Affinage

CCR4

Nocturnin · UniProt Q9UK39

Length
431 aa
Mass
48.2 kDa
Annotated
2026-06-09
100 papers in source corpus 23 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCR4 is a seven-transmembrane chemokine receptor that mediates the directional migration of CCR4-expressing cells in immune trafficking, central tolerance, and pathological metastasis, and it functions as a ligand-driven signaling hub for CCL17 and CCL22 (PMID:8573157, PMID:19062085, PMID:24563252). Its two cognate chemokines act as conformationally selective, biased agonists: CCL22 dominates competitive binding and receptor endocytosis, couples efficiently to β-arrestin, and fully stimulates GTPγS binding, whereas CCL17 requires the C-terminal residue K310 for activation, does not engage β-arrestin, and only partially stimulates G protein coupling (PMID:24563252, PMID:24534492). Surface receptor abundance is set by rapid, ligand-induced endocytosis followed by slow, de novo synthesis-dependent replenishment, and truncation of the cytoplasmic C-terminus blocks this internalization to sustain signaling and enhance chemotaxis toward both ligands (PMID:32052476). This regulatory logic is hijacked in adult T-cell leukemia/lymphoma (ATLL), where somatic gain-of-function truncating mutations at C329/Q330/Y331 impair internalization, increase migration, and enhance CCL22-driven PI3K/AKT activation to confer a growth advantage (PMID:25488980). In normal physiology CCR4 directs post-positive-selection thymocytes into the medulla and promotes their interactions with dendritic cells required for negative selection and prevention of autoimmunity (PMID:26417005), and it recruits Th2/Th17 effector cells into lung and skin during allergic inflammation (PMID:19062085, PMID:29510192). Beyond leukocytes, CCR4 is functionally expressed on platelets, keratinocytes, microglia, and sensory neurons, where CCL17/CCL22 directly activate the neurons to drive postoperative pain (PMID:11248289, PMID:35046040). In epithelial cancers CCR4 promotes invasion, metastasis, and angiogenesis through ERK/NF-κB/MMP and PI3K/AKT signaling cascades (PMID:21479551, PMID:27356745, PMID:28959024). CCR4 transcription is driven by Fra-2/JunD AP-1 heterodimers and by HTLV-1 HBZ acting through GATA3, and is controlled epigenetically by HDAC2 (PMID:18071306, PMID:27402079, PMID:29025909).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1996 Medium

    Established CCR4 as a bona fide chemokine receptor by demonstrating high-affinity ligand binding, answering whether the orphan-like sequence encoded a functional receptor.

    Evidence Radioligand competition binding in CCR4-transfected HL-60 cells for human and murine receptors

    PMID:8573157

    Open questions at the time
    • MIP-1α/RANTES binding not reconciled with later CCL17/CCL22 ligand assignment
    • no signaling output measured
    • no endogenous cell type tested
  2. 2001 Medium

    Extended CCR4 function beyond classical leukocytes by showing it drives platelet activation, raising the question of non-immune receptor roles.

    Evidence Calcium flux, aggregation, anti-CCR4 mAb blockade, and cross-desensitization in primary human platelets, corroborated by IP/WB

    PMID:11110672 PMID:11248289

    Open questions at the time
    • downstream signaling beyond Ca2+ not dissected
    • physiological relevance of platelet CCR4 in vivo unclear
    • requirement for plasma cofactors not mechanistically resolved
  3. 2007 Medium

    Identified the transcriptional driver of CCR4 in leukemia, addressing how the receptor is overexpressed in ATL.

    Evidence AP-1 promoter reporter, Fra-2/JunD vs JunB siRNA, and overexpression in ATL and Jurkat cells

    PMID:18071306

    Open questions at the time
    • upstream signals activating Fra-2/JunD not defined
    • single-lab promoter mechanism
    • not linked to receptor mutation status
  4. 2008 High

    Demonstrated CCR4 is required for effector Th2 trafficking into tissue, defining its core in vivo role in allergic inflammation.

    Evidence Adoptive transfer of CCR4-deficient vs wild-type Th2 cells in a murine allergic airway model

    PMID:19062085

    Open questions at the time
    • chemokine source in lung not pinpointed
    • does not address non-Th2 CCR4 cells
    • ligand bias not considered
  5. 2014 High

    Resolved that CCL17 and CCL22 are conformationally selective biased agonists, reframing CCR4 as a receptor with ligand-specific signaling outputs rather than a single activity.

