{"gene":"CCR4","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1996,"finding":"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.","method":"Radioligand competition binding assay in CCR4-transfected HL-60 cells; Northern blot for tissue distribution","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay in transfected cells, both human and murine receptors tested with two ligands, single lab","pmids":["8573157"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Flow cytometry, immunoprecipitation/Western blot, calcium flux assay, platelet aggregation assay, anti-CCR4 mAb inhibition","journal":"Thrombosis research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (Ca2+ flux, aggregation, mAb blockade, cross-desensitization) in primary human platelets, single lab","pmids":["11248289"],"is_preprint":false},{"year":2002,"finding":"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.","method":"PCR, flow cytometry, immunoprecipitation, Western blot, functional platelet activation assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (IP, WB, functional assays), corroborates findings in PMID:11248289","pmids":["11110672"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Adoptive transfer of CCR4-deficient vs. wild-type antigen-specific Th2 cells in murine allergic pulmonary inflammation model","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with adoptive transfer, specific phenotypic readouts (cell trafficking, cytokines, eosinophilia, mucus), replicated across multiple cell types tested as controls","pmids":["19062085"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Whole transcriptome sequencing of patient samples, functional migration assays, receptor internalization assays, PI3K/AKT signaling assays, long-term in vitro growth assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal functional assays (migration, internalization, signaling, growth), patient samples plus functional validation, single lab but rigorous multi-method approach","pmids":["25488980"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Calcium flux assay, chemotaxis assay, receptor endocytosis assay, competitive ligand binding assay, site-directed mutagenesis (K310 mutation), conformation-specific antibody epitope mapping","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis combined with multiple functional assays (calcium, chemotaxis, endocytosis, binding), two conformation-selective antibodies used, mechanistically rigorous","pmids":["24563252"],"is_preprint":false},{"year":2014,"finding":"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.","method":"β-arrestin recruitment assay, GTPγS binding assay, receptor internalization assay (flow cytometry), chemotaxis assay, competitive binding with allosteric antagonists","journal":"European journal of pharmacology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal functional assays defining distinct signaling pathways, allosteric site mapping, biased agonism between CCL17 and CCL22 established","pmids":["24534492"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Two-photon time-lapse microscopy, CCR4-knockout mouse model, negative selection assays with polyclonal and TCR transgenic thymocytes","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct live imaging combined with genetic knockout, multiple phenotypic readouts (medullary entry, DC interactions, negative selection, autoimmunity), replicated across polyclonal and transgenic settings","pmids":["26417005"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Promoter reporter assay, siRNA knockdown, overexpression studies, gene expression profiling","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter assay, siRNA, and overexpression all in single lab; mechanistic link between AP-1 site, Fra-2/JunD, and CCR4 expression established","pmids":["18071306"],"is_preprint":false},{"year":2016,"finding":"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.","method":"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","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain and loss of function for HBZ, promoter mechanism via GATA3, in vivo migration model, single lab","pmids":["27402079"],"is_preprint":false},{"year":2018,"finding":"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.","method":"CCR4-deficient mouse model, CCR4 antagonist treatment, transcutaneous sensitization model in BALB/c mice, histological and cytokine analyses","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout plus pharmacological blockade with multiple phenotypic readouts, single lab","pmids":["29510192"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Intracerebral hemorrhage mouse model, rCCL17 intranasal administration, pharmacological inhibitors (C021, ML385), CRISPR knockout (CD163), Western blot, immunofluorescence","journal":"Neurotherapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway inhibitors and CRISPR used to establish signaling hierarchy, single lab","pmids":["32783091"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Flow cytometry for CCR4 surface expression and endocytosis, cycloheximide treatment, C-terminal truncation mutants, chemotaxis assay in transfectants and human Th2 cells","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis combined with functional assays, multiple cell types, single lab","pmids":["32052476"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Electrophysiology of dissociated sensory neurons, CCR4 knockout mice, CCR4 siRNA knockdown, pharmacological CCR4 antagonist (C021), transgenic DC-depletion, subcutaneous CCL22 injection pain behavior assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal approaches (electrophysiology, KO, siRNA, pharmacological, DC depletion) across in vitro and in vivo systems establishing direct neuronal CCR4 function","pmids":["35046040"],"is_preprint":false},{"year":2011,"finding":"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.","method":"CCR4 overexpression and RNA interference in breast cancer cell lines, mouse xenograft model, chemotaxis assay, microvessel density measurement","journal":"Breast cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain and loss of function in vivo and in vitro, single lab","pmids":["21479551"],"is_preprint":false},{"year":2016,"finding":"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.","method":"CCR4 siRNA knockdown, overexpression, in vitro invasion assay, in vivo mouse model, MMP13 expression analysis, ERK/NF-κB pathway inhibitors, TNF-α stimulation","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain and loss of function with pathway inhibitors establishing signaling hierarchy, single lab","pmids":["27356745"],"is_preprint":false},{"year":2017,"finding":"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.","method":"CCR4 overexpression and knockdown in HCC cell lines, in vivo tumor growth assay, in vitro invasion/migration assay, pathway analysis (ERK/AKT), MMP2 expression","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss of function with signaling pathway analysis, single lab","pmids":["28959024"],"is_preprint":false},{"year":2017,"finding":"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.","method":"CCR4 overexpression in melanoma cells, in vitro chemotaxis and transendothelial migration assay, in vivo spontaneous brain micrometastasis model, CCR4 small molecule antagonist","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain of function and pharmacological inhibition in vivo and in vitro, single lab","pmids":["28415693"],"is_preprint":false},{"year":2022,"finding":"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.","method":"CCR4 knockdown/overexpression, co-immunoprecipitation of Vav2-Rac1, phospho-MLC assay, migration assay, CCR4 vs. CCR2 axis discrimination","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing Vav2-Rac1 complex, gain/loss of function with mechanistic readouts, single lab","pmids":["35177591"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Cytokine production assay from Th1-polarized normal CD4+ T cells treated with CCR4 ligand CCL17","journal":"The Journal of clinical investigation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single in vitro functional assay, single lab, limited mechanistic detail in abstract","pmids":["28134623"],"is_preprint":false},{"year":2008,"finding":"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.","method":"RT-PCR, protein expression (mRNA/protein level in normal human keratinocytes and HaCaT cells), cytokine ELISA, Boyden chamber migration, wound scratch assay","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (cytokine production, migration) demonstrating receptor functionality in keratinocytes, single lab","pmids":["18782672"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Cell-cell coculture, CCR4 signaling pathway analysis (PI3K/AKT, IP3R, ER stress markers), GRP78-MRP1 interaction studies, drug efflux assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissection through multiple molecular assays and signaling inhibitors, single lab","pmids":["37658050"],"is_preprint":false},{"year":2017,"finding":"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.","method":"siRNA knockdown of specific HDAC isoforms, surface CCR4 flow cytometry, CCR4 mRNA qRT-PCR, patient skin biopsy analysis pre/post vorinostat treatment","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific siRNA with patient sample validation, single lab, establishes HDAC2 as epigenetic regulator of CCR4 expression","pmids":["29025909"],"is_preprint":false}],"current_model":"CCR4 is a seven-transmembrane G protein-coupled chemokine receptor for CCL17 and CCL22 that mediates directional migration of Th2 cells, regulatory T cells, and other CCR4-expressing cells to sites of inflammation (particularly skin, lung); it signals via Gα protein (GTPγS coupling), β-arrestin recruitment (preferentially by CCL22 but not CCL17), and downstream PI3K/AKT, ERK/NF-κB/MMP, and Nrf2 pathways; CCL22 and CCL17 are conformationally selective, biased ligands that activate distinct receptor conformations—CCL22 dominates receptor endocytosis and β-arrestin coupling while CCL17 requires residue K310 for activation; ligand-driven endocytosis leads to receptor degradation requiring de novo synthesis for replenishment; gain-of-function C-terminal truncation mutations in ATLL impair internalization to enhance sustained PI3K/AKT signaling and migration; transcriptionally, CCR4 is regulated by Fra-2/JunD AP-1 heterodimers, HTLV-1 HBZ via GATA3, and HDAC2-dependent chromatin modification; in the thymus, CCR4 mediates medullary entry of post-positive selection thymocytes and their interactions with dendritic cells required for central tolerance; on sensory neurons, CCR4 directly mediates pain signaling activated by skin-resident dendritic cell-derived CCL17/22."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1996,"claim":"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","pmids":["8573157"],"confidence":"Medium","gaps":["MIP-1α/RANTES binding not reconciled with later CCL17/CCL22 ligand assignment","no signaling output measured","no endogenous cell type tested"]},{"year":2001,"claim":"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","pmids":["11248289","11110672"],"confidence":"Medium","gaps":["downstream signaling beyond Ca2+ not dissected","physiological relevance of platelet CCR4 in vivo unclear","requirement for plasma cofactors not mechanistically resolved"]},{"year":2007,"claim":"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","pmids":["18071306"],"confidence":"Medium","gaps":["upstream signals activating Fra-2/JunD not defined","single-lab promoter mechanism","not linked to receptor mutation status"]},{"year":2008,"claim":"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","pmids":["19062085"],"confidence":"High","gaps":["chemokine source in lung not pinpointed","does not address non-Th2 CCR4 cells","ligand bias not considered"]},{"year":2014,"claim":"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","pmids":["24563252","24534492"],"confidence":"High","gaps":["structural basis of the two conformations not solved","biological consequence of bias in vivo unmeasured","kinase pathways downstream of each conformation not separated"]},{"year":2014,"claim":"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","pmids":["25488980"],"confidence":"High","gaps":["mechanism linking sustained signaling to clonal selection in patients incomplete","interaction with HBZ/AP-1 regulation not integrated","in vivo tumor model not used"]},{"year":2015,"claim":"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","pmids":["26417005"],"confidence":"High","gaps":["medullary chemokine gradient source not fully defined","relative contribution of CCR4 vs other receptors in thymus unresolved"]},{"year":2016,"claim":"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","pmids":["27402079"],"confidence":"Medium","gaps":["interplay with Fra-2/JunD regulation not tested together","direct GATA3 binding to promoter not structurally confirmed"]},{"year":2017,"claim":"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","pmids":["27356745","28959024","21479551","28415693"],"confidence":"Medium","gaps":["chemokine ligand specificity across tumor types varies (CCL17/CCL22/CCL2)","single-lab mechanisms per cancer","in vivo ligand source not always defined"]},{"year":2017,"claim":"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","pmids":["29025909"],"confidence":"Medium","gaps":["mechanism of HDAC2 action on CCR4 locus not detailed","relationship to AP-1/GATA3 regulation untested"]},{"year":2018,"claim":"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","pmids":["29510192","37658050"],"confidence":"Medium","gaps":["chemoresistance pathway from receptor to MRP1 has many single-lab steps","skin model does not separate Th2 from Th17 contribution mechanistically"]},{"year":2020,"claim":"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","pmids":["32783091"],"confidence":"Medium","gaps":["ligand bias of CCL17 in microglia not addressed","single-lab pathway hierarchy"]},{"year":2022,"claim":"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","pmids":["35046040","35177591"],"confidence":"High","gaps":["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"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"High","gaps":["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":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,5,6]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[3,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,5,12]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,7,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,14,15,16]}],"complexes":[],"partners":["CCL22","CCL17","ARRB","CCL2","VAV2","RAC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UK39","full_name":"Nocturnin","aliases":["Carbon catabolite repression 4-like protein"],"length_aa":431,"mass_kda":48.2,"function":"Phosphatase which catalyzes the conversion of NADP(+) to NAD(+) and of NADPH to NADH (PubMed:31147539). Shows a small preference for NADPH over NADP(+) (PubMed:31147539). Represses translation and promotes degradation of target mRNA molecules (PubMed:29860338). Plays an important role in post-transcriptional regulation of metabolic genes under circadian control (By similarity). Exerts a rhythmic post-transcriptional control of genes necessary for metabolic functions including nutrient absorption, glucose/insulin sensitivity, lipid metabolism, adipogenesis, inflammation and osteogenesis (By similarity). Plays an important role in favoring adipogenesis over