CCL11

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005615 extracellular space	IBA GO_REF:0000033	ACCEPT	Summary: CCL11/Eotaxin is a secreted chemokine that functions in the extracellular space. UniProt annotates it as "Secreted" (PubMed:8597956). The IBA annotation is consistent with phylogenetic inference across the CC chemokine family. Reason: CCL11 is a secreted protein that acts extracellularly to create chemotactic gradients. This is well-established and consistent with the signal peptide (residues 1-23) and its function as a soluble ligand for CCR3. Supporting Evidence: PMID:8597956 Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia.
GO:0008009 chemokine activity	IBA GO_REF:0000033	ACCEPT	Summary: Chemokine activity is the core molecular function of CCL11. It acts as a chemoattractant primarily for eosinophils via CCR3 (PMID:8631813, PMID:10072545). The IBA annotation is phylogenetically sound across CC chemokines. Reason: CCL11 is definitively a chemokine. Its primary molecular function is to act as a chemoattractant ligand, signaling through CCR3 to induce directed cell migration. This is its canonical and core function. Supporting Evidence: PMID:10072545 Those chemokines acting on CCR3 induced a rapid shape change in eosinophils from all donors; of these, eotaxin and eotaxin-2 were the most potent.
GO:0070098 chemokine-mediated signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: CCL11 is a chemokine ligand that initiates chemokine-mediated signaling through CCR3. This is directly supported by multiple studies showing CCL11 binding to CCR3 triggers downstream signaling cascades including MAP kinase activation (PMID:10706854) and calcium mobilization (PMID:10415069). Reason: As a chemokine, CCL11 inherently participates in chemokine-mediated signaling pathways by binding and activating its receptor CCR3. This is a core function. Supporting Evidence: PMID:10706854 Eotaxin and other CC chemokines acting via CC chemokine receptor-3 (CCR3) are believed to play an integral role in the development of eosinophilic inflammation in asthma and allergic inflammatory diseases.
GO:0061844 antimicrobial humoral immune response mediated by antimicrobial peptide	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: This IBA annotation is propagated from the broader CC chemokine family. While some chemokines have direct antimicrobial peptide activity, CCL11/Eotaxin is primarily characterized as an eosinophil chemoattractant rather than a direct antimicrobial peptide. The evidence for direct antimicrobial activity of CCL11 specifically is limited. Reason: While the IBA annotation reflects a phylogenetically-inferred function shared across CC chemokines, CCL11 is not primarily known for direct antimicrobial peptide activity. Its core function is eosinophil chemotaxis. Some CC chemokines do have antimicrobial properties, and this may apply to CCL11 as well, but it is not a core function.
GO:0048245 eosinophil chemotaxis	IBA GO_REF:0000033	ACCEPT	Summary: Eosinophil chemotaxis is the canonical and best-characterized biological process of CCL11/Eotaxin. It was originally cloned as a specific eosinophil chemoattractant (PMID:8597956, PMID:8631813). The IBA annotation reinforces this across species. Reason: This is arguably the single most defining function of CCL11. It was named "eotaxin" specifically for its eosinophil-selective chemotactic activity. Supporting Evidence: PMID:10072545 Those chemokines acting on CCR3 induced a rapid shape change in eosinophils from all donors; of these, eotaxin and eotaxin-2 were the most potent.
GO:0030335 positive regulation of cell migration	IBA GO_REF:0000033	ACCEPT	Summary: CCL11 promotes cell migration in multiple cell types. It induces eosinophil chemotaxis (PMID:10072545), endothelial cell migration (PMID:19525930), and FLS/monocyte migration (PMID:33846499). The IBA annotation is well-supported. Reason: As a chemokine, positive regulation of cell migration is a core function of CCL11. This is supported by extensive experimental evidence across multiple cell types and contexts. Supporting Evidence: PMID:19525930 All three eotaxins also activated Rac-1 (Supplementary Fig. S3), a small GTPase that is critical in regulating endothelial cell spreading and migration, and promoted human CEC migration in a dose-dependent fashion (Fig. 2f).
GO:0006954 inflammatory response	IBA GO_REF:0000033	ACCEPT	Summary: CCL11 is a pro-inflammatory chemokine that plays a central role in allergic inflammatory responses by recruiting eosinophils to sites of inflammation. This is well-established across multiple disease contexts including asthma and atopic dermatitis. Reason: Involvement in inflammatory response is a core function of CCL11. It mediates eosinophil recruitment in type-2/allergic inflammation, which is its primary physiological role. Supporting Evidence: PMID:10708591 Eotaxin is an eosinophil-specific C-C chemokine that is implicated in the pathogenesis of eosinophilic inflammatory diseases, such as asthma and atopic dermatitis, by acting specifically on its receptor CCR3.
