependent mechanism. D6 constitutively associates with β-arrestin, and an acidic region (not phosphorylation sites) in the cytoplasmic tail is critical for this interaction and subsequent internalization. Neither native D6 nor β-arrestin-uncoupled mutants activate G-protein-mediated signaling, confirming D6 as a non-signaling decoy receptor whose scavenging depends on constitutive β-arrestin-dependent endocytosis. β-arrestin co-immunoprecipitation, clathrin inhibition experiments, mutagenesis of cytoplasmic tail (acidic region vs. phosphorylation sites), calcium flux and chemotaxis assays in transfectants The Journal of biological chemistry High 15084596
2004 ACKR2 (D6) efficiently binds and scavenges most inflammatory CC chemokines (CCR1–CCR5 agonists) but not homeostatic CC chemokines (CCR6/CCR7 agonists). CCR4 agonists CCL17 and CCL22 are recognized by D6 with high affinity and scavenged, reducing their chemotactic activity. CD26-processed truncated forms of CCL22 (lacking N-terminal residues) are not recognized by D6, demonstrating that N-terminal integrity is required for D6 binding. Radioligand binding and competition assays on D6 transfectants; scavenging/degradation assays; CCR4 transfectant chemotaxis; CD26 processing experiments Journal of immunology (Baltimore, Md. : 1950) High 15067078
2004 Milligram quantities of purified ACKR2 (D6) from mammalian transfectants retain full functional activity (displaceable 125I-MIP-1β binding, MIP-1α affinity column binding). Biochemical characterization revealed D6 is N-glycosylated at the N-terminus (dispensable for ligand binding), sulphated, and constitutively phosphorylated (not enhanced by ligand). Over 80% of cellular D6 resides in intracellular vesicular compartments. Protein purification from transfected mammalian cells; radioligand binding; affinity chromatography; N-terminal mutagenesis; metabolic labeling for sulfation and phosphorylation; subcellular fractionation The Biochemical journal High 14723600
2005 ACKR2 (D6)-deficient mice fail to resolve cutaneous inflammation after phorbol ester treatment, accumulating excess residual beta-chemokines that drive an inflammatory pathology resembling psoriasis. This demonstrated that D6 is required for post-inflammatory clearance of beta-chemokines from cutaneous sites in vivo. D6 knockout mice; phorbol ester-induced cutaneous inflammation model; chemokine measurement; histopathology Nature immunology High 15750596
2005 ACKR2 (D6) can function as a coreceptor for primary dual-tropic HIV-1 and HIV-2 isolates on astrocytes. RNA interference knockdown of D6 in primary astrocytes inhibited infection by D6-tropic isolates, establishing a cell-autonomous HIV coreceptor function for D6 in brain cells. HIV-1/HIV-2 infection assays in D6-expressing cell lines and primary astrocytes; siRNA knockdown of D6; chimeric gp120 constructs Journal of virology Medium 16014924
2008 D6 scavenging activity is regulated by unique vesicular trafficking: under resting conditions D6 constitutively recycles through Rab4- and Rab11-dependent pathways, maintaining low surface expression. Chemokine engagement induces dose-dependent Rab11-dependent redistribution of D6 to the plasma membrane, increasing chemokine degradation rate. This ligand-concentration-dependent surface up-regulation (not transcriptional regulation) is the mechanism by which D6 optimizes scavenging activity. Wortmannin and brefeldin A pharmacological inhibition; Rab4/Rab11 dominant-negative constructs; surface expression quantification; chemokine degradation assays Blood High 18480427
2008 The conserved 58-amino acid C-terminal tail of D6 controls constitutive phosphorylation, high protein stability, and intracellular trafficking itinerary, and drives β-arrestin to membranes near the cell surface. A serine cluster in this region is critical for these properties. Deletion of the last 44–58 amino acids abolishes progressive scavenging because ligand engagement of the truncated receptor inhibits subsequent chemokine uptake, revealing the C-terminus is dispensable for initial internalization but indispensable for sustained scavenging. C-terminal deletion and serine cluster mutagenesis in HEK293 cells; GFP-β-arrestin imaging; phosphorylation assays; CCL3 scavenging assays The Journal of biological chemistry High 18201974
2008 Functional D6 is expressed by murine and human hematopoietic cells (highest in B cells and dendritic cells), and this expression is dynamically regulated: LPS down-regulates D6 in myeloid cells, TGF-β up-regulates it, and T-cell activation markedly up-regulates D6 mRNA. D6 expression in myeloid progenitors, mast cells, megakaryocytes, and DCs is dependent on the transcription factor GATA1. Hematopoietic D6 mediates chemokine uptake in a D6-dependent manner. Flow cytometry; RT-PCR; competition chemokine uptake assays in D6-null vs. wild-type leukocytes; GATA1 knockout/knockdown experiments; LPS/TGF-β/anti-CD3 stimulation Journal of immunology (Baltimore, Md. : 1950) High 18714007