osteoblastogenesis and acts as a key regulator of the adipogenesis/osteogenesis balance (By similarity). Promotes adipogenesis by facilitating PPARG nuclear translocation which activates its transcriptional activity (By similarity). Regulates circadian expression of NOS2 in the liver and negatively regulates the circadian expression of IGF1 in the bone (By similarity). Critical for proper development of early embryos (By similarity)","subcellular_location":"Cytoplasm; Nucleus; Cytoplasm, perinuclear region; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q9UK39/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCR4","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CCR4","total_profiled":1310},"omim":[{"mim_id":"621397","title":"PABPN1-LIKE, CYTOPLASMIC; PABPN1L","url":"https://www.omim.org/entry/621397"},{"mim_id":"620509","title":"CCR4-NOT TRANSCRIPTION COMPLEX, SUBUNIT 11; CNOT11","url":"https://www.omim.org/entry/620509"},{"mim_id":"620508","title":"CCR4-NOT TRANSCRIPTION COMPLEX, SUBUNIT 10; CNOT10","url":"https://www.omim.org/entry/620508"},{"mim_id":"620157","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 70; MRD70","url":"https://www.omim.org/entry/620157"},{"mim_id":"620155","title":"RABIN-PAPPAS SYNDROME; RAPAS","url":"https://www.omim.org/entry/620155"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":12.1},{"tissue":"urinary bladder","ntpm":5.1}],"url":"https://www.proteinatlas.org/search/CCR4"},"hgnc":{"alias_symbol":["CC-CKR-4","CMKBR4","CKR4","k5-5","ChemR13","CD194"],"prev_symbol":[]},"alphafold":{"accession":"Q9UK39","domains":[{"cath_id":"3.60.10.10","chopping":"128-424","consensus_level":"high","plddt":96.9309,"start":128,"end":424}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UK39","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UK39-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UK39-F1-predicted_aligned_error_v6.png","plddt_mean":82.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCR4","jax_strain_url":"https://www.jax.org/strain/search?query=CCR4"},"sequence":{"accession":"Q9UK39","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UK39.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UK39/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UK39"}},"corpus_meta":[{"pmid":"25087232","id":"PMC_25087232","title":"CCR4 and its ligands: from bench to bedside.","date":"2014","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25087232","citation_count":346,"is_preprint":false},{"pmid":"22027279","id":"PMC_22027279","title":"The Ccr4--not complex.","date":"2011","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/22027279","citation_count":236,"is_preprint":false},{"pmid":"12485447","id":"PMC_12485447","title":"Increased CCR4 expression in cutaneous T cell lymphoma.","date":"2002","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/12485447","citation_count":225,"is_preprint":false},{"pmid":"32299921","id":"PMC_32299921","title":"The Ccr4-Not complex monitors the translating ribosome for codon optimality.","date":"2020","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/32299921","citation_count":212,"is_preprint":false},{"pmid":"11889047","id":"PMC_11889047","title":"CCR4, a 3'-5' poly(A) RNA and ssDNA exonuclease, is the catalytic component of the cytoplasmic deadenylase.","date":"2002","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11889047","citation_count":209,"is_preprint":false},{"pmid":"11110672","id":"PMC_11110672","title":"Functional expression of CCR1, CCR3, CCR4, and CXCR4 chemokine receptors on human platelets.","date":"2000","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11110672","citation_count":201,"is_preprint":false},{"pmid":"23337855","id":"PMC_23337855","title":"RNA decay machines: deadenylation by the Ccr4-not and Pan2-Pan3 complexes.","date":"2013","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/23337855","citation_count":197,"is_preprint":false},{"pmid":"11786428","id":"PMC_11786428","title":"Expression of the chemokine receptors CCR4, CCR5, and CXCR3 by human tissue-infiltrating lymphocytes.","date":"2002","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/11786428","citation_count":197,"is_preprint":false},{"pmid":"16952304","id":"PMC_16952304","title":"CCR4 as a novel molecular target for immunotherapy of cancer.","date":"2006","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/16952304","citation_count":196,"is_preprint":false},{"pmid":"22416820","id":"PMC_22416820","title":"Ccr4-Not complex: the control freak of eukaryotic cells.","date":"2012","source":"Critical reviews in biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22416820","citation_count":146,"is_preprint":false},{"pmid":"34689996","id":"PMC_34689996","title":"Intratumoral stem-like CCR4+ regulatory T cells orchestrate the immunosuppressive microenvironment in HCC associated with hepatitis B.","date":"2021","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/34689996","citation_count":136,"is_preprint":false},{"pmid":"10637334","id":"PMC_10637334","title":"Isolation and characterization of human orthologs of yeast CCR4-NOT complex subunits.","date":"2000","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/10637334","citation_count":135,"is_preprint":false},{"pmid":"25488980","id":"PMC_25488980","title":"Gain-of-function CCR4 mutations in adult T cell leukemia/lymphoma.","date":"2014","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25488980","citation_count":129,"is_preprint":false},{"pmid":"12882519","id":"PMC_12882519","title":"The CCR4-NOT complex plays diverse roles in mRNA metabolism.","date":"2003","source":"Progress in nucleic acid research and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12882519","citation_count":121,"is_preprint":false},{"pmid":"29099057","id":"PMC_29099057","title":"The C-C Chemokines CCL17 and CCL22 and Their Receptor CCR4 in CNS Autoimmunity.","date":"2017","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29099057","citation_count":108,"is_preprint":false},{"pmid":"19062085","id":"PMC_19062085","title":"Contribution of CCR4 and CCR8 to antigen-specific T(H)2 cell trafficking in allergic pulmonary inflammation.","date":"2008","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19062085","citation_count":105,"is_preprint":false},{"pmid":"19605561","id":"PMC_19605561","title":"The Ccr4-NOT deadenylase subunits CNOT7 and CNOT8 have overlapping roles and modulate cell proliferation.","date":"2009","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/19605561","citation_count":97,"is_preprint":false},{"pmid":"34771703","id":"PMC_34771703","title":"CCR4 as a Therapeutic Target for Cancer Immunotherapy.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34771703","citation_count":93,"is_preprint":false},{"pmid":"31320642","id":"PMC_31320642","title":"Reconstitution of recombinant human CCR4-NOT reveals molecular insights into regulated deadenylation.