GO:0048020 CCR chemokine receptor binding	IBA GO_REF:0000033	ACCEPT	Summary: CCL11 binds CCR3 as its primary receptor (PMID:8631813). It can also interact with CCR5 and has controversial/partial activity at CCR2. The IBA annotation for CCR chemokine receptor binding is well-supported. Reason: CCR chemokine receptor binding is a core molecular function of CCL11. It binds CCR3 with high affinity as its principal receptor. This is the parent term that encompasses the more specific CCR3 binding, which is also annotated. Supporting Evidence: PMID:9712872 The solution structure of the CCR3-specific chemokine, eotaxin, has been determined by NMR spectroscopy.
GO:0005125 cytokine activity	IEA GO_REF:0000043	ACCEPT	Summary: CCL11 is classified as a cytokine (specifically a chemokine, which is a subclass of cytokines). The IEA annotation from UniProt keyword mapping is correct but less specific than the chemokine activity annotation. Reason: Cytokine activity is a parent term of chemokine activity. While less specific, it is not incorrect. The more specific chemokine activity term is also present. Acceptable as a broader IEA annotation.
GO:0005576 extracellular region	IEA GO_REF:0000120	ACCEPT	Summary: CCL11 is a secreted protein that localizes to the extracellular region. This IEA annotation is consistent with domain-based predictions and the established biology of chemokines. Reason: Extracellular region is a broader parent of extracellular space. Both are correct for this secreted chemokine. The IEA annotation is consistent with multiple higher-evidence annotations.
GO:0005615 extracellular space	IEA GO_REF:0000120	ACCEPT	Summary: Duplicate of the IBA annotation for the same term. CCL11 is secreted and acts in the extracellular space. This IEA annotation is redundant with the IBA annotation but not incorrect. Reason: Correct localization for a secreted chemokine. Redundant with IBA but acceptable as independent evidence.
GO:0006935 chemotaxis	IEA GO_REF:0000043	ACCEPT	Summary: CCL11 is a chemotactic factor. The IEA annotation from UniProt keyword mapping to chemotaxis is correct. More specific terms (eosinophil chemotaxis) are also annotated. Reason: Chemotaxis is a core biological process for CCL11. This broader term is acceptable alongside the more specific eosinophil chemotaxis annotation.
GO:0006954 inflammatory response	IEA GO_REF:0000043	ACCEPT	Summary: Duplicate of the IBA annotation for inflammatory response. CCL11 is clearly involved in inflammatory responses. The IEA from keyword mapping is redundant but correct. Reason: Correct annotation, redundant with IBA annotation for the same term.
GO:0006955 immune response	IEA GO_REF:0000002	ACCEPT	Summary: CCL11 participates in immune responses by recruiting eosinophils and other immune cells. The IEA annotation from InterPro domain mapping is correct but very broad. Reason: Immune response is a broad parent term. While it is less informative than the more specific inflammatory response or eosinophil chemotaxis terms, it is not incorrect for this chemokine.
GO:0008009 chemokine activity	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for chemokine activity, redundant with the IBA and IDA annotations for the same term. Correct. Reason: Correct core molecular function. Redundant with higher-evidence annotations.
GO:0005515 protein binding	IPI PMID:18275857 Stromal cell-derived factors 1alpha and 1beta, inflammatory ...	MODIFY	Summary: This IPI annotation is from a study on dipeptidyl peptidase 8 (DPP8) substrates. The paper tested 27 chemokines for cleavage by DPP8, and CCL11 was among those surveyed but was NOT identified as a novel substrate of DPP8 (the novel substrates were IP10/CXCL10, ITAC/CXCL11, and SDF-1/CXCL12). The WITH column shows UniProtKB:P27487 (DPP4). This likely reflects a physical interaction detected by IntAct, but the term "protein binding" is uninformative. Reason: Protein binding is uninformative per curation guidelines. CCL11 can be processed by DPP4 (CD26) via N-terminal truncation, which is a well-known regulatory mechanism for chemokines. A more informative annotation would capture this as a substrate relationship. However, the interaction with DPP4 is real and documented. Proposed replacements: protein binding Supporting Evidence: PMID:18275857 N-terminal truncation of chemokines by proteases including dipeptidyl peptidase (DP) IV significantly alters their biological activity; generally ablating cognate G-protein coupled receptor engagement and often generating potent receptor antagonists.