2007 ACKR2 (D6)-deficient mice show increased susceptibility to chemically induced cutaneous tumor development. D6 deletion alone is sufficient to make resistant mouse strains susceptible to invasive squamous cell carcinoma. Conversely, transgenic D6 expression in keratinocytes dampens cutaneous inflammation and protects from tumor formation. Tumor susceptibility correlates with enhanced T cell and mast cell recruitment, linking D6-mediated chemokine scavenging to tumor suppression by limiting pro-tumorigenic inflammation. D6 knockout mice; keratinocyte-specific D6 transgenic mice; chemical carcinogenesis (DMBA/TPA); immune cell quantification by histology and flow cytometry The Journal of clinical investigation High 17607362
2008 ACKR2 (D6) expressed at the maternal-fetal interface (trophoblasts/placenta) plays a role in regulating chemokine levels during implantation, contributing to the local inflammatory milieu required for successful embryonic implantation and fetal tolerance. Expression analysis in placental/trophoblast tissue; D6-deficient mouse pregnancy models reviewed Placenta Low 18676013
2009 ACKR2 (D6) contributes to the development of dextran sodium sulfate-induced colitis: D6-deficient mice show reduced susceptibility to colitis and reduced clinical symptoms. Mechanistically, D6 deletion did not alter CC chemokine levels or leukocyte balance in the colon, but late in colitis D6-deficient colons showed enhanced IL-17A production by γδ T cells. Antibody neutralization of IL-17A worsened colitis specifically in D6-deficient mice, revealing that D6 regulates colitis by modulating IL-17A secretion by lamina propria γδ T cells. DSS colitis model in D6-deficient mice; cytokine measurements; leukocyte subset quantification; anti-IL-17A neutralizing antibody treatment Journal of immunology (Baltimore, Md. : 1950) Medium 19342683
2012 ACKR2 (D6) prevents adverse ventricular remodeling after myocardial infarction by scavenging inflammatory CC chemokines CCL2 and CCL3 in ischemic heart. D6-deficient mice show increased pathogenic neutrophil and Ly6Chi monocyte infiltration, elevated MMP-9/MMP-2 activity, cardiac rupture, and left ventricular dilation. Bone marrow chimera experiments demonstrated that leukocyte-borne D6 plays no role; cardiac resident (non-hematopoietic) D6 is responsible. CCR2 deficiency in leukocytes rescues the adverse phenotype of D6-deficient mice. D6 knockout mice; myocardial infarction model; bone marrow chimeras; CCR2-deficient bone marrow transfer; cytokine/chemokine ELISA; MMP activity assays; echocardiography Arteriosclerosis, thrombosis, and vascular biology High 22796582
2012 ACKR2 (D6) controls the traffic and immunosuppressive activity of Ly6Chi monocytes. Mice lacking D6 in the non-hematopoietic compartment have selectively increased circulating Ly6Chi monocytes. Under inflammation, these accumulate in secondary lymphoid organs in a CCR2-dependent manner. D6-deficient Ly6Chi monocytes have enhanced immunosuppressive activity, inhibiting adaptive immune responses and partially protecting against graft-versus-host disease. D6 knockout and bone marrow chimera mice; flow cytometry; GVHD model; T-cell suppression assays; CCR2-dependent accumulation experiments Blood High 22504926
2012 ACKR2 (D6) controls macrophage efferocytosis and cytokine secretion during inflammation resolution in a chemokine scavenging-independent manner. D6-deficient mice show increased macrophage numbers and enhanced efferocytosis of apoptotic neutrophils in vivo. D6 is expressed on apoptotic neutrophils, and D6-deficient apoptotic neutrophils are less effective at inducing immune silencing (reduced TNF-α, IL-1β, CCL5 suppression) in macrophages, identifying a scavenging-independent role for neutrophil-expressed D6 in shaping the resolution of inflammation. Zymosan A peritonitis model; D6 knockout mice; in vivo efferocytosis quantification; ex vivo macrophage-neutrophil co-incubation cytokine assays; flow cytometry of human and rodent apoptotic neutrophils FASEB journal Medium 22651933
2013 ACKR2 (D6) expressed on lymphatic endothelial cells (LECs) contributes to selective CCR7 ligand presentation by suppressing inflammatory chemokine binding to LEC surfaces. D6 overexpression reduces immature dendritic cell (DC) adhesion to LECs, while D6 knockdown increases iDC adhesion and displaces mature DCs. LEC D6 expression is induced by IL-6 and IFN-γ, and by Kaposi sarcoma herpesvirus vIL-6. D6 is therefore an essential regulator of inflammatory leukocyte-LEC interactions and immature/mature DC discrimination. D6 overexpression and siRNA knockdown in LECs; DC adhesion assays; cytokine stimulation experiments; in vivo vIL-6 expression; KS/PEL cell line expression analysis Blood High 23479571
