Affinage

CCL21

C-C motif chemokine 21 · UniProt O00585

Length
134 aa
Mass
14.6 kDa
Annotated
2026-06-09
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCL21 is a constitutively expressed CC chemokine that organizes immune cell trafficking and lymphoid tissue architecture by signaling through its Gαi-linked receptor CCR7 (PMID:10620605, PMID:10201903). Presented on the luminal surface of high endothelial venules, it triggers LFA-1–mediated arrest of rolling T cells and is both necessary and sufficient for this adhesion step (PMID:10620605), while acting as a ~1000-fold more potent chemoattractant for mature dendritic cells than for naive T cells (PMID:10201903); CCL21 alone is sufficient to drive DC migration to lymph nodes, full DC maturation, and T cell priming, rendering its paralog CCL19 functionally redundant for these processes (PMID:20201039). Effective trafficking depends on a properly shaped extracellular gradient: disrupting the gradient by ectopic T cell overexpression scrambles directional migration (PMID:11739157), gradient formation in T-zone fibroblastic reticular cells requires interstitial fluid flow (PMID:19734211), and the atypical receptor ACKR4 scavenges both immobilized full-length and cleaved soluble CCL21 to keep barrier-tissue gradients functional (PMID:33875601). Ectopic CCL21 expression is sufficient to nucleate organized ectopic lymphoid tissue with HEVs in a CCR7-dependent, lymphotoxin-independent manner (PMID:10754285, PMID:15470018), and CCL21/CCR7 also recruits NK cells, hematopoietic progenitors, and CCR7+ fibrocytes, the latter driving renal fibrosis (PMID:10496316, PMID:10222066, PMID:16966615). Beyond CCR7, CCL21 was identified by biochemical fractionation as a ligand for the GPCR GPR174, through which it positions B cells at the T–B border and suppresses germinal center formation in a testosterone-dependent manner (PMID:31875850); mouse (but not human) CCL21 additionally signals through CXCR3 to mediate angiostasis (PMID:9653165, PMID:10201891). In neurons, CCL21 is sorted into large dense-core vesicles and transported into axons, where injury-induced neuronal CCL21 reaches dorsal horn microglia and up-regulates the P2X4 receptor to initiate tactile allodynia (PMID:18697841, PMID:21441897). In disease and cancer contexts, CCL21/CCR7 engages ERK/Akt/NF-κB, JAK2/STAT3, and AKT/GSK-3β/Snail signaling to promote migration, invasion, EMT, and metalloproteinase induction (PMID:14517790, PMID:17890452, PMID:32017846, PMID:26667143). CCL21–CCR7 engagement is tuned post-translationally: CCR7 N-terminal sulfotyrosines enhance CCL21 binding (PMID:28841151), and an autoproteolytic C-terminal CCL21 peptide boosts CCR7 signaling ~100-fold through interaction with sialylated O-glycans on the receptor (PMID:34586443). CD4+ T cell costimulation by CCL21 proceeds via a DOCK2/Rac-dependent pathway (PMID:19451552).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1998 Medium

    Established the receptor repertoire of CCL21 beyond CCR7, asking whether it could engage CXC receptors.

    Evidence Calcium flux in mouse CXCR3-transfected cells plus chemokine panel screen

    PMID:9653165

    Open questions at the time
    • Species generality untested at this stage
    • Physiological relevance of CXCR3 signaling not addressed
  2. 1999 High

    Resolved a species-specific receptor difference, showing human CCL21 does not use CXCR3 while remaining a full CCR7 agonist.

    Evidence Calcium flux and radiolabeled IP-10 competition binding in CXCR3 transfectants with CCR7 agonism controls

    PMID:10201891

    Open questions at the time
    • Structural basis for the human/mouse CXCR3 difference not defined
  3. 1999 High

    Defined CCL21 as a potent CCR7 chemoattractant with strong cell-type selectivity for dendritic cells over naive T cells.

    Evidence Transwell chemotaxis and ex vivo skin DC egress assays across multiple DC populations

    PMID:10201903

    Open questions at the time
    • In vivo necessity not yet established
    • Mechanism of DC>T cell potency unexplained
  4. 1999 Medium

    Extended CCL21 chemoattractant activity to hematopoietic progenitors and NK/lymphoid progenitor subsets, distinguishing CCR7- versus CXCR3-mediated effects.

    Evidence Chemotaxis, actin polymerization, and proliferation assays with primary human cells and cross-desensitization

    PMID:10222066 PMID:10496316

    Open questions at the time
    • In vivo relevance for progenitor trafficking untested
    • Single-lab functional assays
  5. 1999 High

    Identified the genetic basis of CCL21 deficiency in plt/plt mice, enabling later loss-of-function interpretation.

    Evidence Genetic mapping and gene deletion/expression analysis

    PMID:10523616

    Open questions at the time
    • Does not address functional consequences directly
  6. 2000 High

    Demonstrated CCL21 is necessary and sufficient on HEVs to convert T cell rolling into firm LFA-1–mediated arrest via CCR7.

    Evidence Intravital microscopy, CCR7 desensitization, and intracutaneous rescue in plt/plt mice

    PMID:10620605

    Open questions at the time
    • Downstream integrin activation signaling not dissected
  7. 2000 High

    Showed CCL21 is sufficient to nucleate organized ectopic lymphoid tissue and mediate antitumor immunity, linking it to tissue organization beyond cell guidance.

    Evidence Transgenic islet expression with CCR7/RAG-1/Ikaros epistasis; tumor transduction with depletion and Matrigel assays

    PMID:10754285 PMID:10925282

    Open questions at the time
    • Stromal cellular intermediates of lymphoid neogenesis not fully defined
  8. 2001 Medium

    Established that a proper CCL21 concentration gradient, not just its presence, is required for productive T cell trafficking.