GO:0005515 protein binding	IPI PMID:21314817 Neuropeptide Y, B-type natriuretic peptide, substance P and ...	MODIFY	Summary: This IPI annotation from a study on fibroblast activation protein-alpha (FAP) substrates. The WITH column shows UniProtKB:P27487 (DPP4). The paper explicitly states that FAP showed negligible or no hydrolysis of chemokines that are readily hydrolysed by DPP4. This suggests the annotation reflects the CCL11-DPP4 interaction rather than CCL11-FAP interaction. Reason: Protein binding is uninformative per curation guidelines. The interaction with DPP4 is the relevant binding interaction here. Proposed replacements: protein binding Supporting Evidence: PMID:21314817 FAP showed negligible or no hydrolysis of eight chemokines that are readily hydrolysed by DPP4.
GO:0005515 protein binding	IPI PMID:23597562 Inhibition of tumor angiogenesis and growth by a small-molec...	MODIFY	Summary: This IPI annotation is from a study on a small-molecule FGF receptor blocker. The WITH column shows UniProtKB:P51677 (CCR3). This reflects the CCL11-CCR3 physical interaction. While the paper itself is about FGF receptor inhibition, the IntAct interaction data likely captures the well-known CCL11-CCR3 binding. Reason: Protein binding is uninformative. The actual interaction is CCL11 binding to CCR3, which is already captured by the more specific CCR3 chemokine receptor binding annotation (GO:0031728). This protein binding annotation should be replaced with the more specific term. Proposed replacements: CCR3 chemokine receptor binding Supporting Evidence: PMID:23597562 Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties.
GO:0005515 protein binding	IPI PMID:28381538 Chemokine interactome mapping enables tailored intervention ...	MODIFY	Summary: This IPI annotation is from the chemokine interactome mapping study by von Hundelshausen et al. (2017). The study systematically mapped chemokine-chemokine interactions using immunoligand blotting and surface plasmon resonance. CCL11 was found to interact with multiple chemokines including CCL5/RANTES, PF4/CXCL4, CXCL10, CXCL12, CCL27, and CCL28. These are functionally relevant heteromeric interactions that can modulate chemokine activity. Reason: Protein binding is uninformative. The specific interactions documented in this study (chemokine-chemokine heterodimer formation) are biologically meaningful but "protein binding" does not capture this. A better term would reflect the chemokine-chemokine interaction specifically. Proposed replacements: CCR chemokine receptor binding Supporting Evidence: PMID:28381538 Heterophilic interactions between chemokines in a given microenvironment may amplify, inhibit, or modulate their activity; however, a systematic evaluation of the chemokine interactome has not been performed.
GO:0002544 chronic inflammatory response	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA from Ensembl Compara ortholog transfer (rat Ccl11). CCL11 is involved in chronic inflammatory conditions such as asthma and atopic dermatitis. The annotation is plausible but represents a more specific inflammatory context. Reason: CCL11 is involved in chronic inflammatory conditions (asthma, atopic dermatitis, RA), but this is a downstream consequence of its chemotactic function rather than a distinct core function. Keeping as non-core.
GO:0002551 mast cell chemotaxis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA from Ensembl Compara (rat ortholog). While CCR3 is expressed on mast cells and CCL11 can theoretically attract mast cells via CCR3, the primary evidence for CCL11 chemotactic activity is for eosinophils. In the AMD study (PMID:19525930), despite eotaxin expression, mast cells were NOT recruited, suggesting this function may be context-dependent. Reason: While theoretically possible given CCR3 expression on mast cells, the evidence for CCL11-mediated mast cell chemotaxis is limited. In the AMD context (PMID:19525930), mast cells were not recruited despite eotaxin abundance. Eosinophil chemotaxis is the primary chemotactic function. Supporting Evidence: PMID:19525930 despite the expression of its ligands eotaxin-1, -2 and -3, neither eosinophils nor mast cells are present in human CNV.
GO:0007015 actin filament organization	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA from Ensembl Compara (rat ortholog). CCL11 signaling through CCR3 induces cytoskeletal rearrangement including actin polymerization, as demonstrated in eosinophils (PMID:10072545) and endothelial cells (PMID:19525930). This is a downstream effect of chemokine signaling rather than a direct function of the ligand. Reason: Actin filament organization occurs in responding cells as a consequence of CCR3 activation by CCL11, not as a direct biochemical function of the CCL11 protein itself. This is a downstream cellular response to the chemokine signal.