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31320642","citation_count":87,"is_preprint":false},{"pmid":"29414279","id":"PMC_29414279","title":"Mogamulizumab (Anti-CCR4) in HTLV-1-Associated Myelopathy.","date":"2018","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29414279","citation_count":86,"is_preprint":false},{"pmid":"11248289","id":"PMC_11248289","title":"The CC chemokines MDC and TARC induce platelet activation via CCR4.","date":"2001","source":"Thrombosis research","url":"https://pubmed.ncbi.nlm.nih.gov/11248289","citation_count":81,"is_preprint":false},{"pmid":"21479551","id":"PMC_21479551","title":"The chemokine receptor CCR4 promotes tumor growth and lung metastasis in breast cancer.","date":"2011","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/21479551","citation_count":77,"is_preprint":false},{"pmid":"28134623","id":"PMC_28134623","title":"A CCR4 antagonist reverses the tumor-promoting microenvironment of renal cancer.","date":"2017","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/28134623","citation_count":77,"is_preprint":false},{"pmid":"19942450","id":"PMC_19942450","title":"Expression of MDC/CCL22 and its receptor CCR4 in rheumatoid arthritis, psoriatic arthritis and osteoarthritis.","date":"2009","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/19942450","citation_count":69,"is_preprint":false},{"pmid":"8573157","id":"PMC_8573157","title":"Molecular cloning of murine CC CKR-4 and high affinity binding of chemokines to murine and human CC CKR-4.","date":"1996","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/8573157","citation_count":68,"is_preprint":false},{"pmid":"26417005","id":"PMC_26417005","title":"CCR4 promotes medullary entry and thymocyte-dendritic cell interactions required for central tolerance.","date":"2015","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26417005","citation_count":65,"is_preprint":false},{"pmid":"27009120","id":"PMC_27009120","title":"miRISC and the CCR4-NOT complex silence mRNA targets independently of 43S ribosomal scanning.","date":"2016","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/27009120","citation_count":65,"is_preprint":false},{"pmid":"30601114","id":"PMC_30601114","title":"RNA-binding proteins distinguish between similar sequence motifs to promote targeted deadenylation by Ccr4-Not.","date":"2019","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/30601114","citation_count":64,"is_preprint":false},{"pmid":"18071306","id":"PMC_18071306","title":"Aberrant expression of Fra-2 promotes CCR4 expression and cell proliferation in adult T-cell leukemia.","date":"2007","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/18071306","citation_count":63,"is_preprint":false},{"pmid":"17389396","id":"PMC_17389396","title":"CCR4/NOT complex associates with the proteasome and regulates histone methylation.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17389396","citation_count":62,"is_preprint":false},{"pmid":"22817755","id":"PMC_22817755","title":"Deadenylation of cytoplasmic mRNA by the mammalian Ccr4-Not complex.","date":"2012","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/22817755","citation_count":61,"is_preprint":false},{"pmid":"29438013","id":"PMC_29438013","title":"The CCR4-NOT deadenylase complex controls Atg7-dependent cell death and heart function.","date":"2018","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/29438013","citation_count":60,"is_preprint":false},{"pmid":"28415693","id":"PMC_28415693","title":"CCR4 is a determinant of melanoma brain metastasis.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28415693","citation_count":58,"is_preprint":false},{"pmid":"27402079","id":"PMC_27402079","title":"HTLV-1 Viral Factor HBZ Induces CCR4 to Promote T-cell Migration and Proliferation.","date":"2016","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/27402079","citation_count":58,"is_preprint":false},{"pmid":"21203959","id":"PMC_21203959","title":"The structural basis for deadenylation by the CCR4-NOT complex.","date":"2010","source":"Protein & cell","url":"https://pubmed.ncbi.nlm.nih.gov/21203959","citation_count":57,"is_preprint":false},{"pmid":"33138308","id":"PMC_33138308","title":"The Regulatory Properties of the Ccr4-Not Complex.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/33138308","citation_count":56,"is_preprint":false},{"pmid":"21044233","id":"PMC_21044233","title":"Immunopathogenesis of lymphoma: focus on CCR4.","date":"2010","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/21044233","citation_count":54,"is_preprint":false},{"pmid":"24641500","id":"PMC_24641500","title":"Recent progress in the development of antagonists to the chemokine receptors CCR3 and CCR4.","date":"2014","source":"Expert opinion on drug discovery","url":"https://pubmed.ncbi.nlm.nih.gov/24641500","citation_count":54,"is_preprint":false},{"pmid":"36116370","id":"PMC_36116370","title":"Regulation of the multisubunit CCR4-NOT deadenylase in the initiation of mRNA degradation.","date":"2022","source":"Current opinion in structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/36116370","citation_count":52,"is_preprint":false},{"pmid":"19707589","id":"PMC_19707589","title":"The CCR4-NOT complex physically and functionally interacts with TRAMP and the nuclear exosome.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19707589","citation_count":52,"is_preprint":false},{"pmid":"28959024","id":"PMC_28959024","title":"Up-regulation of chemokine receptor CCR4 is associated with Human Hepatocellular Carcinoma malignant behavior.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28959024","citation_count":52,"is_preprint":false},{"pmid":"26654242","id":"PMC_26654242","title":"Identification of novel HIV-1 dependency factors in primary CCR4(+)CCR6(+)Th17 cells via a genome-wide transcriptional approach.","date":"2015","source":"Retrovirology","url":"https://pubmed.ncbi.nlm.nih.gov/26654242","citation_count":52,"is_preprint":false},{"pmid":"24904636","id":"PMC_24904636","title":"Novel roles of the multi-functional CCR4-NOT complex in post-transcriptional regulation.","date":"2014","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24904636","citation_count":50,"is_preprint":false},{"pmid":"24534492","id":"PMC_24534492","title":"Internalization of the chemokine receptor CCR4 can be evoked by orthosteric and allosteric receptor antagonists.","date":"2014","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/24534492","citation_count":50,"is_preprint":false},{"pmid":"33811642","id":"PMC_33811642","title":"CCR4 in cutaneous T-cell lymphoma: Therapeutic targeting of a pathogenic driver.","date":"2021","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33811642","citation_count":47,"is_preprint":false},{"pmid":"29510192","id":"PMC_29510192","title":"CCR4 Is Critically Involved in Skin Allergic Inflammation of BALB/c Mice.","date":"2018","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/29510192","citation_count":47,"is_preprint":false},{"pmid":"25776559","id":"PMC_25776559","title":"Ccr4-Not and TFIIS Function Cooperatively To Rescue Arrested RNA Polymerase II.","date":"2015","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25776559","citation_count":46,"is_preprint":false},{"pmid":"32783091","id":"PMC_32783091","title":"Recombinant CCL17 Enhances Hematoma Resolution and Activation of CCR4/ERK/Nrf2/CD163 Signaling Pathway After Intracerebral Hemorrhage in Mice.","date":"2020","source":"Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/32783091","citation_count":45,"is_preprint":false},{"pmid":"28271483","id":"PMC_28271483","title":"The Ccr4-Not Complex: Architecture and Structural Insights.","date":"2017","source":"Sub-cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28271483","citation_count":43,"is_preprint":false},{"pmid":"37658050","id":"PMC_37658050","title":"Tumor-associated macrophages confer colorectal cancer 5-fluorouracil resistance by promoting MRP1 membrane translocation via an intercellular CXCL17/CXCL22-CCR4-ATF6-GRP78 axis.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37658050","citation_count":43,"is_preprint":false},{"pmid":"22975735","id":"PMC_22975735","title":"The control of elongation by the yeast Ccr4-not complex.","date":"2012","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/22975735","citation_count":43,"is_preprint":false},{"pmid":"26804377","id":"PMC_26804377","title":"The architecture of the Schizosaccharomyces pombe CCR4-NOT complex.