    Evidence lck-CCL21 transgenic mice abolishing the gradient with chemotaxis and lymph node analyses

    PMID:11739157

    Open questions at the time
    • Quantitative gradient parameters in vivo not measured
    • Single transgenic model
  9. 2003 Medium

    Defined intracellular signaling (ERK/Akt/NF-κB) and an interdependent IFNγ/CXCL9/CXCL10 effector network downstream of CCL21.

    Evidence Hepatic stellate cell signaling western blots; in vivo cytokine neutralization epistasis in tumors

    PMID:12740040 PMID:14517790

    Open questions at the time
    • Direct receptor-to-kinase coupling not reconstituted
    • Cell-type generality of pathway use unclear
  10. 2004 High

    Confirmed CCR7-dependent, lymphotoxin-independent lymphoid neogenesis in a second organ, generalizing the tissue-organizing function.

    Evidence Thyroglobulin-promoter CCL21 transgenics crossed to L-selectin, lymphotoxin-α, and CCR7 KO mice

    PMID:15470018

    Open questions at the time
    • Initiating stromal cell type for HEV induction not identified
  11. 2006 High

    Revealed CCL21 roles in fibrocyte-driven fibrosis and in terminating immune responses via activation-induced cell death.

    Evidence Anti-CCL21 blockade plus CCR7-null mice in ureteral obstruction; plt/plt immunization with FasL/AICD analysis

    PMID:16966615 PMID:16973962

    Open questions at the time
    • Molecular link from CCR7 to FasL induction not defined
    • Fibrocyte recruitment signaling unresolved
  12. 2008 High

    Showed neuronal CCL21 is sorted into dense-core vesicles and directionally transported into axons, positioning it for neuron-to-glia signaling.

    Evidence Live-cell imaging and subcellular fractionation in neurons

    PMID:18697841

    Open questions at the time
    • Trafficking machinery and release triggers not identified
  13. 2009 High

    Defined CCL21 T cell costimulation through a DOCK2/Rac module and dissected its biochemical wiring.

    Evidence T cell costimulation with DOCK2-deficient and PI3K mutant mice, GTP pull-downs, and lymph node imaging

    PMID:19451552

    Open questions at the time
    • How CCR7 selectively activates DOCK2/Rac over Ras not resolved
  14. 2010 High

    Genetically separated CCL21 from CCL19, establishing CCL21 alone as sufficient for DC homeostasis and priming.

    Evidence CCL19-deficient mice with variable CCL21 and DC migration/maturation/priming readouts

    PMID:20201039

    Open questions at the time
    • Conditions where CCL19 becomes non-redundant not established
  15. 2011 High

    Demonstrated injury-induced neuronal CCL21 initiates neuropathic pain by up-regulating microglial P2X4.

    Evidence CCL21-deficient mice, intrathecal rescue, and P2X4 antagonism with behavioral allodynia assays

    PMID:21441897

    Open questions at the time
    • Receptor on microglia mediating P2X4 induction not identified
  16. 2015 Medium

    Linked CCL21/CCR7 to cancer dissemination programs via VEGF-C/AKT lymphangiogenesis and AKT/GSK-3β/Snail-driven stemness.

    Evidence Orthotopic xenografts with gene manipulation and AKT/PI3K inhibition; sphere and survival assays

    PMID:25744065 PMID:27057280

    Open questions at the time
    • Snail/AKT placement rests on single-inhibitor evidence (#29)
    • Direct receptor-pathway coupling not reconstituted
  17. 2017 Medium

    Defined post-translational tuning of the CCL21–CCR7 interface via CCR7 sulfotyrosines, and a fibroblast podoplanin contact.

    Evidence Protein NMR with sulfotyrosine peptides; co-culture adhesion assays with PDPN overexpression under hypoxia

    PMID:28416768 PMID:28841151

    Open questions at the time
    • CCL21–podoplanin binding inferred functionally, not measured directly (#26)
    • In vivo relevance of sulfotyrosine enhancement untested
  18. 2019 High

    Identified CCL21 as a GPR174 ligand controlling sex-biased B cell positioning, and extended CCL21 signaling to macrophage-driven Th17/osteoclast pathways.

    Evidence Biochemical ligand fractionation, GPR174 calcium flux and KO, hormonal manipulation; macrophage polarization with cytokine blockade

    PMID:31342120 PMID:31875850

    Open questions at the time
    • Structural basis of CCL21–GPR174 engagement not defined
    • Whether GPR174 and CCR7 effects are competitive unknown
  19. 2020 Medium

    Extended CCL21/CCR7 to additional cancer signaling axes (JAK2/STAT3 EMT) and neuron-directed pancreatic cancer cell migration and pain.

    Evidence CCL21 stimulation with JAK2/STAT3 inhibition in OSCC; DRG/PDAC co-culture screen with in vivo neutralization

    PMID:32017846 PMID:32330476

    Open questions at the time
    • Generality of JAK2/STAT3 use across tumors unclear
    • Single-lab pathway placements
  20. 2021 High

    Resolved how CCL21 gradients are sculpted (ACKR4 scavenging of two forms) and how a cleavage peptide amplifies CCR7 signaling, plus an lncRNA-mediated cancer axis.

    Evidence ACKR4-deficient mice with quantification of full-length/soluble CCL21; CCR7 glycosylation mutants with the C21TP peptide; RNA pull-down/RIP for MALAT1/SRSF1/mTOR

    PMID:33875601 PMID:34001131 PMID:34586443

    Open questions at the time
    • Protease generating soluble/C-terminal CCL21 not identified
    • In vivo contribution of glycan-dependent boosting unmeasured

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CCL21 integrates competing CCR7 and GPR174 signals, what proteases generate its soluble and C-terminal forms, and the structural basis for its multi-receptor recognition remain open.
  • No identified protease for CCL21 cleavage products
  • No structure of CCL21 bound to full-length CCR7 or GPR174
  • Mechanism dictating CCR7 vs GPR174 outcome unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005576 extracellular region 3 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-1266738 Developmental Biology 2
Partners
ACKR4CCR7CXCR3GPR174PDPN