    Evidence K310 site-directed mutagenesis, β-arrestin and GTPγS assays, endocytosis, conformation-specific antibodies, and allosteric antagonist mapping

    PMID:24534492 PMID:24563252

    Open questions at the time
    • structural basis of the two conformations not solved
    • biological consequence of bias in vivo unmeasured
    • kinase pathways downstream of each conformation not separated
  6. 2014 High

    Connected CCR4 C-terminal biology to oncogenesis by showing ATLL truncating mutations impair internalization to enhance PI3K/AKT signaling and growth.

    Evidence Transcriptome sequencing of ATLL samples plus migration, internalization, signaling, and long-term growth assays of CCR4-Q330

    PMID:25488980

    Open questions at the time
    • mechanism linking sustained signaling to clonal selection in patients incomplete
    • interaction with HBZ/AP-1 regulation not integrated
    • in vivo tumor model not used
  7. 2015 High

    Defined a non-inflammatory developmental role for CCR4 in central tolerance, answering how thymocytes reach the medulla for negative selection.

    Evidence Two-photon imaging and negative selection assays in CCR4-knockout mice across polyclonal and TCR-transgenic settings

    PMID:26417005

    Open questions at the time
    • medullary chemokine gradient source not fully defined
    • relative contribution of CCR4 vs other receptors in thymus unresolved
  8. 2016 Medium

    Explained virally driven CCR4 induction by showing HTLV-1 HBZ upregulates CCR4 through GATA3, linking infection to receptor expression and T-cell migration/proliferation.

    Evidence HBZ gain/loss of function, GATA3 promoter analysis, and CCR4 antagonist in HBZ transgenic mouse migration model

    PMID:27402079

    Open questions at the time
    • interplay with Fra-2/JunD regulation not tested together
    • direct GATA3 binding to promoter not structurally confirmed
  9. 2017 Medium

    Established CCR4 as a pro-metastatic driver in solid tumors operating through ERK/NF-κB/MMP and ERK/AKT/MMP cascades rather than proliferation.

    Evidence Gain/loss of function with pathway inhibitors and in vivo metastasis models in colorectal, hepatocellular, breast, and melanoma cells

    PMID:21479551 PMID:27356745 PMID:28415693 PMID:28959024

    Open questions at the time
    • chemokine ligand specificity across tumor types varies (CCL17/CCL22/CCL2)
    • single-lab mechanisms per cancer
    • in vivo ligand source not always defined
  10. 2017 Medium

    Identified HDAC2 as an epigenetic regulator of CCR4 expression, providing a therapeutic rationale for HDAC inhibitor downregulation of the receptor.

    Evidence Isoform-specific HDAC siRNA, CCR4 flow/qRT-PCR, and pre/post-vorinostat patient skin biopsies

    PMID:29025909

    Open questions at the time
    • mechanism of HDAC2 action on CCR4 locus not detailed
    • relationship to AP-1/GATA3 regulation untested
  11. 2018 Medium

    Confirmed CCR4's pivotal role in skin allergic inflammation and broadened drug-resistance signaling, showing CCR4 recruits Th2/Th17 cells and supports tumor-associated macrophage-induced chemoresistance.

    Evidence CCR4-deficient mice plus antagonist in atopic dermatitis model; coculture and PI3K/AKT-ER stress dissection in colorectal cancer

    PMID:29510192 PMID:37658050

    Open questions at the time
    • chemoresistance pathway from receptor to MRP1 has many single-lab steps
    • skin model does not separate Th2 from Th17 contribution mechanistically
  12. 2020 Medium

    Extended CCR4 signaling to CNS resident cells, showing CCL17 activation of microglial CCR4 promotes hematoma resolution via an ERK/Nrf2/CD163 axis.

    Evidence Intracerebral hemorrhage model with C021, ML385, and CD163 CRISPR knockout, Western blot and immunofluorescence

    PMID:32783091

    Open questions at the time
    • ligand bias of CCL17 in microglia not addressed
    • single-lab pathway hierarchy
  13. 2022 High

    Demonstrated direct neuronal CCR4 function in pain and a Vav2-Rac1/MLC motility mechanism, expanding CCR4 beyond leukocyte chemotaxis.