GO:0007611 learning or memory	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA from Ensembl Compara (mouse ortholog Ccl11, P48298). Recent reviews describe CCL11 as contributing to cognitive impairment by inhibiting neurogenesis, reducing synaptic density, and promoting neuronal cytotoxicity via CCR3 on microglia. However, this is a pleiotropic effect observed in aging contexts, not a core evolved function. Reason: The link between CCL11 and learning/memory is based on aging studies in mice where elevated blood CCL11 impairs hippocampal neurogenesis and cognition. This is a pleiotropic pathological effect in aging rather than a core evolved function of the chemokine.
GO:0035962 response to interleukin-13	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA from Ensembl Compara (rat ortholog). CCL11 expression is induced by IL-13 (a type-2 cytokine) in various cell types. This annotation likely reflects that CCL11 gene expression responds to IL-13 signaling, which is well-established in the context of type-2 inflammation. Reason: This describes the regulation of CCL11 expression rather than a function of the CCL11 protein. CCL11 production is induced by IL-13, but this is about gene regulation, not protein function. Keep as non-core contextual information.
GO:0045766 positive regulation of angiogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA from Ensembl Compara (mouse ortholog). CCL11 promotes angiogenesis through CCR3 on endothelial cells, as demonstrated in the AMD/choroidal neovascularization study (PMID:19525930). Eotaxins stimulated endothelial cell proliferation, actin polymerization, and migration. This is a well-supported non-core function. Reason: While experimentally supported (PMID:19525930), positive regulation of angiogenesis is a secondary/pleiotropic function of CCL11 rather than its core evolved chemotactic function. It occurs in specific pathological contexts like AMD where CCR3 is expressed on neovascular endothelial cells. Supporting Evidence: PMID:19525930 each of the three eotaxins stimulated human CEC proliferation
GO:0048245 eosinophil chemotaxis	IEA GO_REF:0000107	ACCEPT	Summary: IEA from Ensembl Compara (rat ortholog). Redundant with IBA and IDA annotations for the same term. Eosinophil chemotaxis is the core function of CCL11. Reason: Correct core function. Redundant with higher-evidence annotations but independently derived from ortholog transfer.
GO:0050768 negative regulation of neurogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA from Ensembl Compara (mouse ortholog). CCL11 has been shown to inhibit neurogenesis in mouse aging studies. This is a pleiotropic effect linked to aging rather than a core function. Reason: Negative regulation of neurogenesis is a secondary/aging-related effect of CCL11 observed in mouse studies, not a core evolved function of this chemokine.
GO:0070371 ERK1 and ERK2 cascade	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA from Ensembl Compara (rat ortholog). CCL11 activates ERK2 and p38 MAP kinases in eosinophils (PMID:10706854). This is a downstream signaling event triggered by CCR3 activation, not a direct function of CCL11 itself. Reason: The ERK1/ERK2 cascade is activated downstream of CCR3 signaling upon CCL11 binding. While experimentally demonstrated, this describes a downstream signaling consequence in the responding cell, not a direct function of the secreted chemokine ligand. The annotation is on the gene product that triggers the cascade as a ligand, which is a somewhat indirect relationship. Supporting Evidence: PMID:10706854 Eotaxin (10(-11) to 10(-7) mol/L) induced concentration-dependent phosphorylation of ERK2 and p38.
GO:0070670 response to interleukin-4	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA from Ensembl Compara (rat ortholog). CCL11 expression is induced by IL-4 signaling (via STAT6), which is well-established in the type-2 inflammation context. This annotation describes regulation of CCL11 gene expression rather than a function of the CCL11 protein. Reason: This describes gene regulation (CCL11 expression is induced by IL-4) rather than a function of the CCL11 protein product. Keep as non-core contextual information.