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26804377","citation_count":43,"is_preprint":false},{"pmid":"37653243","id":"PMC_37653243","title":"Specific recognition and ubiquitination of translating ribosomes by mammalian CCR4-NOT.","date":"2023","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/37653243","citation_count":42,"is_preprint":false},{"pmid":"37058474","id":"PMC_37058474","title":"Identifying highly active anti-CCR4 CAR T cells for the treatment of T-cell lymphoma.","date":"2023","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/37058474","citation_count":42,"is_preprint":false},{"pmid":"25496334","id":"PMC_25496334","title":"Mogamulizumab and the treatment of CCR4-positive T-cell lymphomas.","date":"2014","source":"Immunotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/25496334","citation_count":41,"is_preprint":false},{"pmid":"25981299","id":"PMC_25981299","title":"Targeting chemokine receptors in disease--a case study of CCR4.","date":"2015","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25981299","citation_count":41,"is_preprint":false},{"pmid":"20148806","id":"PMC_20148806","title":"CC chemokine receptor 4 (CCR4) in human allergen-induced late nasal responses.","date":"2010","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/20148806","citation_count":41,"is_preprint":false},{"pmid":"27356745","id":"PMC_27356745","title":"CCR4 promotes metastasis via ERK/NF-κB/MMP13 pathway and acts downstream of TNF-α in colorectal cancer.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27356745","citation_count":41,"is_preprint":false},{"pmid":"36555280","id":"PMC_36555280","title":"CC Chemokine Receptor 4 (CCR4) as a Possible New Target for Therapy.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36555280","citation_count":40,"is_preprint":false},{"pmid":"24465968","id":"PMC_24465968","title":"The Not4 E3 ligase and CCR4 deadenylase play distinct roles in protein quality control.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24465968","citation_count":39,"is_preprint":false},{"pmid":"24563252","id":"PMC_24563252","title":"Distinct conformations of the chemokine receptor CCR4 with implications for its targeting in allergy.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24563252","citation_count":38,"is_preprint":false},{"pmid":"35436328","id":"PMC_35436328","title":"Resistance to mogamulizumab is associated with loss of CCR4 in cutaneous T-cell lymphoma.","date":"2022","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/35436328","citation_count":37,"is_preprint":false},{"pmid":"22538464","id":"PMC_22538464","title":"Targeting chemokine receptor CCR4 in adult T-cell leukemia-lymphoma and other T-cell lymphomas.","date":"2012","source":"Current hematologic malignancy reports","url":"https://pubmed.ncbi.nlm.nih.gov/22538464","citation_count":36,"is_preprint":false},{"pmid":"30465800","id":"PMC_30465800","title":"Role of Chemokine Receptor CCR4 and Regulatory T Cells in Wound Healing of Diabetic Mice.","date":"2018","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/30465800","citation_count":36,"is_preprint":false},{"pmid":"35046040","id":"PMC_35046040","title":"Skin-resident dendritic cells mediate postoperative pain via CCR4 on sensory neurons.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/35046040","citation_count":36,"is_preprint":false},{"pmid":"25815716","id":"PMC_25815716","title":"Ccr4-not regulates RNA polymerase I transcription and couples nutrient signaling to the control of ribosomal RNA biogenesis.","date":"2015","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25815716","citation_count":36,"is_preprint":false},{"pmid":"16918452","id":"PMC_16918452","title":"Antagonists of CCR4 as immunomodulatory agents.","date":"2006","source":"Current topics in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16918452","citation_count":35,"is_preprint":false},{"pmid":"39571015","id":"PMC_39571015","title":"Specific tRNAs promote mRNA decay by recruiting the CCR4-NOT complex to translating ribosomes.","date":"2024","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/39571015","citation_count":34,"is_preprint":false},{"pmid":"34816383","id":"PMC_34816383","title":"Dermatologic Events Associated with the Anti-CCR4 Antibody Mogamulizumab: Characterization and Management.","date":"2021","source":"Dermatology and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34816383","citation_count":34,"is_preprint":false},{"pmid":"30926667","id":"PMC_30926667","title":"Hepatic posttranscriptional network comprised of CCR4-NOT deadenylase and FGF21 maintains systemic metabolic homeostasis.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30926667","citation_count":34,"is_preprint":false},{"pmid":"35177591","id":"PMC_35177591","title":"Targeting CCL2-CCR4 axis suppress cell migration of head and neck squamous cell carcinoma.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35177591","citation_count":33,"is_preprint":false},{"pmid":"24391663","id":"PMC_24391663","title":"Heterogeneity and complexity within the nuclease module of the Ccr4-Not complex.","date":"2013","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24391663","citation_count":33,"is_preprint":false},{"pmid":"12459162","id":"PMC_12459162","title":"Expression of CC chemokine receptor 4 (CCR4) mRNA in canine atopic skin lesion.","date":"2002","source":"Veterinary immunology and immunopathology","url":"https://pubmed.ncbi.nlm.nih.gov/12459162","citation_count":33,"is_preprint":false},{"pmid":"32732418","id":"PMC_32732418","title":"ANGEL2 is a member of the CCR4 family of deadenylases with 2',3'-cyclic phosphatase activity.","date":"2020","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/32732418","citation_count":33,"is_preprint":false},{"pmid":"30948432","id":"PMC_30948432","title":"Ccr4-Not maintains genomic integrity by controlling the ubiquitylation and degradation of arrested RNAPII.","date":"2019","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/30948432","citation_count":32,"is_preprint":false},{"pmid":"26550987","id":"PMC_26550987","title":"Clinical Application of Anti-CCR4 Monoclonal Antibody.","date":"2015","source":"Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26550987","citation_count":31,"is_preprint":false},{"pmid":"24904637","id":"PMC_24904637","title":"Insights into the structure and architecture of the CCR4-NOT complex.","date":"2014","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24904637","citation_count":31,"is_preprint":false},{"pmid":"37152278","id":"PMC_37152278","title":"Regulation of eukaryotic mRNA deadenylation and degradation by the Ccr4-Not complex.","date":"2023","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/37152278","citation_count":31,"is_preprint":false},{"pmid":"25944446","id":"PMC_25944446","title":"The enzyme activities of Caf1 and Ccr4 are both required for deadenylation by the human Ccr4-Not nuclease module.","date":"2015","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/25944446","citation_count":31,"is_preprint":false},{"pmid":"18782672","id":"PMC_18782672","title":"CCR4 and CCR10 are expressed on epidermal keratinocytes and are involved in cutaneous immune reaction.","date":"2008","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/18782672","citation_count":29,"is_preprint":false},{"pmid":"21443538","id":"PMC_21443538","title":"Aberrant expression of chemokine receptor CCR4 in human gastric cancer contributes to tumor-induced immunosuppression.","date":"2011","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/21443538","citation_count":28,"is_preprint":false},{"pmid":"22973452","id":"PMC_22973452","title":"Human anti-CCR4 minibody gene transfer for the treatment of cutaneous T-cell lymphoma.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22973452","citation_count":28,"is_preprint":false},{"pmid":"27807034","id":"PMC_27807034","title":"Interaction of CCR4-NOT with EBF1 regulates gene-specific transcription and mRNA stability in B lymphopoiesis.","date":"2016","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/27807034","citation_count":27,"is_preprint":false},{"pmid":"32760393","id":"PMC_32760393","title":"CCR4 Antagonist (C021) Administration Diminishes Hypersensitivity and Enhances the Analgesic Potency of Morphine and Buprenorphine in a Mouse Model of Neuropathic Pain.