    Evidence Electrophysiology of sensory neurons, CCR4 knockout/siRNA/antagonist and DC depletion in postoperative pain; Co-IP of Vav2-Rac1 with phospho-MLC in HNSCC

    PMID:35046040 PMID:35177591

    Open questions at the time
    • intracellular pathway from CCR4 to neuronal excitability not fully mapped
    • Vav2-Rac1 coupling shown by single Co-IP
    • CCL2-CCR4 axis specificity needs broader validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ligand-biased CCR4 conformations are decoded into distinct downstream pathways (β-arrestin vs G protein vs PI3K/AKT vs ERK) across the diverse cell types expressing the receptor remains unresolved.
  • no structural model of CCL17- vs CCL22-bound conformations
  • unifying framework linking receptor trafficking state to signaling output absent
  • cell-type-specific effector wiring not systematically compared

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098631 cell adhesion mediator activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3
Partners
ARRBCCL17CCL2CCL22RAC1VAV2

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Human and murine CCR4 bind MIP-1α and RANTES with high affinity (IC50 ~10-15 nM) in equilibrium competition binding assays in transfected HL-60 cells, establishing CCR4 as a functional chemokine receptor with conserved ligand-binding properties between species. Radioligand competition binding assay in CCR4-transfected HL-60 cells; Northern blot for tissue distribution Biochemical and biophysical research communications Medium 8573157
2001 CCR4 is functionally expressed on human platelets; its ligands MDC (CCL22) and TARC (CCL17) induce platelet aggregation and calcium flux via CCR4, as confirmed by anti-CCR4 mAb blockade. CCL22 fully desensitized CCL17-induced calcium mobilization (cross-desensitization), and platelet aggregation required cyclooxygenase metabolites and plasma components. Flow cytometry, immunoprecipitation/Western blot, calcium flux assay, platelet aggregation assay, anti-CCR4 mAb inhibition Thrombosis research Medium 11248289
2002 CCR4 is expressed on human platelets; CCR4 protein was detected by immunoprecipitation and Western blotting at levels comparable to monocytes, and CCR4 ligands TARC and MDC activated platelets to produce Ca2+ signals, aggregation, and granule release. PCR, flow cytometry, immunoprecipitation, Western blot, functional platelet activation assays Blood Medium 11110672
2008 CCR4 is required for efficient entry of antigen-specific Th2 cells into the lung and airways in allergic pulmonary inflammation; CCR4-deficient Th2 cells showed impaired trafficking into the lung, reduced Th2 cytokine levels in airways, and decreased eosinophilia and mucus production, demonstrated by adoptive transfer experiments. Adoptive transfer of CCR4-deficient vs. wild-type antigen-specific Th2 cells in murine allergic pulmonary inflammation model The Journal of allergy and clinical immunology High 19062085
2014 Somatic gain-of-function truncating mutations in CCR4 (at C329, Q330, or Y331 in the carboxy terminus) occur in 26% of ATLL samples; the CCR4-Q330 nonsense isoform impairs receptor internalization, increases cell migration toward CCL17 and CCL22, enhances PI3K/AKT activation after CCL22 engagement, and confers a growth advantage in long-term in vitro cultures. Whole transcriptome sequencing of patient samples, functional migration assays, receptor internalization assays, PI3K/AKT signaling assays, long-term in vitro growth assays The Journal of experimental medicine High 25488980
2014 CCR4 exists in at least two distinct conformational states differentially activated by its ligands. CCL22 is a dominant ligand showing superiority in receptor endocytosis and competitive binding assays. A single C-terminal residue K310 is required for CCL17-induced but not CCL22-induced CCR4 activation, without affecting binding of either ligand, demonstrating that CCL17 and CCL22 are conformationally selective ligands that interact with CCR4 by substantially different mechanisms. Calcium flux assay, chemotaxis assay, receptor endocytosis assay, competitive ligand binding assay, site-directed mutagenesis (K310 mutation), conformation-specific antibody epitope mapping Journal of immunology High 24563252