GO:0060326 cell chemotaxis	IDA PMID:33846499 Eotaxin-1/CCL11 is involved in cell migration in rheumatoid ...	ACCEPT	Summary: IDA annotation from PMID:33846499 (Wakabayashi et al., 2021). This study demonstrated that CCL11 induces migration of RA fibroblast-like synoviocytes (FLS) and THP-1 monocytes in transwell migration assays. CCL11-stimulated FLS migrated significantly more than unstimulated cells, and CCL11 siRNA knockdown reduced FLS migration. Reason: Cell chemotaxis is a core function of CCL11 as a chemokine. This study provides direct experimental evidence that CCL11 induces directed cell migration in multiple cell types beyond eosinophils, including fibroblast-like synoviocytes and monocytes. Supporting Evidence: PMID:33846499 CCL11-stimulated cells migrated significantly more efficiently than unstimulated cells (mean ± SEM, number of cells per field; 35.8 ± 5.2 and 24.5 ± 4.6, respectively, p < 0.05, Fig. 5A)
GO:0070098 chemokine-mediated signaling pathway	IDA PMID:19525930 CCR3 is a target for age-related macular degeneration diagno...	ACCEPT	Summary: IDA annotation from Takeda et al. (2009, Nature). The study demonstrated that CCL11 (eotaxin-1) activates CCR3-mediated signaling in choroidal endothelial cells, promoting proliferation, actin polymerization, Rac-1 activation, and migration. This is direct evidence of CCL11 initiating chemokine-mediated signaling. Reason: Well-supported by experimental evidence in the Nature paper. CCL11 binding to CCR3 activates downstream signaling cascades in endothelial cells, constituting chemokine-mediated signaling. Supporting Evidence: PMID:19525930 Stimulation of human CECs with any of the three eotaxins induced a rapid polymerization of actin molecules
GO:0050768 negative regulation of neurogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation transferred from mouse ortholog (P48298). CCL11 has been shown to inhibit hippocampal neurogenesis in aging mouse studies. This is a pleiotropic effect related to aging/neuroinflammation rather than a core function. Reason: Based on sequence similarity to mouse Ccl11 which was experimentally shown to inhibit neurogenesis. This is a pleiotropic aging-related effect, not a core evolved function. Redundant with IEA annotation.
GO:0007611 learning or memory	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation transferred from mouse ortholog (P48298). CCL11 affects learning and memory in mouse aging studies. This is a pleiotropic neuroinflammatory effect. Redundant with IEA annotation. Reason: Pleiotropic aging-related effect transferred from mouse ortholog studies. Not a core evolved function of this chemokine.
GO:0046983 protein dimerization activity	IDA PMID:9712872 Solution structure of eotaxin, a chemokine that selectively ...	ACCEPT	Summary: IDA annotation from the NMR structural study by Crump et al. (1998). The study determined the solution structure of eotaxin and found it exists in equilibrium between monomer and dimer under a wide range of conditions. At pH <= 5 and low ionic strength, eotaxin was predominantly monomeric. This is a genuine biophysical property of the protein. Reason: Protein dimerization is an experimentally demonstrated property of CCL11. Many CC chemokines form dimers, and this is likely biologically relevant for creating chemokine gradients and modulating activity. Supporting Evidence: PMID:9712872 The quaternary structure of eotaxin was investigated by ultracentrifugation and NMR, and it was found to be in equilibrium between monomer and dimer under a wide range of conditions.
GO:0031728 CCR3 chemokine receptor binding	IDA PMID:11425309 NMR solution structure and backbone dynamics of the CC chemo...	ACCEPT	Summary: IDA annotation from the eotaxin-3 structural study. Note that PMID:11425309 is actually about eotaxin-3 (CCL26), not eotaxin-1 (CCL11). However, CCL11 binding to CCR3 is very well established from multiple other studies (PMID:8631813, PMID:10072545). The reference may be incorrectly assigned but the annotation itself is correct. Reason: CCR3 binding is the core molecular function of CCL11. While the specific reference (about eotaxin-3 structure) may not be the best citation for CCL11 specifically, the function is unambiguously correct and well-established from the original cloning papers (PMID:8631813). Supporting Evidence: PMID:9712872 The solution structure of the CCR3-specific chemokine, eotaxin, has been determined by NMR spectroscopy.
GO:0048018 receptor ligand activity	IDA PMID:11425309 NMR solution structure and backbone dynamics of the CC chemo...	ACCEPT	Summary: IDA annotation. CCL11 is a receptor ligand (for CCR3). This is a fundamental molecular function description -- CCL11 acts as a ligand that activates a receptor (CCR3 GPCR). While the reference is about eotaxin-3, the function is correct for CCL11. Reason: Receptor ligand activity is a core molecular function of CCL11. It acts as a signaling ligand for the CCR3 G-protein coupled receptor.
GO:0005576 extracellular region	IDA PMID:20041150 Missense mutations in the MEFV gene are associated with fibr...	ACCEPT	Summary: IDA annotation with reference to PMID:20041150, a paper about MEFV gene mutations in fibromyalgia. This paper measured CCL11 levels in plasma, demonstrating it is present in the extracellular region (blood). The annotation is correct for CCL11 localization. Reason: CCL11 is a secreted protein found in the extracellular region. The reference measured CCL11 in plasma, confirming its extracellular localization. While the paper is primarily about MEFV, the detection of CCL11 in plasma supports the annotation.
