CCL21

Summary

CCL21 (C-C motif chemokine ligand 21, HGNC:10620) is a protein-coding gene on chromosome 9p13.3, encoding C-C motif chemokine 21 (O00585). Binds to atypical chemokine receptor ACKR4 and mediates the recruitment of beta-arrestin (ARRB1/2) to ACKR4.

This antimicrobial gene is one of several CC cytokine genes clustered on the p-arm of chromosome 9. Cytokines are a family of secreted proteins involved in immunoregulatory and inflammatory processes. The CC cytokines are proteins characterized by two adjacent cysteines. Similar to other chemokines the protein encoded by this gene inhibits hemopoiesis and stimulates chemotaxis. This protein is chemotactic in vitro for thymocytes and activated T cells, but not for B cells, macrophages, or neutrophils. The cytokine encoded by this gene may also play a role in mediating homing of lymphocytes to secondary lymphoid organs. It is a high affinity functional ligand for chemokine receptor 7 that is expressed on T and B lymphocytes and a known receptor for another member of the cytokine family (small inducible cytokine A19).

Source: NCBI Gene 6366 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 19 total
• GTEx eGene: eQTL in 7 tissues, sQTL in 1 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.12 (unconstrained)
• MANE Select transcript: NM_002989
• Interaction hub: 1,988 STRING partners (top 8% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10620
Approved symbol	CCL21
Name	C-C motif chemokine ligand 21
Location	9p13.3
Locus type	gene with protein product
Status	Approved
Aliases	SLC, exodus-2, TCA4, CKb9, 6Ckine, ECL
Ensembl gene	ENSG00000137077
Ensembl biotype	protein_coding
OMIM	602737
Entrez	6366

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 nonsense_mediated_decay

MANE Select: ENST00000259607

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 1

ENST00000259607, ENST00000378792, ENST00000714162, ENST00000714163, ENST00000885823, ENST00000885824, ENST00001103807, ENST00001135508

RefSeq mRNA: 1 — MANE Select: NM_002989 NM_002989

CCDS: CCDS6571

Canonical transcript exons

ENST00000259607 — 4 exons

Exon	Start	End
ENSE00000928120	34709005	34709427
ENSE00004023038	34710000	34710136
ENSE00004023039	34709500	34709682
ENSE00004023041	34709777	34709897

Expression profiles

Bgee: expression breadth ubiquitous, 206 present calls, max score 99.57.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 13.5437 / max 3019.5796, expressed in 119 samples.

Highest expression (Bgee): lymph node, lobe of thyroid gland, vermiform appendix, caecum, rectum.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CCL21 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 7 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

8 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Brain Caudate basal ganglia	eqtl	4.0e-04	-1.13	9:33818743:C:T
Brain Cerebellar Hemisphere	eqtl	5.5e-03	-1.21	9:35287478:A:G
Esophagus Muscularis	eqtl	1.4e-02	-0.14	9:35603571:GA:G
Testis	sqtl	1.9e-02	-1.76	9:34430101:C:T
Testis	eqtl	2.8e-02	-0.84	9:34742100:C:T
Pituitary	eqtl	3.3e-02	-0.43	9:34577841:A:G
Lung	eqtl	3.3e-02	+0.49	9:34834137:A:G
Muscle Skeletal	eqtl	3.3e-02	+0.22	9:34565082:C:T

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
100543	13.5146	119
100542	0.0291	16