2014 CCR4 receptor internalization can be evoked not only by its agonists but also by orthosteric and allosteric antagonists. CCL22 couples CCR4 efficiently to β-arrestin and stimulates GTPγS binding whereas CCL17 does not couple to β-arrestin and only partially stimulates GTPγS binding. CCL22 potently induces internalization of nearly all surface CCR4, while CCL17 shows only weak internalization effects. Small molecule antagonists binding at two distinct allosteric sites inhibit chemotaxis but only one allosteric site evokes receptor internalization. β-arrestin recruitment assay, GTPγS binding assay, receptor internalization assay (flow cytometry), chemotaxis assay, competitive binding with allosteric antagonists European journal of pharmacology High 24534492
2015 CCR4 promotes medullary entry of post-positive selection thymocytes and efficient thymocyte-dendritic cell interactions required for central tolerance. Using two-photon time-lapse microscopy in CCR4-deficient mice, loss of CCR4 impaired medullary entry of thymocytes, reduced interactions with medullary DCs, impaired negative selection, and led to accumulation of autoreactive T cells in secondary lymphoid organs and autoimmunity. Two-photon time-lapse microscopy, CCR4-knockout mouse model, negative selection assays with polyclonal and TCR transgenic thymocytes The Journal of experimental medicine High 26417005
2007 Fra-2/JunD heterodimers drive CCR4 expression in ATL cells by activating an AP-1 site in the CCR4 promoter. Fra-2 siRNA and JunD siRNA (but not JunB siRNA) reduced CCR4 expression and cell growth in ATL cells, and Fra-2/JunD overexpression promoted growth in Jurkat cells. Promoter reporter assay, siRNA knockdown, overexpression studies, gene expression profiling Oncogene Medium 18071306
2016 The HTLV-1 bZIP factor HBZ induces CCR4 expression in T cells by stimulating GATA3 expression, which activates transcription from the CCR4 promoter. HBZ-induced CCR4 promotes T-cell migration and proliferation; CCR4 antagonist inhibited CD4+ T-cell migration in HBZ transgenic mice, and CCL17/CCL22 enhanced CD4+ T-cell proliferation. Ectopic HBZ expression in human and mouse T cells, HBZ siRNA knockdown in ATL cell lines, CCR4 promoter analysis (GATA3), air pouch migration model in HBZ transgenic mice, CCR4 antagonist treatment Cancer research Medium 27402079
2018 CCR4 deficiency or pharmacological CCR4 antagonism ameliorates allergic skin responses in a BALB/c atopic dermatitis model, demonstrating CCR4 plays a pivotal role in skin allergic inflammation by recruiting CCR4-expressing Th2 and Th17 cells. CCR4-deficient mouse model, CCR4 antagonist treatment, transcutaneous sensitization model in BALB/c mice, histological and cytokine analyses The Journal of investigative dermatology Medium 29510192
2020 CCR4 activation by CCL17 (rCCL17) promotes hematoma resolution after intracerebral hemorrhage in mice via the CCR4/ERK/Nrf2/CD163 signaling pathway. CCR4 is expressed by microglia, and rCCL17 phosphorylated ERK1/2, increased Nrf2 expression, and upregulated CD163, improving neurological outcomes; these effects were blocked by CCR4 inhibitor C021, Nrf2 inhibitor ML385, or CD163 CRISPR knockout. Intracerebral hemorrhage mouse model, rCCL17 intranasal administration, pharmacological inhibitors (C021, ML385), CRISPR knockout (CD163), Western blot, immunofluorescence Neurotherapeutics Medium 32783091
2020 CCR4 cell surface expression is tightly regulated by ligand-induced endocytosis and degradation. CCL17 and CCL22 drive rapid dose-dependent endocytosis; replenishment is slow and sensitive to cycloheximide (requiring de novo synthesis). Truncation of the CCR4 C-terminus by 40 amino acids impairs ligand-induced (but not constitutive) endocytosis, significantly enhancing migration to both ligands. Flow cytometry for CCR4 surface expression and endocytosis, cycloheximide treatment, C-terminal truncation mutants, chemotaxis assay in transfectants and human Th2 cells Journal of leukocyte biology Medium 32052476
2022 CCR4 on sensory neurons mediates postoperative pain. Skin-resident dendritic/Langerhans cells upregulate CCL17 and CCL22 after tissue injury; these act on CCR4-expressing peripheral sensory neurons to directly activate and sensitize them. Electrophysiology showed CCL22 directly activates dissociated sensory neurons and enhances excitability post-injury; CCR4 blockade or genetic silencing (siRNA), as well as CCR4 knockout mice and transgenic DC-depleted mice, significantly reduced acute postoperative pain. Electrophysiology of dissociated sensory neurons, CCR4 knockout mice, CCR4 siRNA knockdown, pharmacological CCR4 antagonist (C021), transgenic DC-depletion, subcutaneous CCL22 injection pain behavior assays Proceedings of the National Academy of Sciences of the United States of America High 35046040