GO:0007010 cytoskeleton organization	IDA PMID:10072545 Differential regulation of eosinophil chemokine signaling vi...	KEEP AS NON CORE	Summary: IDA annotation from Sabroe et al. (1999). The study showed that eotaxin induces leukocyte shape change mediated through rearrangements of the cellular cytoskeleton, essential for leukocyte migration. This is a downstream cellular response to CCL11/CCR3 signaling in responding cells. Reason: Cytoskeleton organization in eosinophils is a downstream consequence of CCR3 activation by CCL11, not a direct function of the CCL11 protein. The ligand triggers cytoskeletal changes in the responding cell. Supporting Evidence: PMID:10072545 Leukocyte shape change responses are mediated through rearrangements of the cellular cytoskeleton in a dynamic process typically resulting in a polarized cell and are essential to the processes of leukocyte migration from the microcirculation into sites of inflammation.
GO:0008009 chemokine activity	IDA PMID:10072545 Differential regulation of eosinophil chemokine signaling vi...	ACCEPT	Summary: IDA annotation from Sabroe et al. (1999). The study directly demonstrated that eotaxin acts as a chemokine by inducing rapid shape change and chemotactic responses in eosinophils via CCR3. This is direct experimental evidence for chemokine activity. Reason: Core molecular function demonstrated by direct experimental evidence. Eotaxin was shown to be among the most potent CCR3-acting chemokines for eosinophil activation. Supporting Evidence: PMID:10072545 Those chemokines acting on CCR3 induced a rapid shape change in eosinophils from all donors; of these, eotaxin and eotaxin-2 were the most potent.
GO:0008360 regulation of cell shape	IDA PMID:10072545 Differential regulation of eosinophil chemokine signaling vi...	KEEP AS NON CORE	Summary: IDA annotation from Sabroe et al. (1999). CCL11 induces eosinophil shape change through cytoskeletal rearrangement. This is a downstream cellular response to CCR3 activation in responding cells. Reason: Regulation of cell shape is a downstream consequence of CCR3 signaling in eosinophils. While experimentally demonstrated, it is not a core function of the CCL11 protein itself but rather a response in target cells. Supporting Evidence: PMID:10072545 Leukocyte shape change responses are mediated through rearrangements of the cellular cytoskeleton in a dynamic process typically resulting in a polarized cell
GO:0048245 eosinophil chemotaxis	IDA PMID:10072545 Differential regulation of eosinophil chemokine signaling vi...	ACCEPT	Summary: IDA annotation from Sabroe et al. (1999). Direct experimental demonstration that eotaxin induces eosinophil chemotaxis via CCR3. This is the core biological function of CCL11. Reason: Core function of CCL11 directly demonstrated experimentally. Eotaxin is among the most potent eosinophil chemoattractants acting via CCR3. Supporting Evidence: PMID:10072545 Those chemokines acting on CCR3 induced a rapid shape change in eosinophils from all donors; of these, eotaxin and eotaxin-2 were the most potent.
GO:0001938 positive regulation of endothelial cell proliferation	IDA PMID:19525930 CCR3 is a target for age-related macular degeneration diagno...	KEEP AS NON CORE	Summary: IDA annotation from Takeda et al. (2009, Nature). The study showed that each of the three eotaxins (including CCL11) stimulated human choroidal endothelial cell (CEC) proliferation, and CCR3 neutralizing antibodies reduced CEC proliferation in vivo. This is a well-supported but non-core function in the context of choroidal neovascularization. Reason: While experimentally well-supported in a high-impact publication, this function is specific to the pathological context of choroidal neovascularization in AMD, where CCR3 is aberrantly expressed on endothelial cells. It is not the core evolved function of CCL11. Supporting Evidence: PMID:19525930 each of the three eotaxins stimulated human CEC proliferation
GO:0030335 positive regulation of cell migration	IDA PMID:19525930 CCR3 is a target for age-related macular degeneration diagno...	ACCEPT	Summary: IDA annotation from Takeda et al. (2009). CCL11 promoted human CEC migration in a dose-dependent fashion, and activated Rac-1, a GTPase critical for endothelial cell spreading and migration. This reinforces the IBA annotation. Reason: Positive regulation of cell migration is a core function of CCL11 as a chemokine. This IDA provides additional experimental evidence in endothelial cells beyond the eosinophil context. Supporting Evidence: PMID:19525930 All three eotaxins also activated Rac-1 (Supplementary Fig. S3), a small GTPase that is critical in regulating endothelial cell spreading and migration, and promoted human CEC migration in a dose-dependent fashion (Fig. 2f).