Top tissues by expression

showing 100 of 289 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lymph node	UBERON:0000029	99.57	gold quality
right lobe of thyroid gland	UBERON:0001119	99.28	gold quality
vermiform appendix	UBERON:0001154	98.67	gold quality
left lobe of thyroid gland	UBERON:0001120	98.59	gold quality
caecum	UBERON:0001153	98.15	gold quality
rectum	UBERON:0001052	97.98	gold quality
thyroid gland	UBERON:0002046	97.82	gold quality
gall bladder	UBERON:0002110	96.97	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.93	gold quality
mucosa of stomach	UBERON:0001199	96.89	gold quality
mucosa of transverse colon	UBERON:0004991	96.46	gold quality
right uterine tube	UBERON:0001302	96.45	gold quality
upper lobe of left lung	UBERON:0008952	96.36	gold quality
upper lobe of lung	UBERON:0008948	95.71	gold quality
small intestine	UBERON:0002108	95.34	gold quality
spleen	UBERON:0002106	95.32	gold quality
lower esophagus	UBERON:0013473	95.10	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.09	gold quality
omental fat pad	UBERON:0010414	94.66	gold quality
lower esophagus mucosa	UBERON:0035834	94.64	gold quality
peritoneum	UBERON:0002358	94.63	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.33	gold quality
left uterine tube	UBERON:0001303	94.20	gold quality
esophagus	UBERON:0001043	94.04	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.48	gold quality
esophagus mucosa	UBERON:0002469	93.18	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.73	gold quality
superficial temporal artery	UBERON:0001614	92.55	gold quality
ileal mucosa	UBERON:0000331	92.50	gold quality
decidua	UBERON:0002450	91.51	gold quality
ectocervix	UBERON:0012249	91.44	gold quality
pericardium	UBERON:0002407	91.39	gold quality
intestine	UBERON:0000160	91.36	gold quality
fundus of stomach	UBERON:0001160	90.96	gold quality
sigmoid colon	UBERON:0001159	90.84	gold quality
vena cava	UBERON:0004087	90.77	gold quality
transverse colon	UBERON:0001157	90.76	gold quality
left coronary artery	UBERON:0001626	90.67	gold quality
smooth muscle tissue	UBERON:0001135	90.51	gold quality
colon	UBERON:0001155	90.51	gold quality
large intestine	UBERON:0000059	90.47	gold quality
colonic epithelium	UBERON:0000397	90.43	gold quality
right lung	UBERON:0002167	90.35	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.06	gold quality
coronary artery	UBERON:0001621	89.99	gold quality
body of uterus	UBERON:0009853	89.67	gold quality
right lobe of liver	UBERON:0001114	89.61	gold quality
lung	UBERON:0002048	89.37	gold quality
penis	UBERON:0000989	89.34	gold quality
skin of abdomen	UBERON:0001416	89.20	gold quality
skin of hip	UBERON:0001554	89.15	gold quality
diaphragm	UBERON:0001103	89.13	gold quality
skin of leg	UBERON:0001511	88.90	gold quality
tonsil	UBERON:0002372	88.34	gold quality
endocervix	UBERON:0000458	88.25	gold quality
nipple	UBERON:0002030	88.15	gold quality
zone of skin	UBERON:0000014	87.59	gold quality
stomach	UBERON:0000945	87.44	gold quality
myometrium	UBERON:0001296	87.05	gold quality
body of stomach	UBERON:0001161	86.89	gold quality
apex of heart	UBERON:0002098	86.88	gold quality
oral cavity	UBERON:0000167	86.40	gold quality
mammalian vulva	UBERON:0000997	86.19	gold quality
trachea	UBERON:0003126	85.90	gold quality
vagina	UBERON:0000996	85.61	gold quality
right ovary	UBERON:0002118	85.25	gold quality
right adrenal gland	UBERON:0001233	84.24	gold quality
right adrenal gland cortex	UBERON:0035827	84.23	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.89	gold quality
lower lobe of lung	UBERON:0008949	83.70	silver quality
left adrenal gland	UBERON:0001234	83.18	gold quality
left adrenal gland cortex	UBERON:0035825	83.12	gold quality
right coronary artery	UBERON:0001625	83.08	gold quality
subcutaneous adipose tissue	UBERON:0002190	83.04	gold quality
mammary duct	UBERON:0001765	83.03	gold quality
adrenal gland	UBERON:0002369	82.93	gold quality
liver	UBERON:0002107	82.84	gold quality
adrenal cortex	UBERON:0001235	82.73	gold quality
duodenum	UBERON:0002114	82.72	gold quality
minor salivary gland	UBERON:0001830	82.44	gold quality
heart left ventricle	UBERON:0002084	82.38	gold quality
cardia of stomach	UBERON:0001162	82.30	gold quality
cardiac ventricle	UBERON:0002082	82.28	gold quality
pharyngeal mucosa	UBERON:0000355	82.15	gold quality
left ovary	UBERON:0002119	82.13	gold quality
upper arm skin	UBERON:0004263	82.09	silver quality
pylorus	UBERON:0001166	81.91	gold quality
fallopian tube	UBERON:0003889	81.63	gold quality
adipose tissue	UBERON:0001013	81.39	gold quality
mouth mucosa	UBERON:0003729	81.31	gold quality
saliva-secreting gland	UBERON:0001044	81.27	gold quality
uterine cervix	UBERON:0000002	81.09	gold quality
prostate gland	UBERON:0002367	80.99	gold quality
cauda epididymis	UBERON:0004360	80.64	gold quality
ovary	UBERON:0000992	80.58	gold quality
adult mammalian kidney	UBERON:0000082	80.53	gold quality
heart right ventricle	UBERON:0002080	80.41	gold quality
connective tissue	UBERON:0002384	80.22	gold quality
thoracic mammary gland	UBERON:0005200	80.19	gold quality
epithelium of mammary gland	UBERON:0003244	80.17	gold quality

Single-cell (SCXA)

Detected in 18 experiment(s), a significant marker in 17.

Experiment	Marker?	Max mean expression
E-MTAB-10137	yes	45995.76
E-HCAD-15	yes	41263.43
E-HCAD-11	yes	31397.04
E-GEOD-130148	yes	31038.15
E-MTAB-6308	yes	30218.16
E-HCAD-24	yes	29918.64
E-MTAB-6653	yes	27341.62
E-MTAB-8410	yes	26921.19
E-CURD-126	yes	26469.51
E-HCAD-1	yes	26438.39
E-MTAB-6701	yes	23683.11
E-MTAB-8322	yes	16735.37
E-MTAB-8142	yes	12549.25
E-MTAB-8381	yes	8518.60
E-CURD-46	yes	8365.37