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 CCL21 (TCA4/SLC/6Ckine/Exodus-2) is constitutively presented on the luminal surface of high endothelial venules (HEVs) in peripheral lymph nodes, where it triggers LFA-1-mediated arrest of rolling T lymphocytes via its receptor CCR7 (a Gαi-linked receptor). Desensitization of CCR7 blocked T cell adherence; desensitization of CXCR4 did not. Intracutaneous injection of CCL21 into plt/plt mice (which lack luminal HEV CCL21) restored T cell arrest, demonstrating CCL21 is both necessary and sufficient for LFA-1 activation on rolling T cells. Intravital microscopy of murine PLNs; adoptive transfer of GFP-labeled T cells; CCR7 desensitization; intracutaneous chemokine injection into plt/plt mice The Journal of experimental medicine High 10620605
1998 Mouse CCL21 (6Ckine) binds and signals through the CXC chemokine receptor CXCR3 in addition to CCR7, inducing calcium flux in CXCR3-transfected cells; it also has angiostatic properties consistent with other CXCR3 ligands. Calcium flux assay in mouse CXCR3-transfected cells; chemokine panel screen Proceedings of the National Academy of Sciences of the United States of America Medium 9653165
1999 Human CCL21 (6Ckine) does NOT bind or signal through human or mouse CXCR3; it does not induce calcium flux in CXCR3-transfected cells and does not compete with radiolabeled IP-10 for CXCR3 binding. Human CCL21 is an equally potent agonist as mouse 6Ckine at human CCR7. This establishes a species-specific difference: mouse but not human CCL21 is a CXCR3 ligand. Calcium flux assay in CXCR3-transfected cells; radiolabeled ligand competition binding; CCR7 agonism assay Journal of immunology (Baltimore, Md. : 1950) High 10201891
1999 CCL21 (SLC/6Ckine/Exodus-2/TCA4) and CCL19 (CKbeta-11) are both ligands for CCR7 and act as potent chemoattractants for mature dendritic cells (MHC class IIhigh B7-2high bone marrow-derived DCs), freshly isolated lymph node DCs, and skin DCs ex vivo, at a potency ~1000-fold greater than their activity on naive T cells. Transwell chemotaxis assay; ex vivo skin DC egress assay Journal of immunology (Baltimore, Md. : 1950) High 10201903
1999 The reduced expression of CCL21 in plt/plt mice results from deletion of one of two 6Ckine genes; a second 6Ckine gene remains intact and expressed in plt mice. This defines the genetic basis for CCL21 deficiency in these mice. Genetic mapping; gene deletion analysis; expression analysis by RT-PCR The Journal of experimental medicine High 10523616
2000 Ectopic expression of CCL21 (TCA4/SLC) in pancreatic islets is sufficient to trigger the development and organization of lymphoid tissue, including high endothelial venules and stromal reticulum, through differential recruitment of CCR7+ T cells, dendritic cells, and B cells. Lymphocyte recruitment required CCR7 expression and was independent of L-selectin or lymphotoxin-α. Transgenic mouse model (islet CCL21 expression); genetic crosses with RAG-1 KO and Ikaros KO mice; histology Journal of immunology (Baltimore, Md. : 1950) High 10754285
2000 Mouse CCL21 (6Ckine/SLC) has antitumor effects via two mechanisms: (1) angiostasis through CXCR3 interaction (demonstrated by Matrigel assay and immunohistochemistry), and (2) immunological mechanisms including recruitment of granulocytes, dendritic cells, and CD8+ T cells to tumors, with induction of CD8+ T cell-mediated and NK cell-mediated tumor resistance. Tumor transduction with CCL21 cDNA; Matrigel angiogenesis assay; in vivo immune cell depletion (anti-CD8, anti-asialo-GM1); tumor challenge in immunocompetent and nude mice; immunohistochemistry Journal of immunology (Baltimore, Md. : 1950) Medium 10925282
1999 CCL21 (SLC/Exodus2/6Ckine/TCA4) acts as a chemoattractant for CD34+ hematopoietic progenitor cells (HPCs), preferentially attracting macrophage progenitors. CCL21 induces actin polymerization in CD34+ cells via CCR7 (not CXCR3). CCL21 also inhibits myeloid progenitor proliferation via CXCR3. Chemotaxis assay with human CD34+ HPCs; actin polymerization assay; progenitor proliferation suppression assay; receptor-specific ligand comparisons Journal of leukocyte biology Medium 10496316
1999 CCL21 (SLC/6Ckine/Exodus2/TCA4) and CCL19 (CKbeta-11) are chemoattractants for CD56+CD16- NK cell subsets and late-stage lymphoid progenitors (CD34-CD19+IgM- B-cell progenitors, CD4+ and CD8+ single-positive thymocytes) via CCR7. CCL21 is an efficient desensitizer of CCL19-dependent NK cell chemotaxis, while CCL19 is only a weak desensitizer of CCL21-dependent chemotaxis. Chemotaxis assay with cord blood and adult peripheral blood NK cells and cell lines; cross-desensitization experiments Cellular immunology Medium 10222066
2002 CCL21 (SLC) and its receptor CCR7 are constitutively expressed in the human kidney (CCR7 in mesangial cells, CCL21 in podocytes). CCR7 activation by CCL21 promotes human mesangial cell migration, proliferation, wound healing in vitro, and protects against Fas antibody-induced apoptosis, suggesting a role in glomerular homeostasis. Immunohistochemistry; RT-PCR; RNase protection assays; FACS; real-time PCR of microdissected glomeruli; migration assay; proliferation assay; wound healing assay; apoptosis assay Journal of immunology (Baltimore, Md. : 1950) Medium 11970971
2003 CCL21 activates CCR7 on hepatic stellate cells (HSCs), stimulating HSC migration and wound healing in vitro. CCR7 activation by CCL21 triggers ERK, Akt, and NF-κB signaling pathways in HSCs, resulting in induction of pro-inflammatory genes. In vitro migration assay; wound healing assay; western blot for signaling pathways; immunohistochemistry; in situ hybridization Gastroenterology Medium 14517790
2006 CCL21/CCR7 blockade reduces the number of CCR7+ fibrocyte infiltration into the kidney and reduces renal fibrosis in a unilateral ureteral obstruction model. CCR7-null mice show concomitant reduction in renal fibrosis, confirming that CCL21/CCR7 signaling drives fibrocyte migration into the kidney and contributes to fibrogenesis. Anti-CCL21 antibody blockade in vivo; CCR7-null mouse model; histology; quantitative PCR for collagen and TGF-β1 Proceedings of the National Academy of Sciences of the United States of America High 16966615