GO:0030838 positive regulation of actin filament polymerization	IDA PMID:19525930 CCR3 is a target for age-related macular degeneration diagno...	KEEP AS NON CORE	Summary: IDA annotation from Takeda et al. (2009). Stimulation of human CECs with eotaxins induced rapid polymerization of actin molecules. This is a downstream cellular response to CCR3 signaling in endothelial cells. Reason: Actin polymerization is a downstream cellular response in target cells following CCR3 activation by CCL11. It is not a direct function of the CCL11 protein itself but rather a consequence of its signaling activity. Supporting Evidence: PMID:19525930 Stimulation of human CECs with any of the three eotaxins induced a rapid polymerization of actin molecules
GO:0005576 extracellular region	TAS Reactome:R-HSA-443986	ACCEPT	Summary: TAS annotation from Reactome pathway "Receptor ACKR2 binds most inflammatory CC chemokines". CCL11 is a secreted protein that binds to ACKR2 (a decoy chemokine receptor) in the extracellular region. This is consistent with its localization as a secreted chemokine. Reason: Correct localization for a secreted chemokine, supported by Reactome pathway curation.
GO:0005576 extracellular region	TAS Reactome:R-HSA-6793978	ACCEPT	Summary: TAS annotation from Reactome pathway "Expression of STAT6-upregulated extracellular proteins". CCL11 is a STAT6-induced secreted protein, consistent with its regulation by IL-4/IL-13 signaling and extracellular localization. Reason: Correct localization. CCL11 is a STAT6-regulated secreted protein.
GO:0006468 protein phosphorylation	TAS PMID:10706854 Eotaxin induces degranulation and chemotaxis of eosinophils ...	MODIFY	Summary: TAS annotation citing Kampen et al. (2000). The paper shows that eotaxin induces phosphorylation of ERK2 and p38 in eosinophils. However, CCL11 is NOT a kinase -- it is a secreted chemokine ligand. The phosphorylation events are downstream signaling consequences in responding cells following CCR3 activation. Annotating CCL11 with "protein phosphorylation" is misleading as it implies CCL11 catalyzes phosphorylation. Reason: CCL11 is a secreted chemokine with no kinase activity. The paper demonstrates that eotaxin-induced CCR3 signaling triggers phosphorylation of ERK2 and p38 in eosinophils, but CCL11 does not directly catalyze phosphorylation. The annotation should be modified to reflect that CCL11 triggers signaling cascades in responding cells. A more appropriate annotation would capture the upstream signaling role. Proposed replacements: chemokine-mediated signaling pathway Supporting Evidence: PMID:10706854 Eotaxin (10(-11) to 10(-7) mol/L) induced concentration-dependent phosphorylation of ERK2 and p38. Phosphorylation was detectable after 30 seconds, peaked at about 1 minute, and returned to baseline after 2 to 5 minutes.
GO:0006874 intracellular calcium ion homeostasis	TAS PMID:10415069 Chemokine receptor expression and signaling in macaque and h...	MARK AS OVER ANNOTATED	Summary: TAS annotation from Klein et al. (1999). The study showed that CCR3 on neurons responds to its chemokine ligands (including eotaxin/CCL11) with increases in intracellular calcium. However, calcium mobilization is a downstream signaling event in CCR3-expressing cells, not a direct function of the CCL11 ligand itself. Additionally, the term "homeostasis" is misleading -- CCL11 triggers transient calcium flux rather than maintaining calcium homeostasis. Reason: Intracellular calcium ion homeostasis is a downstream signaling event in CCR3-expressing cells after CCL11 binding. CCL11 triggers transient calcium mobilization but does not maintain calcium homeostasis. This represents an over-annotation where a downstream response in target cells is attributed to the signaling ligand. Supporting Evidence: PMID:10415069 Chemokine receptors were shown to respond to their appropriate chemokine ligands with increases in intracellular calcium that, in the case of neurons, required predepolarization with KCl.
GO:0006935 chemotaxis	TAS PMID:10706854 Eotaxin induces degranulation and chemotaxis of eosinophils ...	ACCEPT	Summary: TAS annotation from Kampen et al. (2000). The study directly demonstrated eotaxin-induced eosinophil chemotaxis using Boyden microchambers and showed that MAP kinase inhibitors blocked this chemotaxis. Reason: Chemotaxis is a core function of CCL11. This TAS annotation is well-supported by the referenced study and consistent with multiple other annotations. Supporting Evidence: PMID:10706854 We conclude that eotaxin induces a rapid concentration-dependent activation of ERK2 and p38 in eosinophils and that the activation of these MAP kinases is required for eotaxin-stimulated degranulation and directed locomotion.