HPA expression

RNA tissue specificity: Tissue enriched

showing 60 of 74 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Lymph node	tissue	2551.0	low
Tonsil	tissue	936.7	medium
Spleen	tissue	317.3	medium
Appendix	tissue	254.3	low
Fallopian tube	tissue	238.2	not detected
Breast	tissue	169.3	not detected
Adipose tissue	tissue	162.5	not detected
Cervix	tissue	145.8	not detected
Rectum	tissue	127.3	not detected
Esophagus	tissue	117.9	low
Colon	tissue	101.9	low
Thyroid gland	tissue	95.0	not detected
Lung	tissue	93.8	low
Small intestine	tissue	91.5	not detected
Ovary	tissue	80.2	not detected
Gallbladder	tissue	75.8	not detected
Smooth muscle	tissue	64.4	medium
Vagina	tissue	51.0	medium
Urinary bladder	tissue	47.9	not detected
Adrenal gland	tissue	44.2	not detected
Stomach 1	tissue	44.0	not detected
Duodenum	tissue	43.5	not detected
Skin 1	tissue	43.0	not detected
Liver	tissue	41.2	not detected
Endometrium 1	tissue	38.7	not detected
Epididymis	tissue	32.2	not detected
Heart muscle	tissue	31.2	not detected
Tongue	tissue	28.5
Thymus	tissue	26.9
Seminal vesicle	tissue	17.9	not detected
Salivary gland	tissue	15.4	not detected
Pancreas	tissue	14.4	not detected
Prostate	tissue	13.5	not detected
Testis	tissue	9.6	not detected
Kidney	tissue	9.4	not detected
Skeletal muscle	tissue	4.0	not detected
Pituitary gland	tissue	2.5
Choroid plexus	tissue	2.5
Placenta	tissue	1.6	not detected
Cerebral cortex	tissue	1.1	not detected
Amygdala	tissue	1.1
Locus coeruleus	tissue	1.1
Hippocampal formation	tissue	1.1
Retrosplenial and cingulate cortex	tissue	1.1
Olfactory bulb	tissue	1.1
Insular cortex	tissue	1.1
Motor cortex	tissue	1.0
Hippocampus	tissue	1.0	not detected
Retrosplenial cortex	tissue	1.0
Temporal cortex	tissue	1.0
Prefrontal cortex	tissue	0.9
Nucleus accumbens	tissue	0.9
Cerebellum	tissue	0.9	not detected
Entorhinal cortex	tissue	0.9
Ventral forebrain	tissue	0.9
Periaqueductal gray	tissue	0.9
Parathyroid gland	tissue	0.8	not detected
Basal ganglia	tissue	0.8	not detected
Midbrain	tissue	0.8
Hypothalamus	tissue	0.8

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Blood vessel (101.1), Area postrema (2.1), Piriform cortex (1.7), Kolliker-Fuse nucleus (1.6), Anterior cingulate cortex, supragenual-dorsal (1.5).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB2, RELB, SMAD3

miRNA regulators (miRDB)

Targeting CCL21 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

29 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-6884-5P	99.10	64.50	1987
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-4710	98.61	65.96	1048
HSA-MIR-4722-5P	98.46	66.34	1611
HSA-MIR-624-3P	98.37	67.06	1067
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-4768-3P	98.16	66.02	2330
HSA-MIR-4483	98.09	64.12	1642
HSA-MIR-506-5P	98.02	67.41	1065
HSA-MIR-6893-3P	97.79	64.91	1238
HSA-MIR-6812-5P	97.56	65.39	1059
HSA-MIR-342-5P	97.25	64.10	817
HSA-MIR-939-5P	97.10	65.80	1579
HSA-MIR-370-3P	97.09	64.92	1221
HSA-MIR-331-5P	96.59	67.94	705
HSA-MIR-1343-5P	96.48	66.06	1506
HSA-MIR-6742-5P	96.32	64.01	869
HSA-MIR-6747-5P	96.17	64.99	743
HSA-MIR-1293	96.16	64.69	916
HSA-MIR-9900	96.06	65.48	557

Functional genomics

gnomAD constraint: pLI 0.00103, LOEUF 1.12, missense Z 0.493 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000259607 — one region, missense o/e 0.95.

Literature-anchored findings (GeneRIF, showing 40)