2008 In neurons, CCL21 is sorted into large dense-core vesicles (regulated secretory granules) and is preferentially transported into axons (not dendrites), as shown by live-cell imaging. This directed axonal transport positions CCL21 for site-specific neuron-to-microglia signaling. Live-cell imaging; subcellular fractionation; fluorescence microscopy identifying vesicle type FASEB journal : official publication of the Federation of American Societies for Experimental Biology High 18697841
2011 CCL21 is rapidly expressed in injured small-sized primary sensory neurons after peripheral nerve injury and transported to their central terminals in the dorsal horn. Neuronal CCL21 up-regulates microglial P2X4 receptor expression, which is required for tactile allodynia (neuropathic pain). CCL21-deficient mice fail to develop allodynia or up-regulate P2X4; intrathecal injection of CCL21 rescues allodynia in CCL21-deficient nerve-injured mice in a P2X4-dependent manner. Intrathecal CCL21-blocking antibody; CCL21-deficient mice; intrathecal CCL21 injection rescue; P2X4 receptor antagonism; in vitro CCL21 application to microglia; behavioral allodynia assay The EMBO journal High 21441897
2009 CCL21 mediates CD4+ T cell costimulation via CCR7 through a DOCK2/Rac-dependent pathway. CCL21 costimulation during TCR activation increases T cell proliferation, activation marker expression, and enhances Ras- and Rac-GTP formation, Akt, MEK, and ERK phosphorylation. DOCK2 deficiency selectively impairs CCL21-mediated costimulation and Rac-GTP formation without affecting Ras-GTP. PI3Kδ and PI3Kγ are not required. In vitro T cell activation assay; CCL21 costimulation; phosphorylation analysis by western blot; DOCK2-deficient TCR-tg mice; PI3Kδ kinase-dead and PI3Kγ KO mice; lymph node slice live imaging; GTP pull-down assays Blood High 19451552
2009 Fluid flow (interstitial flow through lymph node conduit system) is required for CCL21 expression by T zone fibroblastic reticular cells (TRCs). In a 3D scaffold model, CCL21 secretion by TRCs was undetectable without flow but induced by slow interstitial flow (1–23 µm/min). Blocking lymph flow in mice in vivo down-regulated CCL21 gene expression within 2 hours. 3D scaffold tissue engineering; interstitial flow application; ELISA for CCL21; in vivo lymph flow blockade; real-time PCR Journal of immunology (Baltimore, Md. : 1950) Medium 19734211
2004 Transgenic expression of CCL21 from the thyroglobulin promoter drives lymphocyte recruitment to the thyroid and formation of organized B/T cell-segregated lymphoid tissue with HEVs. Recruitment was CCR7-dependent and independent of L-selectin or lymphotoxin-α, establishing CCL21 as sufficient to induce ectopic lymphoid neogenesis in the thyroid via CCR7. Transgenic mouse model; genetic crosses (L-selectin KO, lymphotoxin-α KO, CCR7-deficient mice); histology; flow cytometry Journal of immunology (Baltimore, Md. : 1950) High 15470018
2007 CCL21/CCR7 interaction up-regulates MMP-9 production in B-CLL cells via the ERK1/2/c-Fos signaling pathway and increased MMP-9 mRNA. MMP-9 is functionally involved in CCL21-driven B-CLL cell migration through Matrigel and HUVEC monolayers; blockade by anti-CCR7 antibodies, CCR7-siRNA, ERK1/2 inhibitor (U0126), anti-MMP-9, or TIMP-1 all inhibited migration. Gelatin zymography; ERK1/2 inhibition; CCR7-siRNA transfection; western blot; RT-PCR; Matrigel invasion assay; HUVEC migration assay; antibody blockade Blood High 17890452
2001 Transgenic overexpression of CCL21 in T cells (under lck promoter), which abolishes the normal CCL21 concentration gradient, disrupts T cell migration in response to CCL21 and CCL19, alters lymph node T cell subpopulations, and disrupts lymph node architecture. This establishes that CCL21-mediated T cell trafficking requires a proper concentration gradient. Transgenic mouse model (lck-CCL21); chemotaxis assay; lymph node histology and flow cytometry Blood Medium 11739157
2010 CCL21 alone (without CCL19) is sufficient to mediate DC migration from peripheral tissues to lymph nodes, full DC maturation, and efficient T cell priming in vivo. Complete deficiency of both CCL19 and CCL21 (but not CCL19 alone) causes abnormal DC frequencies and localization. CCL19 is therefore redundant for DC homeostasis and function in vivo. CCL19-deficient mice with variable CCL21 levels; flow cytometry of DC populations; skin DC migration assay; T cell priming assay European journal of immunology High 20201039
2019 CCL21 is identified as a ligand for GPR174 (an X-chromosome-encoded GPCR) by biochemical fractionation of conditioned media. CCL21 triggers GPR174-dependent calcium flux and preferentially induces migration of male B cells. GPR174 becomes associated with more Gαi protein in male than female B cells, an effect regulated by testosterone. GPR174-CCL21 suppresses germinal center formation in males by positioning B cells toward the T-B border rather than the follicular center. Biochemical fractionation of conditioned media; calcium flux assay; B cell migration assay; co-immunoprecipitation of GPR174-Gαi; orchidectomy and testosterone treatment; GPR174-conditional KO; experimental autoimmune encephalomyelitis model Nature High 31875850
2015 CCL21/CCR7 axis promotes breast cancer-associated lymphangiogenesis by regulating VEGF-C expression and secretion from breast cancer cells via AKT signaling. CCL21/CCR7 promotes proliferation, migration, and tube formation of primary lymphatic endothelial cells. In vivo, CCR7 expression by breast cancer cells promotes lymph-vascular recruitment. CCR7/CCL21 gene manipulation in orthotopic xenograft model; quantitative RT-PCR; immunohistochemistry; LEC proliferation/migration/tube formation assays; AKT pathway inhibition Molecular cancer Medium 25744065
2020 CCL21/CCR7 interaction promotes EMT and enhances cancer stem cell properties in OSCC cells via activation of the JAK2/STAT3 signaling pathway. CCL21 stimulation increases phospho-JAK2 and phospho-STAT3; JAK2/STAT3 inhibitor suppresses CCL21-induced EMT and stemness. CCR7 knockdown or overexpression modulates these effects. Exogenous CCL21 stimulation; CCR7 knockdown/overexpression; western blot for JAK2/STAT3 phosphorylation; JAK2/STAT3 inhibitor; migration/invasion/tumorsphere assays Journal of cellular physiology Medium 32017846
