CCR4 (C-C Motif Chemokine Receptor 4) Gene
A key regulator of immune cell trafficking, implicated in T-cell malignancies, allergic inflammation, and potential therapeutic targeting.
Gene Information Card
| Symbol | CCR4 |
|---|---|
| Full Name | C-C motif chemokine receptor 4 |
| Gene Type | Protein coding |
| Chromosomal Location | 3p22.3 |
| NCBI Gene ID | 1233 ncbi.nlm.nih.gov/gene/1233 |
| Ensembl ID | ENSG00000183813 |
| UniProt ID | P51679 |
| OMIM ID | 604836 |
| HGNC ID | 1605 |
| Aliases | CD194, C-C CKR-4, CC-CKR-4, CCR-4, ChemR13, HGCN:14099, K5-5 |
Description
The CCR4 gene encodes C-C motif chemokine receptor 4, a G-protein coupled receptor (GPCR) for members of the C-C chemokine family, specifically CCL17 (TARC) and CCL22 (MDC). CCR4 is predominantly expressed on the surface of type 2 helper T (Th2) cells, regulatory T (Treg) cells, and cutaneous lymphocyte-associated antigen (CLA)-positive skin-homing T cells. It plays a central role in the trafficking of these cells to inflammatory sites, particularly the skin and lungs, and is involved in immune responses, allergic inflammation, and the pathogenesis of certain T-cell malignancies. Due to its selective expression on Th2 and Treg cells, CCR4 is a significant therapeutic target for conditions like atopic dermatitis, asthma, and adult T-cell leukemia/lymphoma (ATLL).
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Disease | Mechanism | Evidence |
| Adult T-cell Leukemia/Lymphoma (ATLL) | CCR4 is highly expressed on ATLL cells. The HTLV-1 Tax protein can transactivate the CCR4 promoter, leading to overexpression. This promotes tumor cell survival, migration, and immune evasion. Anti-CCR4 antibody (mogamulizumab) is used for treatment. | OMIM: 604836; PMID: 20516128; PMID: 24753542 |
| Cutaneous T-cell Lymphoma (CTCL) | CCR4 is expressed on malignant T cells in CTCL, particularly in mycosis fungoides and Sézary syndrome. It facilitates the homing of malignant cells to the skin, contributing to the characteristic skin lesions. | PMID: 12506029; PMID: 16931686 |
| Atopic Dermatitis (Eczema) | CCR4 is highly expressed on Th2 cells that infiltrate the skin. Its ligands CCL17 and CCL22 are elevated in the skin of patients, driving the recruitment of Th2 cells and contributing to the allergic inflammatory response. | PMID: 10438934; PMID: 11369816 |
| Asthma | CCR4 expression on Th2 cells is implicated in the allergic airway inflammation characteristic of asthma. The CCR4-CCL17/CCL22 axis recruits Th2 cells to the lungs, promoting eosinophilia and mucus production. | PMID: 10438934; PMID: 11369816 |
| T-cell Non-Hodgkin Lymphoma (NHL) | CCR4 is expressed in a subset of peripheral T-cell lymphomas (PTCL) and is associated with a poorer prognosis. It is a potential therapeutic target in these aggressive diseases. | PMID: 24753542; PMID: 23940216 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Tissue | nTPM | Level |
| Spleen | 12.3 | Medium |
| Lymph Node | 10.1 | Medium |
| Blood | 8.5 | Low |
| Bone Marrow | 6.2 | Low |
| Lung | 3.1 | Low |
| Skin | 2.8 | Low |
| Thymus | 2.5 | Low |
| Appendix | 2.1 | Low |
| Tonsil | 1.9 | Low |
| Other Tissues | <1.0 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Cell Line | nTPM | Notes |
| Jurkat (T-cell leukemia) | 15.2 | High expression; used as a model for T-cell signaling. |
| MOLT-4 (T-cell leukemia) | 12.8 | High expression; reflects T-cell lineage. |
| CCRF-CEM (T-cell leukemia) | 10.5 | Moderate to high expression. |
| HUT-78 (CTCL) | 18.1 | Very high expression; derived from Sézary syndrome patient. |
| HH (CTCL) | 16.4 | High expression; another CTCL cell line. |
| K-562 (CML) | 0.5 | Low/not detected; non-T-cell lineage. |
| HeLa (Cervical cancer) | 0.2 | Not detected; non-hematopoietic. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| Variant | Type | Frequency | Effect |