2011 CCR4 overexpression in breast cancer cells promotes tumor growth and lung metastasis in mice; CCR4 knockdown reduces these effects. CCR4 overexpression enhances chemotaxis toward CCL17 and increases microvessel density in tumors in vivo, but does not affect proliferation in vitro, suggesting CCR4 promotes metastasis and angiogenesis rather than direct proliferation. CCR4 overexpression and RNA interference in breast cancer cell lines, mouse xenograft model, chemotaxis assay, microvessel density measurement Breast cancer research and treatment Medium 21479551
2016 CCR4 promotes colorectal cancer metastasis via the ERK/NF-κB/MMP13 signaling pathway. CCR4 silencing attenuated invasion and metastasis while CCR4 overexpression enhanced them. TNF-α upregulates CCR4 expression through NF-κB activation, placing CCR4 downstream of TNF-α in CRC cells. CCR4 siRNA knockdown, overexpression, in vitro invasion assay, in vivo mouse model, MMP13 expression analysis, ERK/NF-κB pathway inhibitors, TNF-α stimulation Oncotarget Medium 27356745
2017 CCR4 in hepatocellular carcinoma cells promotes metastasis and EMT via ERK/AKT/MMP2 pathway; MMP2 was identified as a direct downstream target of CCR4. CCR4 overexpression promoted tumor growth in vivo, potentially via neovascularization, but did not affect proliferation in vitro. CCR4 overexpression and knockdown in HCC cell lines, in vivo tumor growth assay, in vitro invasion/migration assay, pathway analysis (ERK/AKT), MMP2 expression Scientific reports Medium 28959024
2017 CCR4 is a determinant of melanoma brain metastasis; CCL22 and CCL17 are upregulated in the brain at earliest stages of metastasis preceding melanoma infiltration. CCL17 induced migration and transendothelial migration of melanoma cells in vitro. CCR4-overexpressing melanoma cells produced higher loads of brain micrometastasis in vivo; CCR4 antagonist reduced tumorigenicity and micrometastasis formation. CCR4 overexpression in melanoma cells, in vitro chemotaxis and transendothelial migration assay, in vivo spontaneous brain micrometastasis model, CCR4 small molecule antagonist Oncotarget Medium 28415693
2022 CCR4-mediated cell migration in head and neck squamous cell carcinoma is driven by the CCL2-CCR4 axis (not CCL2-CCR2), which induces formation of a Vav2-Rac1 complex and phosphorylation of myosin light chain (MLC) to regulate cell motility. CCR4 knockdown/overexpression, co-immunoprecipitation of Vav2-Rac1, phospho-MLC assay, migration assay, CCR4 vs. CCR2 axis discrimination Cell death & disease Medium 35177591
2017 CCL17-induced IFN-γ production is reduced when Th1-polarized CD4+ T cells are exposed to CCR4 ligand, demonstrating direct involvement of CCR4 signaling in Th1/Th2 immune balance. Cytokine production assay from Th1-polarized normal CD4+ T cells treated with CCR4 ligand CCL17 The Journal of clinical investigation Low 28134623
2008 CCR4 is functionally expressed on epidermal keratinocytes; CCL17 (CCR4 ligand) but not CCL27 (CCR10 ligand) induced production of IL-12 p40, GM-CSF, and NGF by keratinocytes; both CCL17 and CCL27 induced keratinocyte migration in Boyden chamber and wound scratch assays. RT-PCR, protein expression (mRNA/protein level in normal human keratinocytes and HaCaT cells), cytokine ELISA, Boyden chamber migration, wound scratch assay Cytokine Medium 18782672
2018 CCR4 on CRC cells mediates TAM-induced 5-FU resistance via PI3K/AKT activation downstream of CCL17 and CCL22 signaling, leading to inactivation of IP3R, ER calcium aggregation, ATF6 activation, GRP78 upregulation, and MRP1 membrane translocation to promote drug efflux. Cell-cell coculture, CCR4 signaling pathway analysis (PI3K/AKT, IP3R, ER stress markers), GRP78-MRP1 interaction studies, drug efflux assays Cell death & disease Medium 37658050
2017 HDAC2 regulates CCR4 expression in T-cell lymphoma cells; HDAC2 knockdown (using isoform-specific siRNA) reduces CCR4 mRNA and surface protein levels most efficiently among class I HDACs, and vorinostat (pan-HDAC inhibitor) downregulates CCR4 expression in vitro and in clinical skin samples. siRNA knockdown of specific HDAC isoforms, surface CCR4 flow cytometry, CCR4 mRNA qRT-PCR, patient skin biopsy analysis pre/post vorinostat treatment Haematologica Medium 29025909