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32760393","citation_count":27,"is_preprint":false},{"pmid":"32207684","id":"PMC_32207684","title":"CCR4, a RNA decay factor, is hijacked by a plant cytorhabdovirus phosphoprotein to facilitate virus replication.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32207684","citation_count":27,"is_preprint":false},{"pmid":"37984453","id":"PMC_37984453","title":"Clinical and molecular effects of oral CCR4 antagonist RPT193 in atopic dermatitis: A Phase 1 study.","date":"2023","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/37984453","citation_count":26,"is_preprint":false},{"pmid":"32428547","id":"PMC_32428547","title":"Radiation-Enhanced Expression of CCL22 in Nasopharyngeal Carcinoma is Associated With CCR4+ CD8 T Cell Recruitment.","date":"2020","source":"International journal of radiation oncology, biology, physics","url":"https://pubmed.ncbi.nlm.nih.gov/32428547","citation_count":25,"is_preprint":false},{"pmid":"31724732","id":"PMC_31724732","title":"Nuclear Ccr4-Not mediates the degradation of telomeric and transposon transcripts at chromatin in the Drosophila germline.","date":"2020","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/31724732","citation_count":25,"is_preprint":false},{"pmid":"17965252","id":"PMC_17965252","title":"The Ccr4-not complex regulates Skn7 through Srb10 kinase.","date":"2007","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/17965252","citation_count":25,"is_preprint":false},{"pmid":"28947948","id":"PMC_28947948","title":"Discovery of AZD-2098 and AZD-1678, Two Potent and Bioavailable CCR4 Receptor Antagonists.","date":"2017","source":"ACS medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/28947948","citation_count":25,"is_preprint":false},{"pmid":"36951092","id":"PMC_36951092","title":"RNA binding proteins Smaug and Cup induce CCR4-NOT-dependent deadenylation of the nanos mRNA in a reconstituted system.","date":"2023","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/36951092","citation_count":24,"is_preprint":false},{"pmid":"34038562","id":"PMC_34038562","title":"Crystal structure and functional properties of the human CCR4-CAF1 deadenylase complex.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/34038562","citation_count":24,"is_preprint":false},{"pmid":"35634277","id":"PMC_35634277","title":"CCR4 and CCR5 Involvement in Monocyte-Derived Macrophage Migration in Neuroinflammation.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35634277","citation_count":23,"is_preprint":false},{"pmid":"26628988","id":"PMC_26628988","title":"The abnormal expression of CCR4 and CCR6 on Tregs in rheumatoid arthritis.","date":"2015","source":"International journal of clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26628988","citation_count":23,"is_preprint":false},{"pmid":"32052476","id":"PMC_32052476","title":"A degradatory fate for CCR4 suggests a primary role in Th2 inflammation.","date":"2020","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/32052476","citation_count":23,"is_preprint":false},{"pmid":"38009591","id":"PMC_38009591","title":"Roles of the CCR4-Not complex in translation and dynamics of co-translation events.","date":"2023","source":"Wiley interdisciplinary reviews. RNA","url":"https://pubmed.ncbi.nlm.nih.gov/38009591","citation_count":22,"is_preprint":false},{"pmid":"32238456","id":"PMC_32238456","title":"The CCR4-NOT complex maintains liver homeostasis through mRNA deadenylation.","date":"2020","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/32238456","citation_count":22,"is_preprint":false},{"pmid":"29025909","id":"PMC_29025909","title":"Histone deacetylase inhibitors downregulate CCR4 expression and decrease mogamulizumab efficacy in CCR4-positive mature T-cell lymphomas.","date":"2017","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/29025909","citation_count":22,"is_preprint":false},{"pmid":"18095942","id":"PMC_18095942","title":"CCR4 and CCR10 ligands play additive roles in mouse contact hypersensitivity.","date":"2008","source":"Experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/18095942","citation_count":22,"is_preprint":false},{"pmid":"30230587","id":"PMC_30230587","title":"CCL17-CCR4 axis promotes metastasis via ERK/MMP13 pathway in bladder cancer.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30230587","citation_count":21,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47205,"output_tokens":6224,"usd":0.117487,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15133,"output_tokens":4424,"usd":0.093132,"stage2_stop_reason":"end_turn"},"total_usd":0.210619,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"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.\",\n      \"method\": \"Radioligand competition binding assay in CCR4-transfected HL-60 cells; Northern blot for tissue distribution\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay in transfected cells, both human and murine receptors tested with two ligands, single lab\",\n      \"pmids\": [\"8573157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Flow cytometry, immunoprecipitation/Western blot, calcium flux assay, platelet aggregation assay, anti-CCR4 mAb inhibition\",\n      \"journal\": \"Thrombosis research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (Ca2+ flux, aggregation, mAb blockade, cross-desensitization) in primary human platelets, single lab\",\n      \"pmids\": [\"11248289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"PCR, flow cytometry, immunoprecipitation, Western blot, functional platelet activation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (IP, WB, functional assays), corroborates findings in PMID:11248289\",\n      \"pmids\": [\"11110672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Adoptive transfer of CCR4-deficient vs. wild-type antigen-specific Th2 cells in murine allergic pulmonary inflammation model\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with adoptive transfer, specific phenotypic readouts (cell trafficking, cytokines, eosinophilia, mucus), replicated across multiple cell types tested as controls\",\n      \"pmids\": [\"19062085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Whole transcriptome sequencing of patient samples, functional migration assays, receptor internalization assays, PI3K/AKT signaling assays, long-term in vitro growth assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal functional assays (migration, internalization, signaling, growth), patient samples plus functional validation, single lab but rigorous multi-method approach\",\n      \"pmids\": [\"25488980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Calcium flux assay, chemotaxis assay, receptor endocytosis assay, competitive ligand binding assay, site-directed mutagenesis (K310 mutation), conformation-specific antibody epitope mapping\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis combined with multiple functional assays (calcium, chemotaxis, endocytosis, binding), two conformation-selective antibodies used, mechanistically rigorous\",\n      \"pmids\": [\"24563252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"β-arrestin recruitment assay, GTPγS binding assay, receptor internalization assay (flow cytometry), chemotaxis assay, competitive binding with allosteric antagonists\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal functional assays defining distinct signaling pathways, allosteric site mapping, biased agonism between CCL17 and CCL22 established\",\n      \"pmids\": [\"24534492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Two-photon