2015 CCL21-CCR7 signaling up-regulates MUC1 via the ERK1/2 pathway in esophageal squamous cell carcinoma (ESCC) cells. CCL21 activates ERK1/2 and Akt; ERK1/2 phosphorylates Sp1, which increases Sp1 binding to the MUC1 promoter at -99/-90. MUC1 knockdown suppresses CCL21-induced invasion and migration. Western blot; luciferase reporter assay; ChIP; CCR7-siRNA; ERK1/2/Akt inhibitors; qRT-PCR; transwell invasion/migration assay Journal of experimental & clinical cancer research : CR Medium 26667143
2019 CCL21 stimulation of macrophages increases M1 polarization (CD14+CD86+), elevating IL-6 and IL-23 transcription. These CCL21-induced M1 cytokines differentiate naïve T cells to Th17 cells (not Th1), which then drive osteoclastogenesis. Blockade of IL-6, IL-23, or IL-17 impairs CCL21-induced osteoclastogenesis. CCL21 also promotes neovascularization in RA. In vitro macrophage polarization; T cell differentiation assay; osteoclastogenesis assay; cytokine blocking antibodies; flow cytometry; RA mouse model Cellular and molecular life sciences : CMLS Medium 31342120
2021 CCL21 exists in two forms in steady-state barrier tissues: full-length immobilized and cleaved soluble CCL21. Both forms are regulated/scavenged by ACKR4. Without ACKR4, CCL21 gradients in barrier sites are saturated and nonfunctional, preventing DCs from homing directly to lymphatic vessels; excess soluble CCL21 from peripheral tissues accumulates in downstream lymph nodes. ACKR4-deficient mice; quantitative measurement of CCL21 forms in skin and LNs; DC migration assays; flow cytometry Proceedings of the National Academy of Sciences of the United States of America High 33875601
2017 CCL21 binds to podoplanin (PDPN) expressed on cancer-associated fibroblasts (CAFs). This CCL21/PDPN interaction modulates the CCL21/CCR7 axis in a hypoxia-dependent manner, affecting NK cell and tumor cell adhesion to endothelial cells and CAFs. Hypoxia-induced PDPN overexpression reduces adhesion in the absence of CCL21, acting as an anti-adhesion molecule. Co-culture adhesion assays; hypoxia induction; CCR7/CCL21 expression analysis; PDPN overexpression model; microRNA analysis (miR-210, miR-21, miR-29b) Oncotarget Low 28416768
2017 CCR7 sulfotyrosine (sY) at positions 8 and 17 enhances CCL21 binding affinity compared to unmodified tyrosine or phosphotyrosine. sY8-containing peptides bind near the α-helix of CCL21, while sY17-containing peptides bind near the N-loop and β3-strand. This defines the structural basis for posttranslational modification-enhanced CCL21-CCR7 interaction. Protein NMR spectroscopy with CCL21 and CCR7 N-terminal peptides containing Y, pY, or sY International journal of molecular sciences High 28841151
2021 A 41-amino acid C-terminal peptide of CCL21 (C21TP), released by proteolytic cleavage, boosts CCL21 chemotactic activity by up to 25-fold and CCR7 signaling by ~100-fold. This boosting effect is dependent on O-glycosylations in the CCR7 N-terminus and involves direct interaction of the positively charged C21TP with sialylated O-glycans in the CCR7 N-terminus, creating a more accessible receptor conformation for CCL21 docking. This effect does not involve glycosaminoglycan (GAG)-mediated cell-surface retention. Chemotaxis assay; CCR7 signaling assay; CCR7 N-terminus glycosylation mutants; peptide interaction experiments; GAG competition assays Cellular and molecular life sciences : CMLS Medium 34586443
2015 CCL21 facilitates chemoresistance and cancer stem cell properties in colorectal cancer cells via AKT/GSK-3β/Snail signaling. CCL21 increases Snail protein (but not mRNA) levels, indicating post-transcriptional regulation; CCL21 phosphorylates both AKT and GSK-3β. PI3K/Akt inhibitor (LY294002) abolishes CCL21-induced chemoresistance and stem cell properties. CCL21 stimulation; western blot; RT-PCR; PI3K/Akt inhibition; sphere formation assay; cell survival assay Oxidative medicine and cellular longevity Low 27057280
2020 Sensory neuron-derived CCL21 promotes migration of pancreatic cancer cells toward sensory neurons via CCR7 expressed on PDAC cells. Neutralization of CCL21 or its receptor CCR7 in mice with orthotopic tumors significantly reduces nociceptive hypersensitivity and nerve fiber hypertrophy, without affecting tumor infiltration by T cells or neutrophils. RNA-interference screen in DRG neuron/PDAC co-cultures; neutralizing antibody treatment in orthotopic mouse model; behavioral pain assays; immunohistochemistry; immunoblotting Gastroenterology Medium 32330476
2003 SLC/CCL21-mediated antitumor responses in vivo require IFNγ, MIG/CXCL9, and IP-10/CXCL10. In vivo depletion of any one of these cytokines reduces CCL21 antitumor efficacy and causes concomitant decreases in the others, demonstrating interdependence. Neutralization of any one also reduces CXCR3+ T cells and CD11c+ DCs at the tumor site. In vivo cytokine/chemokine neutralization (depletion antibodies); tumor challenge model; cytokine measurement at tumor site; flow cytometry for immune cell populations Molecular cancer Medium 12740040
2006 CCL21 and CCL19 expressed in secondary lymphoid organs promote activation-induced cell death (AICD) of antigen-responding CD4+ T cells during the clonal contraction phase, partially through enhancing Fas ligand expression. In plt mice lacking CCL19/CCL21, antigen-responsive T cells failed to undergo normal AICD, resulting in prolonged clonal expansion. plt/plt mouse immunization model; AICD frequency measurement; in vitro CD3/CD28 stimulation with CCL19/CCL21; Fas ligand expression analysis; apoptosis assays Blood Medium 16973962
2021 CCL21 stimulation of gastric carcinoma cells induces MALAT1 lncRNA expression in a time- and dose-dependent manner. MALAT1 targets miR-202-3p, thereby upregulating SRSF1 and activating mTOR signaling. CCL21 promotes GC cell malignant phenotypes and EMT in vitro and tumorigenesis in vivo through this MALAT1/SRSF1/mTOR axis. RNA pull-down; RIP (RNA binding protein immunoprecipitation); plasmid transfection; CCL21 time- and dose-response; in vitro phenotypic assays; in vivo tumorigenesis Journal of translational medicine Medium 34001131