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 CCR4 and its ligands: from bench to bedside. International immunology 346 25087232
2011 The Ccr4--not complex. Gene 236 22027279
2002 Increased CCR4 expression in cutaneous T cell lymphoma. The Journal of investigative dermatology 225 12485447
2020 The Ccr4-Not complex monitors the translating ribosome for codon optimality. Science (New York, N.Y.) 212 32299921
2002 CCR4, a 3'-5' poly(A) RNA and ssDNA exonuclease, is the catalytic component of the cytoplasmic deadenylase. The EMBO journal 209 11889047
2000 Functional expression of CCR1, CCR3, CCR4, and CXCR4 chemokine receptors on human platelets. Blood 201 11110672
2013 RNA decay machines: deadenylation by the Ccr4-not and Pan2-Pan3 complexes. Biochimica et biophysica acta 197 23337855
2002 Expression of the chemokine receptors CCR4, CCR5, and CXCR3 by human tissue-infiltrating lymphocytes. The American journal of pathology 197 11786428
2006 CCR4 as a novel molecular target for immunotherapy of cancer. Cancer science 196 16952304
2012 Ccr4-Not complex: the control freak of eukaryotic cells. Critical reviews in biochemistry and molecular biology 146 22416820
2021 Intratumoral stem-like CCR4+ regulatory T cells orchestrate the immunosuppressive microenvironment in HCC associated with hepatitis B. Journal of hepatology 136 34689996
2000 Isolation and characterization of human orthologs of yeast CCR4-NOT complex subunits. Nucleic acids research 135 10637334
2014 Gain-of-function CCR4 mutations in adult T cell leukemia/lymphoma. The Journal of experimental medicine 129 25488980
2003 The CCR4-NOT complex plays diverse roles in mRNA metabolism. Progress in nucleic acid research and molecular biology 121 12882519
2017 The C-C Chemokines CCL17 and CCL22 and Their Receptor CCR4 in CNS Autoimmunity. International journal of molecular sciences 108 29099057
2008 Contribution of CCR4 and CCR8 to antigen-specific T(H)2 cell trafficking in allergic pulmonary inflammation. The Journal of allergy and clinical immunology 105 19062085
2009 The Ccr4-NOT deadenylase subunits CNOT7 and CNOT8 have overlapping roles and modulate cell proliferation. Molecular biology of the cell 97 19605561
2021 CCR4 as a Therapeutic Target for Cancer Immunotherapy. Cancers 93 34771703
2019 Reconstitution of recombinant human CCR4-NOT reveals molecular insights into regulated deadenylation. Nature communications 87 31320642
2018 Mogamulizumab (Anti-CCR4) in HTLV-1-Associated Myelopathy. The New England journal of medicine 86 29414279
2001 The CC chemokines MDC and TARC induce platelet activation via CCR4. Thrombosis research 81 11248289
2017 A CCR4 antagonist reverses the tumor-promoting microenvironment of renal cancer. The Journal of clinical investigation 77 28134623
2011 The chemokine receptor CCR4 promotes tumor growth and lung metastasis in breast cancer. Breast cancer research and treatment 77 21479551
2009 Expression of MDC/CCL22 and its receptor CCR4 in rheumatoid arthritis, psoriatic arthritis and osteoarthritis. Cytokine 69 19942450
1996 Molecular cloning of murine CC CKR-4 and high affinity binding of chemokines to murine and human CC CKR-4. Biochemical and biophysical research communications 68 8573157
2016 miRISC and the CCR4-NOT complex silence mRNA targets independently of 43S ribosomal scanning. The EMBO journal 65 27009120
2015 CCR4 promotes medullary entry and thymocyte-dendritic cell interactions required for central tolerance. The Journal of experimental medicine 65 26417005
2019 RNA-binding proteins distinguish between similar sequence motifs to promote targeted deadenylation by Ccr4-Not. eLife 64 30601114
2007 Aberrant expression of Fra-2 promotes CCR4 expression and cell proliferation in adult T-cell leukemia. Oncogene 63 18071306
2007 CCR4/NOT complex associates with the proteasome and regulates histone methylation. Proceedings of the National Academy of Sciences of the United States of America 62 17389396
2012 Deadenylation of cytoplasmic mRNA by the mammalian Ccr4-Not complex. Biochemical Society transactions 61 22817755
2018 The CCR4-NOT deadenylase complex controls Atg7-dependent cell death and heart function. Science signaling 60 29438013
2017 CCR4 is a determinant of melanoma brain metastasis. Oncotarget 58 28415693
2016 HTLV-1 Viral Factor HBZ Induces CCR4 to Promote T-cell Migration and Proliferation. Cancer research 58 27402079
2010 The structural basis for deadenylation by the CCR4-NOT complex. Protein & cell 57 21203959