• located in high endothelial venules in an appropriate location to induce transendothelial migration of CLL cells into lymph nodes (PMID:11929789)
• the expression of CCL21 but not CCL19 or 20 was highly induced in endothelial cells of T-cell autoimmune diseases (PMID:12393410)
• CCL21 binding to CCR7 on primary lymphocytes brings about rapid Jak2 phosphorylation. (PMID:12393730)
• Cathepsin D specifically cleaves this protein that is expressed in human breast cancer. (PMID:12651610)
• Most blood vessels in tissue samples from patients with rheumatoid arthritis and ulcerative colitis express CCL21, and many perivascular CD45RA+ naive T cells are found in these tissues, but not in psoriasis, where CCL21+ vessels are rare. (PMID:12707342)
• CCL21 is an antimicrobial protein with bacteriocidal activity against E. coli and S. aureus. (PMID:12949249)
• Expression of CCL21 during chronic hepatitis C is implicated in the recruitment of T lymphocytes and the organization of inflammatory lymphoid tissue and may promote fibrogenesis in the inflamed areas via activation of CCR7 on hepatic stellate cells (PMID:14517790)
• monocyte-derived dendritic cell migration to CCL19 and CCL21 is dependent on phospholipase C and intracellular calcium flux but not on phosphatidylinositol-3 kinase (PMID:14592837)
• 6Ckine may be a potential chemoattractant for endometrial NK cells. (PMID:14667884)
• expression of CCL21, and TLRs 2 and 4 is predominantly induced in the peripheral lymphatic endothelium of the small intestinal microcirculation (PMID:14709406)
• CCL21, a constitutively expressed chemokine, is strongly upregulated in human lymphatic vessels during a Th1/Tc1 allergic inflammatory response. (PMID:14726633)
• Evidence is provided that human CCL21 is a functional ligand for endogenously expressed CXCR3 in human adult microglia. (PMID:14978072)
• CCL21 chemokine has a role in regulating chemokine receptor CCR7 in malignant melanoma (PMID:15073111)
• Activation of CCR7 on mesangial cells by SLC/CCL21 enhances the degree and firmness of cell adhesion and increases cell spreading and the formation of cell-cell contacts (PMID:15569314)
• The CCL-21 chemokine migrated poorly towards the (GFP)-transduced umbilical cord blood (UCB) CD34+ cells. (PMID:15674360)
• no CCL21 mRNA could be detected in high endothelial venules, whereas immunostaining revealed CCL21 protein (PMID:15863780)
• The acquisition of lymphoid features in periductal foci in Sjogrens syndrome is associated with the expression of CXCL13 and CCL21 within the infiltrate. (PMID:15934082)
• The CCL19,CCL21/CCR7 chemokine system is expressed in inflamed muscles of polymyositis and may be involved in the pathomechanism of polymyositis. (PMID:16887149)
• Despite sharing only 25% sequence identity with CCL19, the amino terminal hexapeptide of CCL21 is capable of performing an in vitro role similar to that of CCL19, resulting in G protein activation of the CCR7 receptor. (PMID:16904643)
• chemokine ligand 21 modulates the functional properties of idiopathic pulmonary fibrosis/usual interstitial pneumonia fibroblasts, but not normal fibroblasts (PMID:17331965)
• Results of electrophoresis of the purified SLC protein showed that the molecular weight was larger than the predicted molecular weight. (PMID:17460916)
• The abundance of CD83+ plasmacytoid dendritic cells (DCs) in perivascular areas and the overexpression of CCL19 and CCL21 in perivascular cellular foci suggest plasmacytoid DCs are central to the muscle inflammation in juvenile dermatomyositis. (PMID:17469160)
• prostate-associated lymphoid aggregates, frequently below the epithelia, arranged in B cell follicles expressed CXCL13, and parafollicular T cell areas showed CCL21 expression. (PMID:17474076)
• CXCL13 and CCL21 are expressed in ectopic lymphoid follicles in cutaneous lymphoproliferative disorders. (PMID:17495955)
• after HIV-1 infection of CCL19- or CCL21-treated CD4(+) T-cells, low-level HIV-1 production but high concentrations of integrated HIV-1 DNA, approaching that seen in mitogen-stimulated T-cell blasts, was observed (PMID:17881634)
• CCL21 significantly increased B-cell chronic lymphocytic leukemia MMP-9 production (PMID:17890452)
• knee synovial fluid CCL 21 levels were found to be increased in Rheumatoid arthritis patients as compared to Behcets disease and osteoarthritis patients (PMID:17949547)
• the pattern of CCL21 production in SLOs is maintained during inflammation and that the phenotypic and functional properties of stromal cells, found in SLO T-cell areas, are reproduced at ectopic sites. (PMID:17982129)
• in salivary gland MALT lymphoma the lymphoid chemokines CXCL13 and CCL21 are directly implicated in the organization of ectopic reactive lymphoid tissue (PMID:18354239)
• experiments performed to investigate the survival, adhesion, and metalloproteases secretion indicate that CXCL13 combined with CCL19 and CCL21 mainly affects the chemotaxis of Sezary syndrome cells (PMID:18757429)
• Independent of arrestin 2 or arrestin 3 expression, CCR7/CCL21 internalize. (PMID:18802075)
• Our study implied that lower level of CCL21 in colorectal cancer tissue supports the idea that cancer is related to immunodeficiency (PMID:19082456)
• CCL21 enhances the invasive ability of SW480 cells, induces MMP-9 expression, and promotes the survival of SW480 cells. (PMID:19624896)
• prolonged TLR4 engagement is required for the generation of polySia-expressing DCs that facilitate CCL21 capture and subsequent CCL21-directed migration (PMID:19750015)
• Dendritic cell transfected with secondary lymphoid-tissue chemokine and/or interleukin-2 gene-enhanced cytotoxicity of T-lymphocyte in human bladder tumor cell S in vitro. (PMID:19832038)
• Although CCL21 attracts both human T and B cells, it acts more strongly on naive pathogenic antibody-producing B cells. (PMID:19847900)
• In patients with inflammatory polyarthritis carriage of 1 or more risk alleles of the CCL21 gene was associated with increased cardiovascular disease mortality, whereas carriage of 2 copies was associated with increased all-cause mortality. (PMID:20461788)
• Analysis of migratory and prosurvival pathways induced by the homeostatic chemokines CCL19 and CCL21 in B-cell chronic lymphocytic leukemia. (PMID:20488224)
• Polysialyted NRP2 enhances dendritic cell migration of basic C-terminal ergion of CCL21. (PMID:20488940)
• These results imply a direct role for CCL21 in lymphatic transmigration that involves the selective use of integrin activation in inflammation. (PMID:20739459)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ccl21f	ENSMUSG00000073878
mus_musculus	Ccl21d	ENSMUSG00000094065
mus_musculus	Ccl21a	ENSMUSG00000094686
mus_musculus	Ccl21b	ENSMUSG00000095675
mus_musculus	Ccl21e	ENSMUSG00000096596
rattus_norvegicus	Ccl21	ENSRNOG00000034290