time-lapse microscopy, CCR4-knockout mouse model, negative selection assays with polyclonal and TCR transgenic thymocytes\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct live imaging combined with genetic knockout, multiple phenotypic readouts (medullary entry, DC interactions, negative selection, autoimmunity), replicated across polyclonal and transgenic settings\",\n      \"pmids\": [\"26417005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Promoter reporter assay, siRNA knockdown, overexpression studies, gene expression profiling\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter assay, siRNA, and overexpression all in single lab; mechanistic link between AP-1 site, Fra-2/JunD, and CCR4 expression established\",\n      \"pmids\": [\"18071306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain and loss of function for HBZ, promoter mechanism via GATA3, in vivo migration model, single lab\",\n      \"pmids\": [\"27402079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"CCR4-deficient mouse model, CCR4 antagonist treatment, transcutaneous sensitization model in BALB/c mice, histological and cytokine analyses\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout plus pharmacological blockade with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"29510192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Intracerebral hemorrhage mouse model, rCCL17 intranasal administration, pharmacological inhibitors (C021, ML385), CRISPR knockout (CD163), Western blot, immunofluorescence\",\n      \"journal\": \"Neurotherapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway inhibitors and CRISPR used to establish signaling hierarchy, single lab\",\n      \"pmids\": [\"32783091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Flow cytometry for CCR4 surface expression and endocytosis, cycloheximide treatment, C-terminal truncation mutants, chemotaxis assay in transfectants and human Th2 cells\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis combined with functional assays, multiple cell types, single lab\",\n      \"pmids\": [\"32052476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Electrophysiology of dissociated sensory neurons, CCR4 knockout mice, CCR4 siRNA knockdown, pharmacological CCR4 antagonist (C021), transgenic DC-depletion, subcutaneous CCL22 injection pain behavior assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal approaches (electrophysiology, KO, siRNA, pharmacological, DC depletion) across in vitro and in vivo systems establishing direct neuronal CCR4 function\",\n      \"pmids\": [\"35046040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"CCR4 overexpression and RNA interference in breast cancer cell lines, mouse xenograft model, chemotaxis assay, microvessel density measurement\",\n      \"journal\": \"Breast cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain and loss of function in vivo and in vitro, single lab\",\n      \"pmids\": [\"21479551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"CCR4 siRNA knockdown, overexpression, in vitro invasion assay, in vivo mouse model, MMP13 expression analysis, ERK/NF-κB pathway inhibitors, TNF-α stimulation\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain and loss of function with pathway inhibitors establishing signaling hierarchy, single lab\",\n      \"pmids\": [\"27356745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"CCR4 overexpression and knockdown in HCC cell lines, in vivo tumor growth assay, in vitro invasion/migration assay, pathway analysis (ERK/AKT), MMP2 expression\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss of function with signaling pathway analysis, single lab\",\n      \"pmids\": [\"28959024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"CCR4 overexpression in melanoma cells, in vitro chemotaxis and transendothelial migration assay, in vivo spontaneous brain micrometastasis model, CCR4 small molecule antagonist\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain of function and pharmacological inhibition in vivo and in vitro, single lab\",\n      \"pmids\": [\"28415693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"CCR4 knockdown/overexpression, co-immunoprecipitation of Vav2-Rac1, phospho-MLC assay, migration assay, CCR4 vs. CCR2 axis discrimination\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing Vav2-Rac1 complex, gain/loss of function with mechanistic readouts, single lab\",\n      \"pmids\": [\"35177591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Cytokine production assay from Th1-polarized normal CD4+ T cells treated with CCR4 ligand CCL17\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single in vitro functional assay, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"28134623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"RT-PCR, protein expression (mRNA/protein level in normal human keratinocytes and HaCaT cells), cytokine ELISA, Boyden chamber migration, wound scratch assay\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (cytokine production, migration) demonstrating receptor functionality in keratinocytes, single lab\",\n      \"pmids\": [\"18782672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Cell-cell coculture, CCR4 signaling pathway analysis (PI3K/AKT, IP3R, ER stress markers), GRP78-MRP1 interaction studies, drug efflux assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissection through multiple molecular assays and signaling inhibitors, single lab\",\n      \"pmids\": [\"37658050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown of specific HDAC isoforms, surface CCR4 flow cytometry, CCR4 mRNA qRT-PCR, patient skin biopsy analysis pre/post vorinostat treatment\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific siRNA with patient sample validation, single lab, establishes HDAC2 as epigenetic regulator of CCR4 expression\",\n      \"pmids\": [\"29025909\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCR4 is a seven-transmembrane G protein-coupled chemokine receptor for CCL17 and CCL22 that mediates directional migration of Th2 cells, regulatory T cells, and other CCR4-expressing cells to sites of inflammation (particularly skin, lung); it signals via Gα protein (GTPγS coupling), β-arrestin recruitment (preferentially by CCL22 but not CCL17), and downstream PI3K/AKT, ERK/NF-κB/MMP, and Nrf2 pathways; CCL22 and CCL17 are conformationally selective, biased ligands that activate distinct receptor conformations—CCL22 dominates receptor endocytosis and β-arrestin coupling while CCL17 requires residue K310 for activation; ligand-driven endocytosis leads to receptor degradation requiring de novo synthesis for replenishment; gain-of-function C-terminal truncation mutations in ATLL impair internalization to enhance sustained PI3K/AKT signaling and migration; transcriptionally, CCR4 is regulated by Fra-2/JunD AP-1 heterodimers, HTLV-1 HBZ via GATA3, and HDAC2-dependent chromatin modification; in the thymus, CCR4 mediates medullary entry of post-positive selection thymocytes and their interactions with dendritic cells required for central tolerance; on sensory neurons, CCR4 directly mediates pain signaling activated by skin-resident dendritic cell-derived CCL17/22.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #3, #5]. Its two cognate chemokines act as conformationally selective, biased agonists: CCL22 dominates competitive binding and receptor endocytosis, couples efficiently to \\u03b2-arrestin, and fully stimulates GTP\\u03b3S binding, whereas CCL17 requires the C-terminal residue K310 for activation, does not engage \\u03b2-arrestin, and only partially stimulates G protein coupling [#5, #6]. 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 [#12]. 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 [#4]. 