2020 The Regulatory Properties of the Ccr4-Not Complex. Cells 56 33138308
2014 Recent progress in the development of antagonists to the chemokine receptors CCR3 and CCR4. Expert opinion on drug discovery 54 24641500
2010 Immunopathogenesis of lymphoma: focus on CCR4. Cancer science 54 21044233
2022 Regulation of the multisubunit CCR4-NOT deadenylase in the initiation of mRNA degradation. Current opinion in structural biology 52 36116370
2017 Up-regulation of chemokine receptor CCR4 is associated with Human Hepatocellular Carcinoma malignant behavior. Scientific reports 52 28959024
2015 Identification of novel HIV-1 dependency factors in primary CCR4(+)CCR6(+)Th17 cells via a genome-wide transcriptional approach. Retrovirology 52 26654242
2009 The CCR4-NOT complex physically and functionally interacts with TRAMP and the nuclear exosome. PloS one 52 19707589
2014 Internalization of the chemokine receptor CCR4 can be evoked by orthosteric and allosteric receptor antagonists. European journal of pharmacology 50 24534492
2014 Novel roles of the multi-functional CCR4-NOT complex in post-transcriptional regulation. Frontiers in genetics 50 24904636
2021 CCR4 in cutaneous T-cell lymphoma: Therapeutic targeting of a pathogenic driver. European journal of immunology 47 33811642
2018 CCR4 Is Critically Involved in Skin Allergic Inflammation of BALB/c Mice. The Journal of investigative dermatology 47 29510192
2015 Ccr4-Not and TFIIS Function Cooperatively To Rescue Arrested RNA Polymerase II. Molecular and cellular biology 46 25776559
2020 Recombinant CCL17 Enhances Hematoma Resolution and Activation of CCR4/ERK/Nrf2/CD163 Signaling Pathway After Intracerebral Hemorrhage in Mice. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 45 32783091
2023 Tumor-associated macrophages confer colorectal cancer 5-fluorouracil resistance by promoting MRP1 membrane translocation via an intercellular CXCL17/CXCL22-CCR4-ATF6-GRP78 axis. Cell death & disease 43 37658050
2017 The Ccr4-Not Complex: Architecture and Structural Insights. Sub-cellular biochemistry 43 28271483
2016 The architecture of the Schizosaccharomyces pombe CCR4-NOT complex. Nature communications 43 26804377
2012 The control of elongation by the yeast Ccr4-not complex. Biochimica et biophysica acta 43 22975735
2023 Identifying highly active anti-CCR4 CAR T cells for the treatment of T-cell lymphoma. Blood advances 42 37058474
2023 Specific recognition and ubiquitination of translating ribosomes by mammalian CCR4-NOT. Nature structural & molecular biology 42 37653243
2016 CCR4 promotes metastasis via ERK/NF-κB/MMP13 pathway and acts downstream of TNF-α in colorectal cancer. Oncotarget 41 27356745
2015 Targeting chemokine receptors in disease--a case study of CCR4. European journal of pharmacology 41 25981299
2014 Mogamulizumab and the treatment of CCR4-positive T-cell lymphomas. Immunotherapy 41 25496334
2010 CC chemokine receptor 4 (CCR4) in human allergen-induced late nasal responses. Allergy 41 20148806
2022 CC Chemokine Receptor 4 (CCR4) as a Possible New Target for Therapy. International journal of molecular sciences 40 36555280
2014 The Not4 E3 ligase and CCR4 deadenylase play distinct roles in protein quality control. PloS one 39 24465968
2014 Distinct conformations of the chemokine receptor CCR4 with implications for its targeting in allergy. Journal of immunology (Baltimore, Md. : 1950) 38 24563252
2022 Resistance to mogamulizumab is associated with loss of CCR4 in cutaneous T-cell lymphoma. Blood 37 35436328
2022 Skin-resident dendritic cells mediate postoperative pain via CCR4 on sensory neurons. Proceedings of the National Academy of Sciences of the United States of America 36 35046040
2018 Role of Chemokine Receptor CCR4 and Regulatory T Cells in Wound Healing of Diabetic Mice. The Journal of investigative dermatology 36 30465800
2015 Ccr4-not regulates RNA polymerase I transcription and couples nutrient signaling to the control of ribosomal RNA biogenesis. PLoS genetics 36 25815716
2012 Targeting chemokine receptor CCR4 in adult T-cell leukemia-lymphoma and other T-cell lymphomas. Current hematologic malignancy reports 36 22538464
2006 Antagonists of CCR4 as immunomodulatory agents. Current topics in medicinal chemistry 35 16918452
2024 Specific tRNAs promote mRNA decay by recruiting the CCR4-NOT complex to translating ribosomes. Science (New York, N.Y.) 34 39571015