Paralogs (26): CX3CL1 (ENSG00000006210), CCL26 (ENSG00000006606), CCL22 (ENSG00000102962), CCL17 (ENSG00000102970), CCL24 (ENSG00000106178), CCL7 (ENSG00000108688), CCL2 (ENSG00000108691), CCL8 (ENSG00000108700), CCL1 (ENSG00000108702), CCL20 (ENSG00000115009), CCL25 (ENSG00000131142), XCL1 (ENSG00000143184), XCL2 (ENSG00000143185), CCL11 (ENSG00000172156), CCL19 (ENSG00000172724), CCL13 (ENSG00000181374), CCL5 (ENSG00000271503), CCL23 (ENSG00000274736), CCL16 (ENSG00000275152), CCL4 (ENSG00000275302), CCL18 (ENSG00000275385), CCL15 (ENSG00000275718), CCL4L2 (ENSG00000276070), CCL3L3 (ENSG00000276085), CCL14 (ENSG00000276409), CCL3 (ENSG00000277632)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1349183) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 8 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal spleen morphology	1
decreased thymocyte number	1
abnormal negative T cell selection	1
decreased B cell number	1
lacrimal gland inflammation	1
decreased alpha-beta T cell number	1
small thymus medulla	1
decreased tear production	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Macaca fascicularis	P61274	100.0%	Diamond
Macaca mulatta	P61275	100.0%	Diamond
Pongo abelii	Q5RA36	98.0%	Diamond
Sus scrofa	P42831	95.9%	Diamond
Bos taurus	P80343	95.9%	Diamond
Canis lupus familiaris	Q68AZ0	94.6%	Diamond
Equus caballus	Q8MKD0	85.7%	Diamond
Oryctolagus cuniculus	P28292	76.5%	Diamond
Cavia porcellus	P80325	67.7%	Diamond
Human herpesvirus 8 strain GK18	F5HET8	52.3%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
CCL27	protein-coding	10850
PHF24	protein-coding	23349
IL11RA	protein-coding	3590
CCL19	protein-coding	6363
SPATA31F3	protein-coding	100129969
SPATA31F1	protein-coding	259308
DNAJB5-DT	ncRNA	101926900
DNAJB5	protein-coding	25822
GALT	protein-coding	2592

Protein

Protein identifiers

C-C motif chemokine 21 — O00585 (reviewed: O00585)

Alternative names: 6Ckine, Beta-chemokine exodus-2, Secondary lymphoid-tissue chemokine, Small-inducible cytokine A21

All UniProt accessions (4): A0AAQ5BHL9, A0AAQ5BHN2, O00585, Q5VZ73

UniProt curated annotations — full annotation on UniProt →

Function. Binds to atypical chemokine receptor ACKR4 and mediates the recruitment of beta-arrestin (ARRB1/2) to ACKR4. Binds to chemokine receptor CCR7. Does not bind to chemokine receptor CXCR3. Binds to G protein-coupled receptor GPR174. Inhibits hemopoiesis and stimulates chemotaxis. Chemotactic in vitro for thymocytes and activated T-cells, but not for B-cells, macrophages, or neutrophils. Shows preferential activity towards naive T-cells. May play a role in mediating homing of lymphocytes to secondary lymphoid organs.

Subunit / interactions. Monomer PubMed:22221265. Interacts with PDPN; relocalizes PDPN to the basolateral membrane. Interacts with TNFAIP6 (via Link domain) PubMed:27044744.

Subcellular location. Secreted.

Tissue specificity. Highly expressed in high endothelial venules of lymph nodes, spleen and appendix. Intermediate levels found in small intestine, thyroid gland and trachea. Low level expression in thymus, bone marrow, liver, and pancreas. Also found in tonsil, fetal heart and fetal spleen.

Similarity. Belongs to the intercrine beta (chemokine CC) family.

RefSeq proteins (1): NP_002980* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001811	Chemokine_IL8-like_dom	Domain
IPR034133	Chemokine_CC_DCCL	Domain
IPR036048	Interleukin_8-like_sf	Homologous_superfamily
IPR039809	Chemokine_b/g/d	Family

Pfam: PF00048

UniProt features (15 total): strand 3, disulfide bond 3, helix 2, region of interest 2, compositionally biased region 2, signal peptide 1, chain 1, turn 1

Structure

Experimental structures (PDB)

5 structures by resolution:

PDB	Title	Method	Resolution (Å)
5EKI	Crystal Structure of Truncated CCL21	X-RAY DIFFRACTION	1.9
9XHI	Structure of the CCL21-CCR7-Gi-scFv16 complex	ELECTRON MICROSCOPY	3.2
9KO4	A Cryo_EM structure of CCR7 complex with CCL21	ELECTRON MICROSCOPY	3.3
9L16	A local Cryo_EM structure of CCR7 complex with CCL21	ELECTRON MICROSCOPY	3.5
2L4N	Solution Structure of the Chemokine CCL21	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00585-F1	73.71	0.14