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 The ABCs of membrane transporters in health and disease (SLC series): introduction. Molecular aspects of medicine 454 23506860
2018 Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release. Nature 306 30464343
2000 The CC chemokine thymus-derived chemotactic agent 4 (TCA-4, secondary lymphoid tissue chemokine, 6Ckine, exodus-2) triggers lymphocyte function-associated antigen 1-mediated arrest of rolling T lymphocytes in peripheral lymph node high endothelial venules. The Journal of experimental medicine 304 10620605
2009 Analysis and update of the human solute carrier (SLC) gene superfamily. Human genomics 250 19164095
2006 Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis. Proceedings of the National Academy of Sciences of the United States of America 223 16966615
2005 Association of CXCL13 and CCL21 expression with the progressive organization of lymphoid-like structures in Sjögren's syndrome. Arthritis and rheumatism 198 15934082
1999 The CC chemokine receptor-7 ligands 6Ckine and macrophage inflammatory protein-3 beta are potent chemoattractants for in vitro- and in vivo-derived dendritic cells. Journal of immunology (Baltimore, Md. : 1950) 191 10201903
1998 The CC chemokine 6Ckine binds the CXC chemokine receptor CXCR3. Proceedings of the National Academy of Sciences of the United States of America 181 9653165
2019 The SLC transporter in nutrient and metabolic sensing, regulation, and drug development. Journal of molecular cell biology 177 30239845
2016 Common and biased signaling pathways of the chemokine receptor CCR7 elicited by its ligands CCL19 and CCL21 in leukocytes. Journal of leukocyte biology 159 26729814
1999 The reduced expression of 6Ckine in the plt mouse results from the deletion of one of two 6Ckine genes. The Journal of experimental medicine 159 10523616
2016 SLC Transporters: Structure, Function, and Drug Discovery. MedChemComm 153 27672436
2004 CCL21 chemokine regulates chemokine receptor CCR7 bearing malignant melanoma cells. Clinical cancer research : an official journal of the American Association for Cancer Research 151 15073111
2011 Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development. The EMBO journal 140 21441897
2000 Cutting edge: ectopic expression of the chemokine TCA4/SLC is sufficient to trigger lymphoid neogenesis. Journal of immunology (Baltimore, Md. : 1950) 139 10754285
2009 Fluid flow regulates stromal cell organization and CCL21 expression in a tissue-engineered lymph node microenvironment. Journal of immunology (Baltimore, Md. : 1950) 128 19734211
2011 Characterization of CCL19 and CCL21 in rheumatoid arthritis. Arthritis and rheumatism 125 21225692
2020 CXCL10 and CCL21 Promote Migration of Pancreatic Cancer Cells Toward Sensory Neurons and Neural Remodeling in Tumors in Mice, Associated With Pain in Patients. Gastroenterology 123 32330476
2000 Antitumor effects of the mouse chemokine 6Ckine/SLC through angiostatic and immunological mechanisms. Journal of immunology (Baltimore, Md. : 1950) 119 10925282
2003 The chemokine CCL21 modulates lymphocyte recruitment and fibrosis in chronic hepatitis C. Gastroenterology 117 14517790
2015 The role of CCL21/CCR7 chemokine axis in breast cancer-induced lymphangiogenesis. Molecular cancer 115 25744065
2013 Microarray-based detection and expression analysis of ABC and SLC transporters in drug-resistant ovarian cancer cell lines. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 109 23462296
2020 The Role of the SLC Transporters Protein in the Neurodegenerative Disorders. Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology 101 32329299
2012 Pharmacotherapy in pregnancy; effect of ABC and SLC transporters on drug transport across the placenta and fetal drug exposure. Journal of drug targeting 95 22994411
2019 A GPR174-CCL21 module imparts sexual dimorphism to humoral immunity. Nature 94 31875850
2016 SLC transporters as a novel class of tumour suppressors: identity, function and molecular mechanisms. The Biochemical journal 92 27118869
2020 CCL21/CCR7 interaction promotes EMT and enhances the stemness of OSCC via a JAK2/STAT3 signaling pathway. Journal of cellular physiology 88 32017846
2019 CCL21/CCR7 signaling in macrophages promotes joint inflammation and Th17-mediated osteoclast formation in rheumatoid arthritis. Cellular and molecular life sciences : CMLS 82 31342120
2007 Matrix metalloproteinase-9 is up-regulated by CCL21/CCR7 interaction via extracellular signal-regulated kinase-1/2 signaling and is involved in CCL21-driven B-cell chronic lymphocytic leukemia cell invasion and migration. Blood 82 17890452
2020 The Role of CCL21/CCR7 Chemokine Axis in Breast Cancer Progression. Cancers 80 32340161
2010 CCL21 is sufficient to mediate DC migration, maturation and function in the absence of CCL19. European journal of immunology 79 20201039
2002 Roles of SLC/CCL21 and CCR7 in human kidney for mesangial proliferation, migration, apoptosis, and tissue homeostasis. Journal of immunology (Baltimore, Md. : 1950) 77 11970971
2019 SLC Family Transporters. Advances in experimental medicine and biology 75 31571165