GO:0006954 inflammatory response	TAS PMID:10708591 Cell-type-dependent induction of eotaxin and CCR3 by ionizin...	ACCEPT	Summary: TAS annotation from Huber et al. (2000). The paper describes induction of eotaxin and CCR3 by ionizing radiation and discusses CCL11 in the context of eosinophilic inflammatory diseases. Reason: Inflammatory response is a core process for CCL11. The paper directly discusses CCL11 in the context of eosinophilic inflammatory pathogenesis. Supporting Evidence: PMID:10708591 Eotaxin is an eosinophil-specific C-C chemokine that is implicated in the pathogenesis of eosinophilic inflammatory diseases, such as asthma and atopic dermatitis, by acting specifically on its receptor CCR3.
GO:0007155 cell adhesion	TAS PMID:10201960 Eotaxin activates T cells to chemotaxis and adhesion only if...	KEEP AS NON CORE	Summary: TAS annotation from Jinquan et al. (1999). The study showed that eotaxin, in combination with IL-2 and IL-4, enhances expression of adhesion molecules (ICAM-1, CD29, CD49a, CD49b) on T lymphocytes and promotes adhesion and aggregation. However, the adhesion effect required prior IL-2/IL-4 stimulation to induce CCR3 expression on T cells and is an indirect consequence of chemokine signaling. Reason: Cell adhesion promotion by CCL11 is context-dependent (requires IL-2/IL-4 co-stimulation to induce CCR3 on T cells) and is a downstream consequence of CCR3 signaling rather than a direct adhesion function. Supporting Evidence: PMID:10201960 In combination with IL-2 and IL-4, eotaxin enhances the expression of adhesion molecules such as ICAM-1 and several integrins (CD29, CD49a, and CD49b) on T lymphocytes and thus promotes adhesion and aggregation of T lymphocytes.
GO:0007165 signal transduction	TAS PMID:10706854 Eotaxin induces degranulation and chemotaxis of eosinophils ...	ACCEPT	Summary: TAS annotation from Kampen et al. (2000). The study demonstrated that eotaxin induces signal transduction through CCR3, activating ERK2 and p38 MAP kinases. Signal transduction is a very broad term; more specific terms are available. Reason: While very broad, signal transduction is correct for CCL11 as a signaling ligand that activates receptor-mediated signaling cascades. More specific terms (chemokine-mediated signaling pathway) are also annotated.
GO:0009314 response to radiation	TAS PMID:10708591 Cell-type-dependent induction of eotaxin and CCR3 by ionizin...	MARK AS OVER ANNOTATED	Summary: TAS annotation from Huber et al. (2000). The paper showed that CCL11 (eotaxin) expression is upregulated by ionizing radiation in human dermal fibroblasts. This describes the regulation of CCL11 gene expression in response to radiation, not a function of the CCL11 protein. Reason: This annotation describes the induction of CCL11 gene expression by ionizing radiation, not a function of the CCL11 protein itself. The CCL11 protein does not sense or respond to radiation; rather, its expression is upregulated by radiation in certain cell types. This is an annotation about gene regulation inappropriately applied to the gene product. Supporting Evidence: PMID:10708591 the expression of eotaxin is upregulated upon treatment with ionizing radiation (IR) in human dermal fibroblasts
GO:0009615 response to virus	TAS PMID:9558100 Dendritic cells express multiple chemokine receptors used as...	MARK AS OVER ANNOTATED	Summary: TAS annotation from Rubbert et al. (1998). The paper describes CCR3 as an HIV coreceptor on dendritic cells. CCR3 is identified as an eotaxin receptor on dendritic cells that may be used for HIV entry. However, this paper does not demonstrate a role for CCL11 in response to virus -- rather, it shows that the CCL11 receptor CCR3 can be exploited by HIV for cell entry. This is an over-annotation. Reason: The cited paper describes CCR3 (the eotaxin receptor) as an HIV coreceptor on dendritic cells. This does not demonstrate that CCL11 protein itself participates in response to virus. The viral exploitation of CCR3 is a property of the receptor, not the chemokine ligand. Supporting Evidence: PMID:9558100 CCR3, the eotaxin receptor, initially identified on eosinophils, is expressed on DC and may be used as an entry coreceptor by certain dual-tropic strains.

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Falcon

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