Antibody-complex structures (SAbDab)

1 antibodies co-crystallized with this protein: 9KO4

Human Protein Atlas

Protein class: Predicted secreted proteins, Plasma proteins, Cancer-related genes, Candidate cancer biomarkers

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH enhanced

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (3)

Type	Positions
Disulfide bond	31–57, 32–75, 103–122

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 8; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

8 pathways:

ID	Pathway	Evidence
R-HSA-380108	Chemokine receptors bind chemokines	curated
R-HSA-418594	G alpha (i) signalling events	curated
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)	—
R-HSA-388396	GPCR downstream signalling	—
R-HSA-500792	GPCR ligand binding	—
R-HSA-375276	Peptide ligand-binding receptors	—
R-HSA-162582	Signal Transduction	—
R-HSA-372790	Signaling by GPCR	—

MSigDB gene sets: 355 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, MODULE_92, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_DENDRITIC_CELL_MIGRATION, GOBP_REGULATION_OF_T_CELL_CHEMOTAXIS, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_RESPONSE_TO_PROSTAGLANDIN_E, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_LIPID

GO Biological Process (47): establishment of T cell polarity (GO:0001768), immunological synapse formation (GO:0001771), positive regulation of cell-matrix adhesion (GO:0001954), dendritic cell chemotaxis (GO:0002407), positive regulation of dendritic cell antigen processing and presentation (GO:0002606), inflammatory response (GO:0006954), immune response (GO:0006955), G protein-coupled receptor signaling pathway (GO:0007186), cell-cell signaling (GO:0007267), positive regulation of glycoprotein biosynthetic process (GO:0010560), positive regulation of T cell chemotaxis (GO:0010820), positive regulation of cell migration (GO:0030335), positive regulation of actin filament polymerization (GO:0030838), positive regulation of pseudopodium assembly (GO:0031274), T cell costimulation (GO:0031295), ruffle organization (GO:0031529), positive regulation of cell adhesion mediated by integrin (GO:0033630), mesangial cell-matrix adhesion (GO:0035759), chemokine (C-C motif) ligand 21 signaling pathway (GO:0038116), CCL21-activated CCR7 signaling pathway (GO:0038120), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), positive regulation of JNK cascade (GO:0046330), eosinophil chemotaxis (GO:0048245), positive regulation of receptor-mediated endocytosis (GO:0048260), cell maturation (GO:0048469), positive regulation of chemotaxis (GO:0050921), release of sequestered calcium ion into cytosol (GO:0051209), positive regulation of filopodium assembly (GO:0051491), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), cell chemotaxis (GO:0060326), antimicrobial humoral immune response mediated by antimicrobial peptide (GO:0061844), chemokine-mediated signaling pathway (GO:0070098), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cellular response to prostaglandin E stimulus (GO:0071380), positive regulation of neutrophil chemotaxis (GO:0090023), dendritic cell dendrite assembly (GO:0097026), positive regulation of phospholipase C/protein kinase C signal transduction (GO:0141214), negative regulation of leukocyte tethering or rolling (GO:1903237), cellular response to chemokine (GO:1990869), positive regulation of cell motility (GO:2000147), positive regulation of T cell migration (GO:2000406), positive regulation of myeloid dendritic cell chemotaxis (GO:2000529), negative regulation of dendritic cell dendrite assembly (GO:2000548), negative regulation of dendritic cell apoptotic process (GO:2000669), chemotaxis (GO:0006935), signal transduction (GO:0007165), cell migration (GO:0016477)

GO Molecular Function (6): chemokine activity (GO:0008009), CCR7 chemokine receptor binding (GO:0031732), chemokine receptor binding (GO:0042379), CCR chemokine receptor binding (GO:0048020), cytokine activity (GO:0005125), protein binding (GO:0005515)

GO Cellular Component (1): extracellular region (GO:0005576)

Reactome top-level categories

6 top-level categories:

Category	Pathways
Signaling by GPCR	2
Peptide ligand-binding receptors	1
GPCR downstream signalling	1
Signal Transduction	1
GPCR ligand binding	1
Class A/1 (Rhodopsin-like receptors)	1

GO top-level categories

56 GO namespaces:

Category	Terms
cell-matrix adhesion	2
chemokine receptor binding	2
establishment of lymphocyte polarity	1
T cell activation	1
cell-cell recognition	1
lymphocyte activation	1
regulation of cell-matrix adhesion	1
positive regulation of cell-substrate adhesion	1
leukocyte chemotaxis	1
dendritic cell migration	1
dendritic cell antigen processing and presentation	1
positive regulation of antigen processing and presentation	1
regulation of dendritic cell antigen processing and presentation	1
defense response	1
immune system process	1
response to stimulus	1
G protein-coupled receptor activity	1
signal transduction	1
cell communication	1
signaling	1
glycoprotein biosynthetic process	1
positive regulation of macromolecule biosynthetic process	1
regulation of glycoprotein biosynthetic process	1
positive regulation of glycoprotein metabolic process	1
T cell chemotaxis	1
regulation of T cell chemotaxis	1
positive regulation of lymphocyte chemotaxis	1
positive regulation of T cell migration	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
actin filament polymerization	1
regulation of actin filament polymerization	1
positive regulation of protein polymerization	1
positive regulation of cytoskeleton organization	1
positive regulation of supramolecular fiber organization	1
pseudopodium assembly	1
regulation of pseudopodium assembly	1
positive regulation of plasma membrane bounded cell projection assembly	1
lymphocyte costimulation	1
positive regulation of T cell activation	1
plasma membrane bounded cell projection organization	1
cell adhesion mediated by integrin	1
regulation of cell adhesion mediated by integrin	1
positive regulation of cell adhesion	1
chemokine-mediated signaling pathway	1
chemokine (C-C motif) ligand 21 signaling pathway	1
C-C chemokine receptor CCR7 signaling pathway	1
cytokine activity	1
cell chemotaxis	1
CCR chemokine receptor binding	1
G protein-coupled receptor binding	1
cytokine receptor binding	1
receptor ligand activity	1
binding	1
cellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 27 of 55 annotations. The rest are phylogenetic / computational / electronic (IEA).