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 [#7], and it recruits Th2/Th17 effector cells into lung and skin during allergic inflammation [#3, #10]. Beyond leukocytes, CCR4 is functionally expressed on platelets, keratinocytes, microglia, and sensory neurons, where CCL17/CCL22 directly activate the neurons to drive postoperative pain [#1, #13]. In epithelial cancers CCR4 promotes invasion, metastasis, and angiogenesis through ERK/NF-\\u03baB/MMP and PI3K/AKT signaling cascades [#14, #15, #16]. 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 [#8, #9, #22].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established CCR4 as a bona fide chemokine receptor by demonstrating high-affinity ligand binding, answering whether the orphan-like sequence encoded a functional receptor.\",\n      \"evidence\": \"Radioligand competition binding in CCR4-transfected HL-60 cells for human and murine receptors\",\n      \"pmids\": [\"8573157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MIP-1\\u03b1/RANTES binding not reconciled with later CCL17/CCL22 ligand assignment\", \"no signaling output measured\", \"no endogenous cell type tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Extended CCR4 function beyond classical leukocytes by showing it drives platelet activation, raising the question of non-immune receptor roles.\",\n      \"evidence\": \"Calcium flux, aggregation, anti-CCR4 mAb blockade, and cross-desensitization in primary human platelets, corroborated by IP/WB\",\n      \"pmids\": [\"11248289\", \"11110672\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"downstream signaling beyond Ca2+ not dissected\", \"physiological relevance of platelet CCR4 in vivo unclear\", \"requirement for plasma cofactors not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified the transcriptional driver of CCR4 in leukemia, addressing how the receptor is overexpressed in ATL.\",\n      \"evidence\": \"AP-1 promoter reporter, Fra-2/JunD vs JunB siRNA, and overexpression in ATL and Jurkat cells\",\n      \"pmids\": [\"18071306\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"upstream signals activating Fra-2/JunD not defined\", \"single-lab promoter mechanism\", \"not linked to receptor mutation status\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated CCR4 is required for effector Th2 trafficking into tissue, defining its core in vivo role in allergic inflammation.\",\n      \"evidence\": \"Adoptive transfer of CCR4-deficient vs wild-type Th2 cells in a murine allergic airway model\",\n      \"pmids\": [\"19062085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"chemokine source in lung not pinpointed\", \"does not address non-Th2 CCR4 cells\", \"ligand bias not considered\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"K310 site-directed mutagenesis, \\u03b2-arrestin and GTP\\u03b3S assays, endocytosis, conformation-specific antibodies, and allosteric antagonist mapping\",\n      \"pmids\": [\"24563252\", \"24534492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"structural basis of the two conformations not solved\", \"biological consequence of bias in vivo unmeasured\", \"kinase pathways downstream of each conformation not separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected CCR4 C-terminal biology to oncogenesis by showing ATLL truncating mutations impair internalization to enhance PI3K/AKT signaling and growth.\",\n      \"evidence\": \"Transcriptome sequencing of ATLL samples plus migration, internalization, signaling, and long-term growth assays of CCR4-Q330\",\n      \"pmids\": [\"25488980\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mechanism linking sustained signaling to clonal selection in patients incomplete\", \"interaction with HBZ/AP-1 regulation not integrated\", \"in vivo tumor model not used\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a non-inflammatory developmental role for CCR4 in central tolerance, answering how thymocytes reach the medulla for negative selection.\",\n      \"evidence\": \"Two-photon imaging and negative selection assays in CCR4-knockout mice across polyclonal and TCR-transgenic settings\",\n      \"pmids\": [\"26417005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"medullary chemokine gradient source not fully defined\", \"relative contribution of CCR4 vs other receptors in thymus unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Explained virally driven CCR4 induction by showing HTLV-1 HBZ upregulates CCR4 through GATA3, linking infection to receptor expression and T-cell migration/proliferation.\",\n      \"evidence\": \"HBZ gain/loss of function, GATA3 promoter analysis, and CCR4 antagonist in HBZ transgenic mouse migration model\",\n      \"pmids\": [\"27402079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"interplay with Fra-2/JunD regulation not tested together\", \"direct GATA3 binding to promoter not structurally confirmed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established CCR4 as a pro-metastatic driver in solid tumors operating through ERK/NF-\\u03baB/MMP and ERK/AKT/MMP cascades rather than proliferation.\",\n      \"evidence\": \"Gain/loss of function with pathway inhibitors and in vivo metastasis models in colorectal, hepatocellular, breast, and melanoma cells\",\n      \"pmids\": [\"27356745\", \"28959024\", \"21479551\", \"28415693\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"chemokine ligand specificity across tumor types varies (CCL17/CCL22/CCL2)\", \"single-lab mechanisms per cancer\", \"in vivo ligand source not always defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified HDAC2 as an epigenetic regulator of CCR4 expression, providing a therapeutic rationale for HDAC inhibitor downregulation of the receptor.\",\n      \"evidence\": \"Isoform-specific HDAC siRNA, CCR4 flow/qRT-PCR, and pre/post-vorinostat patient skin biopsies\",\n      \"pmids\": [\"29025909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism of HDAC2 action on CCR4 locus not detailed\", \"relationship to AP-1/GATA3 regulation untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"CCR4-deficient mice plus antagonist in atopic dermatitis model; coculture and PI3K/AKT-ER stress dissection in colorectal cancer\",\n      \"pmids\": [\"29510192\", \"37658050\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"chemoresistance pathway from receptor to MRP1 has many single-lab steps\", \"skin model does not separate Th2 from Th17 contribution mechanistically\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended CCR4 signaling to CNS resident cells, showing CCL17 activation of microglial CCR4 promotes hematoma resolution via an ERK/Nrf2/CD163 axis.\",\n      \"evidence\": \"Intracerebral hemorrhage model with C021, ML385, and CD163 CRISPR knockout, Western blot and immunofluorescence\",\n      \"pmids\": [\"32783091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ligand bias of CCL17 in microglia not addressed\", \"single-lab pathway hierarchy\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated direct neuronal CCR4 function in pain and a Vav2-Rac1/MLC motility mechanism, expanding CCR4 beyond leukocyte chemotaxis.\",\n      \"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\",\n      \"pmids\": [\"35046040\", \"35177591\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ligand-biased CCR4 conformations are decoded into distinct downstream pathways (\\u03b2-arrestin vs G protein vs PI3K/AKT vs ERK) across the diverse cell types expressing the receptor remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 5, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 7, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 14, 15, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CCL22\", \"CCL17\", \"ARRB\", \"CCL2\", \"VAV2\", \"RAC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}