2021 Dermatologic Events Associated with the Anti-CCR4 Antibody Mogamulizumab: Characterization and Management. Dermatology and therapy 34 34816383
2019 Hepatic posttranscriptional network comprised of CCR4-NOT deadenylase and FGF21 maintains systemic metabolic homeostasis. Proceedings of the National Academy of Sciences of the United States of America 34 30926667
2022 Targeting CCL2-CCR4 axis suppress cell migration of head and neck squamous cell carcinoma. Cell death & disease 33 35177591
2020 ANGEL2 is a member of the CCR4 family of deadenylases with 2',3'-cyclic phosphatase activity. Science (New York, N.Y.) 33 32732418
2013 Heterogeneity and complexity within the nuclease module of the Ccr4-Not complex. Frontiers in genetics 33 24391663
2002 Expression of CC chemokine receptor 4 (CCR4) mRNA in canine atopic skin lesion. Veterinary immunology and immunopathology 33 12459162
2019 Ccr4-Not maintains genomic integrity by controlling the ubiquitylation and degradation of arrested RNAPII. Genes & development 32 30948432
2023 Regulation of eukaryotic mRNA deadenylation and degradation by the Ccr4-Not complex. Frontiers in cell and developmental biology 31 37152278
2015 The enzyme activities of Caf1 and Ccr4 are both required for deadenylation by the human Ccr4-Not nuclease module. The Biochemical journal 31 25944446
2015 Clinical Application of Anti-CCR4 Monoclonal Antibody. Oncology 31 26550987
2014 Insights into the structure and architecture of the CCR4-NOT complex. Frontiers in genetics 31 24904637
2008 CCR4 and CCR10 are expressed on epidermal keratinocytes and are involved in cutaneous immune reaction. Cytokine 29 18782672
2012 Human anti-CCR4 minibody gene transfer for the treatment of cutaneous T-cell lymphoma. PloS one 28 22973452
2011 Aberrant expression of chemokine receptor CCR4 in human gastric cancer contributes to tumor-induced immunosuppression. Cancer science 28 21443538
2020 CCR4, a RNA decay factor, is hijacked by a plant cytorhabdovirus phosphoprotein to facilitate virus replication. eLife 27 32207684
2020 CCR4 Antagonist (C021) Administration Diminishes Hypersensitivity and Enhances the Analgesic Potency of Morphine and Buprenorphine in a Mouse Model of Neuropathic Pain. Frontiers in immunology 27 32760393
2016 Interaction of CCR4-NOT with EBF1 regulates gene-specific transcription and mRNA stability in B lymphopoiesis. Genes & development 27 27807034
2023 Clinical and molecular effects of oral CCR4 antagonist RPT193 in atopic dermatitis: A Phase 1 study. Allergy 26 37984453
2020 Nuclear Ccr4-Not mediates the degradation of telomeric and transposon transcripts at chromatin in the Drosophila germline. Nucleic acids research 25 31724732
2020 Radiation-Enhanced Expression of CCL22 in Nasopharyngeal Carcinoma is Associated With CCR4+ CD8 T Cell Recruitment. International journal of radiation oncology, biology, physics 25 32428547
2017 Discovery of AZD-2098 and AZD-1678, Two Potent and Bioavailable CCR4 Receptor Antagonists. ACS medicinal chemistry letters 25 28947948
2007 The Ccr4-not complex regulates Skn7 through Srb10 kinase. Eukaryotic cell 25 17965252
2023 RNA binding proteins Smaug and Cup induce CCR4-NOT-dependent deadenylation of the nanos mRNA in a reconstituted system. Nucleic acids research 24 36951092
2021 Crystal structure and functional properties of the human CCR4-CAF1 deadenylase complex. Nucleic acids research 24 34038562
2022 CCR4 and CCR5 Involvement in Monocyte-Derived Macrophage Migration in Neuroinflammation. Frontiers in immunology 23 35634277
2020 A degradatory fate for CCR4 suggests a primary role in Th2 inflammation. Journal of leukocyte biology 23 32052476
2015 The abnormal expression of CCR4 and CCR6 on Tregs in rheumatoid arthritis. International journal of clinical and experimental medicine 23 26628988
2023 Roles of the CCR4-Not complex in translation and dynamics of co-translation events. Wiley interdisciplinary reviews. RNA 22 38009591
2020 The CCR4-NOT complex maintains liver homeostasis through mRNA deadenylation. Life science alliance 22 32238456
2017 Histone deacetylase inhibitors downregulate CCR4 expression and decrease mogamulizumab efficacy in CCR4-positive mature T-cell lymphomas. Haematologica 22 29025909
2008 CCR4 and CCR10 ligands play additive roles in mouse contact hypersensitivity. Experimental dermatology 22 18095942
2018 CCL17-CCR4 axis promotes metastasis via ERK/MMP13 pathway in bladder cancer. Journal of cellular biochemistry 21 30230587

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