27 experimentally-supported GO terms:

GO term	NS	Evidence
CCL21-activated CCR7 signaling pathway	BP	direct assay
G protein-coupled receptor signaling pathway	BP	direct assay
cell chemotaxis	BP	direct assay
cellular response to prostaglandin E stimulus	BP	direct assay
dendritic cell chemotaxis	BP	direct assay
establishment of T cell polarity	BP	direct assay
mesangial cell-matrix adhesion	BP	direct assay
negative regulation of dendritic cell apoptotic process	BP	direct assay
negative regulation of leukocyte tethering or rolling	BP	direct assay
positive regulation of ERK1 and ERK2 cascade	BP	direct assay
positive regulation of JNK cascade	BP	direct assay
positive regulation of T cell migration	BP	direct assay
positive regulation of actin filament polymerization	BP	direct assay
positive regulation of canonical NF-kappaB signal transduction	BP	direct assay
positive regulation of cell adhesion mediated by integrin	BP	direct assay
positive regulation of cell motility	BP	direct assay
positive regulation of cell-matrix adhesion	BP	direct assay
positive regulation of filopodium assembly	BP	direct assay
positive regulation of myeloid dendritic cell chemotaxis	BP	direct assay
positive regulation of neutrophil chemotaxis	BP	direct assay
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	BP	direct assay
positive regulation of phospholipase C/protein kinase C signal transduction	BP	direct assay
positive regulation of pseudopodium assembly	BP	direct assay
release of sequestered calcium ion into cytosol	BP	direct assay
ruffle organization	BP	direct assay
chemokine activity	MF	direct assay
chemokine receptor binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,988 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CCL21	CCR7	P32248	961
CCL21	CXCL13	O43927	938
CCL21	CXCL12	P48061	892
CCL21	CXCR5	P32302	889
CCL21	CCL27	Q9Y4X3	837
CCL21	ACKR4	Q9NPB9	824
CCL21	CXCR4	P30991	812
CCL21	CCL25	O15444	802
CCL21	ACKR2	O00590	799
CCL21	CD4	P01730	790
CCL21	CD8A	P01732	775
CCL21	CXCR3	P49682	764
CCL21	CXCL10	P02778	763
CCL21	LYVE1	Q9Y5Y7	751
CCL21	CXCL11	O14625	740

IntAct

Human interaction partners of CCL21 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 33 partners by confidence:

Partner	Interaction type	MIscore	Records
JPH3	physical association	0.560	3
OTP	physical association	0.560	3
TMEM107	physical association	0.560	3
TTMP	physical association	0.560	3
CCL17	direct interaction	0.560	2
CCL5	direct interaction	0.560	2
CXCL12	direct interaction	0.560	2
PF4	direct interaction	0.560	2
CCL13	direct interaction	0.440	2
CCL26	direct interaction	0.440	2
CCL28	direct interaction	0.440	2
CXCL10	direct interaction	0.440	2
CXCL14	direct interaction	0.440	2
CXCL9	direct interaction	0.440	2
PF4V1	direct interaction	0.440	2
CCL23	direct interaction	0.440	1
CCL24	direct interaction	0.440	1
CXCL11	direct interaction	0.440	1
CXCL17	direct interaction	0.440	1
CXCL2	direct interaction	0.440	1
LRRK1	direct interaction	0.440	1
LRRK2	direct interaction	0.440	1
PPBP	direct interaction	0.440	1
XCL1	direct interaction	0.440	1
XCL2	direct interaction	0.440	1
HNRNPA2B1	physical association	0.400	1
OPG170	physical association	0.400	1
SMARCB1	physical association	0.400	1
GOT2	physical association	0.370	1
CLTCL1	association	0.350	1

BioGRID (46 interactions; top human partners by supporting records): CCL13 (Reconstituted Complex; 2 records), CCL26 (Reconstituted Complex; 2 records), CCL28 (Reconstituted Complex; 2 records), CLTCL1 (Affinity Capture-MS; 2 records), CXCL10 (Reconstituted Complex; 2 records), CXCL14 (Reconstituted Complex; 2 records), CXCL9 (Reconstituted Complex; 2 records), KLHL26 (Affinity Capture-MS; 2 records), PF4V1 (Reconstituted Complex; 2 records), TRIP6 (Affinity Capture-MS; 2 records), ACKR4 (Reconstituted Complex), C3orf52 (Two-hybrid), CCL17 (Reconstituted Complex), CCL23 (Reconstituted Complex), CCL24 (Reconstituted Complex)