2013 ACKR2 (D6) engagement by chemokine ligands activates a β-arrestin1-dependent, G protein-independent signaling pathway leading to phosphorylation of the actin-binding protein cofilin through the Rac1-PAK1-LIMK1 cascade. This signaling pathway is required for increased D6 surface abundance and for its chemokine-scavenging activity, demonstrating that D6 is not truly 'silent' but rather a signaling receptor using a distinct non-G protein pathway to regulate its own scavenging function. β-arrestin1 co-IP; Rac1/PAK1/LIMK1 pathway inhibitors and dominant-negative constructs; cofilin phosphorylation assays; D6 surface expression quantification; scavenging assays Science signaling High 23633677
2014 ACKR2 (D6) expression in Kaposi sarcoma is inversely correlated with tumor aggressiveness and macrophage infiltration. In a KS experimental model with B-Raf V600E mutation, inhibition of B-Raf or the downstream ERK pathway induced D6 expression. In progressing human KS tumors, ERK activation correlates with reduced D6 levels. D6-competent tumors are promoted by adoptive transfer of wild-type but not CCR2-deficient macrophages, revealing that B-Raf-ERK pathway-driven downregulation of D6 unleashes CCL2-mediated pro-angiogenic macrophage recruitment. Human KS tumor analysis; B-Raf inhibitor treatment; ERK inhibitor treatment; D6 expression quantification; macrophage adoptive transfer (WT vs. CCR2-KO); tumor growth assays Cancer immunology research High 24844911
2014 ACKR2-deficient mice display increased lymphatic vessel density in multiple tissues under resting and regenerating conditions, associated with enhanced fluid drainage and a hypotensive phenotype. This phenotype is developmentally established. Conversely, CCR2-deficient mice show reduced lymphatic vessel density. Increased proximity of pro-lymphangiogenic macrophages to developing lymphatic vessel surfaces in ACKR2-deficient mice (and reduced proximity in CCR2-deficient mice) reveals that ACKR2 and CCR2 reciprocally regulate vessel density by controlling pro-lymphangiogenic macrophage recruitment. ACKR2-KO and CCR2-KO mice; lymphatic vessel density quantification across tissues; tissue fluid drainage measurement; blood pressure measurement; embryonic skin analysis; macrophage proximity quantification The EMBO journal High 25271254
2016 ACKR2 limits the spread of psoriasiform inflammation from primary lesions to remote skin sites. Localized inflammation and IFN-γ up-regulate ACKR2 in remote tissues, protecting them from inflammatory spread. ACKR2 controls inflammatory T-cell chemotaxis and positioning within the skin, preventing epidermal influx associated with lesion development. Imiquimod-induced psoriasiform inflammation model; clinical samples; primary human cell cultures; in vitro migration assays; ACKR2 expression quantification in remote vs. lesional skin; IFN-γ stimulation The Journal of investigative dermatology High 27568525
2016 ACKR2 controls branching morphogenesis in the postnatal mammary gland. ACKR2 is differentially expressed during mammary gland development; Ackr2-/- mice display precocious mammary gland development with increased macrophage recruitment and increased density of the ductal epithelial network. ACKR2 knockout mice; mammary gland whole mount analysis; macrophage quantification by immunohistochemistry; ductal network density measurement at multiple developmental time points Development (Cambridge, England) Medium 27888192
2018 ACKR2 is expressed in hematopoietic precursors and downregulated during myeloid differentiation. Genetic inactivation of ACKR2 results in increased inflammatory chemokine receptor levels in precursors and enhanced release of neutrophils from bone marrow with increased anti-metastatic activity. In NeuT-driven mammary carcinogenesis, ACKR2 deficiency increases primary tumor growth but protects against metastasis via neutrophil-mediated anti-metastatic activity. ACKR2 knockout mice; flow cytometry of bone marrow precursors; NeuT transgenic mammary carcinoma model; 4T1 orthotopic and B16F10 i.v. metastasis models; chemokine receptor expression analysis Nature communications High 29445158