2004 A novel model for lymphocytic infiltration of the thyroid gland generated by transgenic expression of the CC chemokine CCL21. Journal of immunology (Baltimore, Md. : 1950) 73 15470018
1999 CCR7 ligands, SLC/6Ckine/Exodus2/TCA4 and CKbeta-11/MIP-3beta/ELC, are chemoattractants for CD56(+)CD16(-) NK cells and late stage lymphoid progenitors. Cellular immunology 72 10222066
2021 The role of SLC transporters for brain health and disease. Cellular and molecular life sciences : CMLS 69 34971415
2003 SLC/CCL21-mediated anti-tumor responses require IFNgamma, MIG/CXCL9 and IP-10/CXCL10. Molecular cancer 66 12740040
2023 Targeting SLC transporters: small molecules as modulators and therapeutic opportunities. Trends in biochemical sciences 64 37355450
2014 Neuronal CC chemokines: the distinct roles of CCL21 and CCL2 in neuropathic pain. Frontiers in cellular neuroscience 62 25147499
2020 CCL21-loaded 3D hydrogels for T cell expansion and differentiation. Biomaterials 61 32829146
2019 The RNA-Binding Protein YBX3 Controls Amino Acid Levels by Regulating SLC mRNA Abundance. Cell reports 61 31189097
2019 A Network of SLC and ABC Transporter and DME Genes Involved in Remote Sensing and Signaling in the Gut-Liver-Kidney Axis. Scientific reports 59 31417100
2009 CCL21 mediates CD4+ T-cell costimulation via a DOCK2/Rac-dependent pathway. Blood 59 19451552
1999 Cutting edge: species specificity of the CC chemokine 6Ckine signaling through the CXC chemokine receptor CXCR3: human 6Ckine is not a ligand for the human or mouse CXCR3 receptors. Journal of immunology (Baltimore, Md. : 1950) 55 10201891
2017 Potentiating SLC transporter activity: Emerging drug discovery opportunities. Biochemical pharmacology 54 28214518
2015 CCL21-CCR7 promotes the lymph node metastasis of esophageal squamous cell carcinoma by up-regulating MUC1. Journal of experimental & clinical cancer research : CR 53 26667143
2008 Expression, transport, and axonal sorting of neuronal CCL21 in large dense-core vesicles. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 53 18697841
1999 SLC/exodus2/6Ckine/TCA4 induces chemotaxis of hematopoietic progenitor cells: differential activity of ligands of CCR7, CXCR3, or CXCR4 in chemotaxis vs. suppression of progenitor proliferation. Journal of leukocyte biology 53 10496316
2021 "SLC-omics" of the kidney: solute transporters along the nephron. American journal of physiology. Cell physiology 49 34191628
2002 Endothelial induction of the T-cell chemokine CCL21 in T-cell autoimmune diseases. Blood 49 12393410
2021 SLC-30A9 is required for Zn2+ homeostasis, Zn2+ mobilization, and mitochondrial health. Proceedings of the National Academy of Sciences of the United States of America 46 34433664
2023 Distinct tissue niches direct lung immunopathology via CCL18 and CCL21 in severe COVID-19. Nature communications 43 36774347
2020 Alteration in the Function and Expression of SLC and ABC Transporters in the Neurovascular Unit in Alzheimer's Disease and the Clinical Significance. Aging and disease 42 32257549
2015 CCL21 Facilitates Chemoresistance and Cancer Stem Cell-Like Properties of Colorectal Cancer Cells through AKT/GSK-3β/Snail Signals. Oxidative medicine and cellular longevity 42 27057280
2006 Role of CCL21 and CCL19 in allergic inflammation in the ovalbumin-specific murine asthmatic model. The Journal of allergy and clinical immunology 41 16675330
2014 Contribution of homeostatic chemokines CCL19 and CCL21 and their receptor CCR7 to coronary artery disease. Arteriosclerosis, thrombosis, and vascular biology 40 24990231
2021 Urinary small extracellular vesicles derived CCL21 mRNA as biomarker linked with pathogenesis for diabetic nephropathy. Journal of translational medicine 36 34404433
2014 CCL21/CCR7 axis activating chemotaxis accompanied with epithelial-mesenchymal transition in human breast carcinoma. Medical oncology (Northwood, London, England) 36 25142946
2020 The pathogenic importance of CCL21 and CCR7 in rheumatoid arthritis. Cytokine & growth factor reviews 35 32499193
2023 CCL21/CCR7 axis as a therapeutic target for autoimmune diseases. International immunopharmacology 34 37331295
2021 Scavenging of soluble and immobilized CCL21 by ACKR4 regulates peripheral dendritic cell emigration. Proceedings of the National Academy of Sciences of the United States of America 34 33875601
2023 In silico analysis of the solute carrier (SLC) family in cancer indicates a link among DNA methylation, metabolic adaptation, drug response, and immune reactivity. Frontiers in pharmacology 33 37397501
2022 Antiproliferative effects of sulphonamide carbonic anhydrase inhibitors C18, SLC-0111 and acetazolamide on bladder, glioblastoma and pancreatic cancer cell lines. Journal of enzyme inhibition and medicinal chemistry 33 34894950
2017 Tumor hypoxia modulates podoplanin/CCL21 interactions in CCR7+ NK cell recruitment and CCR7+ tumor cell mobilization. Oncotarget 33 28416768
2020 ACKR4 restrains antitumor immunity by regulating CCL21. The Journal of experimental medicine 32 32289156
2015 Differential ligand-signaling network of CCL19/CCL21-CCR7 system. Database : the journal of biological databases and curation 32 26504105