| c.925C>T (p.Arg309Cys) | Missense | Rare (<0.1%) | Located in the third intracellular loop; may affect G-protein coupling and signaling efficiency. Clinical significance is uncertain. |
| c.1010G>A (p.Arg337His) | Missense | Rare (<0.1%) | Located in the C-terminal tail; may affect receptor internalization or desensitization. Clinical significance is uncertain. |
| c.64G>A (p.Val22Ile) | Missense | Rare (<0.1%) | Located in the N-terminal extracellular domain; may affect ligand binding. Clinical significance is uncertain. |
| c.883C>T (p.Pro295Ser) | Missense | Rare (<0.1%) | Located in the sixth transmembrane domain; may affect receptor conformation. Clinical significance is uncertain. |
| Copy Number Gain | CNV | Observed in ATLL and CTCL | Amplification of the CCR4 locus can lead to increased expression, promoting tumor cell survival and migration. |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in CCR4 are rare and not well-characterized. They could potentially impair immune cell trafficking, leading to immunodeficiency or altered inflammatory responses. However, no specific pathogenic loss-of-function variants have been firmly established in clinical databases.
Gain of Function (GOF)
Gain-of-function mutations are not commonly reported in CCR4. However, overexpression due to copy number gains or transcriptional activation (e.g., by HTLV-1 Tax) can be considered a functional 'gain' at the protein level, leading to enhanced signaling and tumorigenesis.
Dominant Negative (DN)
No dominant-negative mutations have been described for CCR4. As a GPCR, it functions as a monomer or homodimer, and a dominant-negative effect would require a mutant subunit to interfere with the wild-type receptor's function, which has not been observed.
View complete mutation data：
Gene Ontology (GO)
| • C-C chemokine receptor activity | • C-C chemokine binding |
| • G protein-coupled receptor activity | • Signal transducer activity |
| • Cell surface receptor signaling pathway | • Chemokine-mediated signaling pathway |
| • Cell chemotaxis | • Immune response |
| • Inflammatory response | • Positive regulation of cytosolic calcium ion concentration |
| • Plasma membrane | • Integral component of plasma membrane |
Pathways
• Chemokine signaling pathway (KEGG: hsa04062)
• Cytokine-cytokine receptor interaction (KEGG: hsa04060)
• T cell receptor signaling pathway (KEGG: hsa04660)
• Th1 and Th2 cell differentiation (KEGG: hsa04658)
• Hematopoietic cell lineage (KEGG: hsa04640)
• G alpha (i) signaling events (Reactome: R-HSA-418594)
• Peptide ligand-binding receptors (Reactome: R-HSA-375276)
Protein Summary
CCR4 is a 360-amino acid, seven-transmembrane G-protein coupled receptor. It is a class A (rhodopsin-like) GPCR. The protein consists of an extracellular N-terminus involved in ligand binding, seven hydrophobic transmembrane alpha-helices, three extracellular and three intracellular loops, and an intracellular C-terminus. Upon binding its ligands CCL17 or CCL22, CCR4 undergoes a conformational change, activating heterotrimeric G proteins of the Gi family. This leads to inhibition of adenylate cyclase, decrease in cAMP, and activation of downstream signaling pathways including PI3K/AKT, MAPK/ERK, and PLC/PKC. These pathways regulate cell migration (chemotaxis), actin polymerization, adhesion, and survival. CCR4 is post-translationally modified by N-linked glycosylation, which is important for proper cell surface expression. It is also constitutively internalized and recycled, a process regulated by its C-terminal tail.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| CCR4 Knockout HEK293 Cell Line | EDJ-KQ3206 | Human | 1233 | Details Get a Quote |
| CCR4 Knockout HeLa Cell Line | EDJ-KQ52932 | Human | 1233 | Details Get a Quote |
| CCR4 Knockout A-549 Cell Line | EDJ-KQ61400 | Human | 1233 | Details Get a Quote |
| CCR4 Knockout HCT 116 Cell Line | EDJ-KQ69894 | Human | 1233 | Details Get a Quote |
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