2018 ACKR2 expressed in pulmonary resident (non-hematopoietic) cells drives pulmonary fibrosis by tuning the influx of CCR2+ and CCR5+ IFNγ-producing γδT cells. ACKR2-/- mice show reduced lethality and lung fibrosis in a bleomycin model, with early increased CCL5, CCL12, CCL17, IFNγ, and increased CCR2+/CCR5+ γδT cells in airways counterbalanced by reduced Th17 influx. Depletion of γδT cells reverses the protective phenotype of ACKR2-/- mice. Bleomycin fibrosis model; ACKR2-KO mice; bone marrow chimeras; CCR2-KO and CCR5-KO mice; antibody-mediated γδT cell depletion; cytokine/chemokine profiling; leukocyte subset analysis American journal of physiology. Lung cellular and molecular physiology High 29469612
2019 ACKR2 mediates pro-EMT and migratory responses stimulated by the orphan chemokine CXCL14 in breast cancer cells. Loss-of-function experiments identified ACKR2 as the receptor through which fibroblast-derived CXCL14 stimulates breast cancer EMT, migration, invasion, and lung colonization. CXCL14-induced NOS1 is downstream of ACKR2 and required for the pro-EMT effects, defining an autocrine CXCL14/ACKR2/NOS1 pathway. siRNA/shRNA loss-of-function for ACKR2; in vitro EMT, migration, invasion assays; xenograft model with CXCL14-overexpressing fibroblasts; tail-vein metastasis assay; NOS1 inhibition Clinical cancer research Medium 30850359
2021 ACKR2 (D6) binds and internalizes the CXC chemokine CXCL10, identifying the first non-CC chemokine agonist for ACKR2. β-arrestin recruitment assays revealed CXCL10 as a strong agonist for ACKR2, and ACKR2 reduced extracellular CXCL10 availability. DPP4/CD26 N-terminal processing of CXCL10 drastically reduced its activity at ACKR2, unlike CC chemokines, pointing to different receptor binding pocket occupancy by CC vs. CXC chemokines. NanoBiT and NanoBRET β-arrestin recruitment assays; ACKR2 internalization assays; DPP4 processing of CXCL10; competitive binding Cancers Medium 33801414
2023 ACKR2 mediates CXCL14-promoted lung cancer metastasis via a PLCβ3-PKCα-c-Src-NF-κB signaling cascade leading to EMT and increased cell motility. ACKR2 knockdown abolished CXCL14-induced cancer cell motility in vitro and in an orthotopic model. This identifies a specific intracellular signaling pathway downstream of ACKR2 in cancer cells distinct from its classical scavenging function. ACKR2 knockdown (siRNA); migration and wound healing assays; luciferase reporter assay for NF-κB; Western blot for PLCβ3/PKCα/c-Src phosphorylation; orthotopic lung cancer metastasis model; TCGA/GEO dataset analysis for expression correlation International journal of biological sciences Medium 37056937
2024 ACKR2+ chemoradiotherapy (CCRT)-resistant cervical cancer tumor cells drive CD8+ T cell senescence. Mechanistically, ACKR2 expression is upregulated by CCRT and by ligation of CC chemokines from activated myeloid and T cells; ACKR2+ tumor cells then produce TGF-β which drives CD8+ T cell senescence, compromising antitumor immunity and promoting tumor recurrence. Single-cell RNA sequencing of human cervical cancer tissues before/after CCRT; in vitro co-culture experiments; TGF-β blocking; retrospective clinical analysis Cell reports. Medicine Medium 38723624
1999 The MIP-1α isoform LD78β (MIP-1αP) has ~15-20-fold enhanced binding affinity for D6 (ACKR2) compared to LD78α, attributable to a proline residue at position 2. This demonstrated that N-terminal residues of CC chemokines critically determine binding affinity at ACKR2. Radioligand binding competition assays on D6-expressing transfectants; proline-2 mutagenesis; CCR5 and D6 affinity comparison The Journal of biological chemistry High 10364178
2012 D6 (ACKR2) expression is markedly elevated in 'uninvolved' psoriatic skin (epidermis and lymphatic endothelium) where inflammatory chemokines are elevated but plaques do not form, suggesting D6 acts as a suppressor of lesion development. D6 expression drops in perilesional and lesional skin coincident with plaque development. Trauma reduces D6 expression in uninvolved skin, consistent with trauma-mediated reduction in D6 triggering the Koebner phenomenon. D6 is also elevated in peripheral blood leukocytes of psoriatic patients. Immunohistochemistry of human psoriatic skin biopsies (uninvolved, perilesional, lesional); mRNA quantification; D6 measurement in peripheral blood leukocytes The American journal of pathology Medium 22867710

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2002 CCL27-CCR10 interactions regulate T cell-mediated skin inflammation. Nature medicine 612 11821900
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2012 Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population. PloS one 312 23251661
2020 CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands. International journal of molecular sciences 301 33076281
2003 CCR10 expression is a common feature of circulating and mucosal epithelial tissue IgA Ab-secreting cells. The Journal of clinical investigation 263 12671049
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