SIGNOR signaling

2 signaling interactions:

A	Effect	B	Mechanism
CCL21	up-regulates	CCR7	binding
CCL21	“up-regulates activity”	ACKR4	binding

Ligand–receptor pairs (CellPhoneDB) (2)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

2 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
CCR7	ligand	Signaling by Chemokines
ACKR4	ligand	Signaling by Chemokines

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 33 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Chemokine receptors bind chemokines	14	124.8×	3e-26
G alpha (i) signalling events	12	22.3×	6e-13
Class A/1 (Rhodopsin-like receptors)	6	21.2×	5e-06
Peptide ligand-binding receptors	6	21.2×	5e-06
GPCR ligand binding	6	18.3×	9e-06
Signaling by GPCR	6	11.4×	1e-04
GPCR downstream signalling	5	10.3×	9e-04

GO biological processes:

GO term	Partners	Fold	FDR
chemokine-mediated signaling pathway	12	125.5×	1e-20
monocyte chemotaxis	5	93.7×	8e-08
neutrophil chemotaxis	8	73.7×	7e-12
antimicrobial humoral immune response mediated by antimicrobial peptide	12	62.7×	2e-17
chemotaxis	13	57.0×	3e-18
cell chemotaxis	9	53.8×	4e-12
cell-cell signaling	11	24.7×	2e-11
inflammatory response	17	20.7×	2e-17

Disease & clinical

Genetic variants

Variant evidence for CCL21: 19 ClinVar records (0 pathogenic / likely pathogenic); 13 GWAS associations.

ClinVar

19 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	14
Likely benign	2
Benign	1

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 26 predictions of 212):

Position(s)	Effect	Δscore	Sites
9:34709523	donor_gain	1.0000
9:34709532	donor_gain	0.9900
9:34709558	donor_gain	0.9900
9:34709683–34709684	acceptor_loss	0.9900	5
9:34709775–34709776	donor_loss	0.9900	6
9:34709783	donor_gain	0.9900
9:34709998–34709999	donor_loss	0.9900	5
9:34709772	donor_loss	0.9800
9:34709998	donor_loss	0.9800
9:34709428–34709429	acceptor_loss	0.9700	4

AlphaMissense

185 missense substitutions predicted likely pathogenic (of 859 scored), across 52 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F64	8	0.939	0.996
D30	8	0.882	0.949
C75	7	0.982	0.994
C57	7	0.979	0.994
C32	7	0.969	0.986
C31	7	0.963	0.981
W82	7	0.953	0.998
V83	6	0.871	0.966
Q51	6	0.866	0.983
G56	6	0.830	0.949
I40	6	0.791	0.986
P78	6	0.753	0.812
D77	6	0.685	0.852
Y48	5	0.939	0.982
Y35	5	0.806	0.946
I62	5	0.805	0.955
S36	5	0.766	0.831
S47	5	0.590	0.601
A61	4	0.938	0.981
V45	4	0.795	0.989

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Papillary Cell Carcinoma (TCGA)	unfavorable	0.000727

Disease associations

OMIM: gene MIM:602737 | disease phenotypes:

GWAS associations

13 associations:

Study	Trait	p-value
GCST002318_38	Rheumatoid arthritis	2e-15
GCST002318_89	Rheumatoid arthritis	3e-15
GCST006959_159	Rheumatoid arthritis	1e-13
GCST006959_48	Rheumatoid arthritis	2e-13
GCST009877_7	Rheumatoid arthritis	4e-11
GCST006048_33	Rheumatoid arthritis (ACPA-positive)	5e-11
GCST006585_1206	Blood protein levels	2e-10
GCST005568_13	Rheumatoid arthritis (ACPA-positive)	1e-9
GCST009873_37	Autoimmune traits (pleiotropy)	1e-9
GCST005537_28	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	6e-9
GCST005569_14	Rheumatoid arthritis	9e-9
GCST000232_8	Rheumatoid arthritis	3e-8
GCST009874_34	Celiac disease	5e-6

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

30 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
usnic acid	affects cotreatment, increases expression	2
Arsenic	decreases expression, affects expression, affects cotreatment	2
Nickel	increases expression	2
propionaldehyde	decreases expression	1
bromoacetate	decreases expression	1
ferrous sulfate	decreases expression	1
1-nitropyrene	decreases expression	1
Capecitabine	decreases expression	1
Air Pollutants	increases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Dihydroxyacetone	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	decreases expression	1
Ferric Compounds	increases expression	1
Fluorides	decreases expression, affects cotreatment	1
Hydrogen Peroxide	increases secretion	1
Latex	increases expression	1
Lipopolysaccharides	affects cotreatment, increases expression	1
Methotrexate	decreases expression	1
Mustard Gas	increases secretion	1
Perfume	increases expression	1
Silicon Dioxide	decreases expression	1
Valproic Acid	decreases methylation	1
Zearalenone	increases expression	1
Aflatoxin B1	increases methylation	1
Asbestos, Amphibole	affects expression	1
Zinc Compounds	increases expression	1
Sodium Selenite	increases expression	1
Particulate Matter	increases abundance, increases expression	1
Soot	decreases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.