2011 CCL21 (SLC) improves tumor protection by a DNA vaccine in a Her2/neu mouse tumor model. Cancer gene therapy 31 21997231
2017 Multiple SLC and ABC Transporters Contribute to the Placental Transfer of Entecavir. Drug metabolism and disposition: the biological fate of chemicals 30 28062543
2021 SLC gene mutations and pediatric neurological disorders: diverse clinical phenotypes in a Saudi Arabian population. Human genetics 29 34797406
2013 Dichotomy of CCL21 and CXCR3 in nerve injury-evoked and autoimmunity-evoked hyperalgesia. Brain, behavior, and immunity 29 23643685
2012 Cloning, expression and characterization of CCL21 and CCL25 chemokines in zebrafish. Developmental and comparative immunology 29 22842207
2014 CCL19 and CCL21 modulate the inflammatory milieu in atherosclerotic lesions. Drug design, development and therapy 28 25473269
2009 CCL21-induced calcium transients and proliferation in primary mouse astrocytes: CXCR3-dependent and independent responses. Brain, behavior, and immunity 27 19401230
2023 CCL21-DC in situ vaccination in murine NSCLC overcomes resistance to immunotherapy and generates systemic tumor-specific immunity. Journal for immunotherapy of cancer 26 37730274
2022 Transcriptional Regulation of Solute Carrier (SLC) Drug Transporters. Drug metabolism and disposition: the biological fate of chemicals 26 35644529
2018 Fluorescently Tagged CCL19 and CCL21 to Monitor CCR7 and ACKR4 Functions. International journal of molecular sciences 26 30518137
2021 CCL21 activation of the MALAT1/SRSF1/mTOR axis underpins the development of gastric carcinoma. Journal of translational medicine 25 34001131
2021 Natural inspired ligustrazine-based SLC-0111 analogues as novel carbonic anhydrase inhibitors. European journal of medicinal chemistry 25 34871842
2006 Chemokines CCL19 and CCL21 promote activation-induced cell death of antigen-responding T cells. Blood 25 16973962
2021 Renal and non-renal response of ABC and SLC transporters in chronic kidney disease. Expert opinion on drug metabolism & toxicology 23 33749483
2016 CCL21/IL21-armed oncolytic adenovirus enhances antitumor activity against TERT-positive tumor cells. Virus research 23 27157859
2015 Anti-CCL21 antibody attenuates infarct size and improves cardiac remodeling after myocardial infarction. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 23 26393504
2014 CCL21 and IFNγ recruit and activate tumor specific T cells in 3D scaffold model of breast cancer. Anti-cancer agents in medicinal chemistry 23 24237220
2023 SLC-0111, an inhibitor of carbonic anhydrase IX, attenuates hepatoblastoma cell viability and migration. Frontiers in oncology 22 36776327
2023 CCL21-CCR7 signaling promotes microglia/macrophage recruitment and chemotherapy resistance in glioblastoma. Cellular and molecular life sciences : CMLS 22 37314567
2021 The C-terminal peptide of CCL21 drastically augments CCL21 activity through the dendritic cell lymph node homing receptor CCR7 by interaction with the receptor N-terminus. Cellular and molecular life sciences : CMLS 22 34586443
2020 Role of SLC transporters in toxicity induced by anticancer drugs. Expert opinion on drug metabolism & toxicology 22 32276560
2016 Kidney versus Liver Specification of SLC and ABC Drug Transporters, Tight Junction Molecules, and Biomarkers. Drug metabolism and disposition: the biological fate of chemicals 22 27044799
2012 oxLDL downregulates the dendritic cell homing factors CCR7 and CCL21. Mediators of inflammation 22 22619482
2019 CCL21 Induces mTOR-dependent MALAT1 Expression, Leading to Cell Migration in Cutaneous T-Cell Lymphoma. In vivo (Athens, Greece) 21 31028199
2015 SAMP1/YitFc mice develop ileitis via loss of CCL21 and defects in dendritic cell migration. Gastroenterology 21 25620669
2014 Increased CCL19 and CCL21 levels promote fibroblast ossification in ankylosing spondylitis hip ligament tissue. BMC musculoskeletal disorders 21 25260647
2003 Fluctuation of 6Ckine expression in human endometrium during the menstrual cycle. Fertility and sterility 21 14667884
2001 Transgenic overexpression of the CC chemokine CCL21 disrupts T-cell migration. Blood 21 11739157
2019 CCL21-expression and accumulation of CCR7+ NK cells in livers of patients with primary sclerosing cholangitis. European journal of immunology 20 30785638
2020 CCL21 Programs Immune Activity in Tumor Microenvironment. Advances in experimental medicine and biology 19 32060847
2017 CCR7 Sulfotyrosine Enhances CCL21 Binding. International journal of molecular sciences 19 28841151
2021 Cell-surface SLC nucleoside transporters and purine levels modulate BRD4-dependent chromatin states. Nature metabolism 18 33972798
2020 Clinical Significance of CBS and CCL21 in Gallbladder Adenocarcinomas and Squamous Cell/Adenosquamous Carcinomas. Applied immunohistochemistry & molecular morphology : AIMM 18 32044878
2006 Role of SLC xenobiotic transporters and their regulatory mechanisms PDZ proteins in drug delivery and disposition. Journal of controlled release : official journal of the Controlled Release Society 18 16876283

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