Affinage

CCBE1

Collagen and calcium-binding EGF domain-containing protein 1 · UniProt Q6UXH8

Length
406 aa
Mass
44.1 kDa
Annotated
2026-04-28
38 papers in source corpus 16 papers cited in narrative 16 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCBE1 is a secreted extracellular matrix protein that functions as an essential co-factor for VEGF-C maturation and lymphangiogenesis, with additional roles in erythropoiesis, cardiac development, and meningeal lymphatic maintenance. Its collagen repeat domain enhances ADAMTS3-mediated proteolytic cleavage of pro-VEGF-C into the mature form that activates VEGFR3 signaling, while its N-terminal EGF-like domain colocalizes pro-VEGF-C and ADAMTS3 at the lymphatic endothelial cell surface to facilitate processing (PMID:24552833, PMID:25814692, PMID:28687807). Beyond lymphangiogenesis, CCBE1 is required cell-nonautonomously for fetal liver erythroblastic island formation through macrophage function (PMID:23426945), supports epicardial cell migration and ventricular myocardium development (PMID:36293499), and maintains meningeal lymphatic integrity in adults (PMID:38141283). CCBE1 transcription is positively regulated by E2F7/8 and YAP/TAZ-TEAD4 and negatively regulated by TGFβ-SMAD signaling (PMID:24069224, PMID:36781122, PMID:32089745).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2011 High

    Establishing that CCBE1 is required for lymphatic endothelial cell budding and acts as a potentiator rather than independent driver of VEGF-C-induced lymphangiogenesis resolved the question of whether CCBE1 functions autonomously or as a co-factor in lymphatic development.

    Evidence Ccbe1 knockout mouse analysis combined with corneal micropocket lymphangiogenesis assay and ECM binding assay

    PMID:21778431

    Open questions at the time
    • The molecular target through which CCBE1 enhances VEGF-C activity was unknown
    • Whether CCBE1 acts on VEGF-C directly or on its receptor was not resolved
    • ECM binding partners were not identified
  2. 2013 High

    Discovery that E2F7/8 directly bind and activate the CCBE1 promoter established the first transcriptional regulatory axis for CCBE1 expression in lymphangiogenesis, while identification of CCBE1's role in fetal erythropoiesis revealed a lymphangiogenesis-independent function.

    Evidence ChIP for E2F binding at CCBE1 promoter with zebrafish genetic rescue; Ccbe1 null and conditional KO mice with erythroblastic island formation assays

    PMID:23426945 PMID:24069224

    Open questions at the time
    • Whether E2F7/8 regulation is conserved in mammals was not confirmed
    • The macrophage-intrinsic mechanism by which CCBE1 supports erythroblastic island formation was undefined
    • Whether erythropoietic and lymphangiogenic functions share a common molecular pathway was unknown
  3. 2014 High

    Demonstrating that CCBE1 enhances ADAMTS3-mediated proteolytic processing of pro-VEGF-C into mature VEGF-C identified the precise biochemical mechanism by which CCBE1 drives VEGFR3 signaling and lymphangiogenesis.

    Evidence Cell-based VEGF-C processing assays with defined enzyme and substrate, AAV co-transduction in mouse muscle, and zebrafish genetic epistasis with ERK signaling readouts

    PMID:24523457 PMID:24552833

    Open questions at the time
    • Which structural domain of CCBE1 was required for enhancing ADAMTS3 activity was not yet determined
    • Whether CCBE1 directly contacts ADAMTS3 or pro-VEGF-C was unresolved
  4. 2015 High

    Domain dissection revealed that the collagen repeat domain is essential for VEGF-C processing and lymphangiogenesis in vivo, while the EGF-like domain is partially dispensable, establishing a domain-specific functional hierarchy.

    Evidence Knock-in mice expressing CCBE1 domain deletions combined with zebrafish rescue and in vitro processing assays

    PMID:25814692

    Open questions at the time
    • The role of the EGF-like domain under limiting ADAMTS3 conditions was not yet appreciated
    • Structural basis for how the collagen domain enhances ADAMTS3 catalysis was not determined
  5. 2017 High

    Showing that the N-terminal EGF-like domain colocalizes pro-VEGF-C with ADAMTS3 at the cell surface—and becomes critical when ADAMTS3 is limiting—resolved the apparent contradiction with collagen domain essentiality and established a bipartite activation model.

    Evidence Domain-deletion recombinant proteins in cell-based processing assays with colocalization microscopy and transgenic mouse validation

    PMID:28687807

    Open questions at the time
    • Direct binding affinities between CCBE1 domains and ADAMTS3/VEGF-C were not measured
    • No structural model of the ternary complex exists
  6. 2018 Medium

    Demonstrating that CCBE1 loss impairs cardiac mesoderm differentiation from embryonic stem cells extended CCBE1's developmental roles beyond lymphangiogenesis and erythropoiesis.

    Evidence shRNA knockdown and neutralizing antibody blockade during mouse ESC differentiation with cardiomyocyte marker analysis

    PMID:30281646

    Open questions at the time
    • The signaling pathway mediating CCBE1's role in cardiomyocyte differentiation was not identified
    • Whether this reflects a VEGF-C-dependent or independent mechanism was not tested
  7. 2020 Medium

    Identification of TGFβ-SMAD-mediated transcriptional repression of CCBE1 revealed a negative regulatory axis that modulates VEGF-C maturation in the tumor microenvironment.

    Evidence ChIP for SMAD binding at CCBE1 locus, HLEC tube formation, hindfoot lymphatic metastasis model

    PMID:32089745

    Open questions at the time
    • Whether TGFβ regulation of CCBE1 operates outside of cancer contexts was not tested
    • Relative contribution of SMAD-mediated repression versus E2F-mediated activation in vivo was not determined
  8. 2022 Medium

    Demonstrating that copper stress suppresses CCBE1 via hypermethylation of E2F7/8 binding sites provided an epigenetic layer of regulation, while epicardial CCBE1 knockout revealed its requirement for ventricular myocardium compaction and epicardial EMT.

    Evidence ChIP and methylation analysis of ccbe1 promoter in zebrafish; Ccbe1 KO mouse epicardial explant assays and RNA-seq

    PMID:35034208 PMID:36293499

    Open questions at the time
    • Whether the epicardial phenotype involves VEGF-C processing or a distinct pathway was not resolved
    • Relevance of copper-induced epigenetic regulation to human disease was not established
  9. 2023 Medium

    Multiple studies expanded CCBE1 biology: YAP/TAZ-TEAD4 was identified as a positive transcriptional regulator; CCBE1 was shown to bind TGFβR2 and inhibit DRP1-Ser616 phosphorylation to suppress mitochondrial fission; adult CCBE1 deletion caused meningeal lymphatic regression; and CAVIN1 was identified as a secretion partner.

    Evidence ChIP for TEAD4 at CCBE1 enhancer; Co-IP of CCBE1-TGFβR2 with DRP1 phosphorylation and mitochondrial morphology analysis; inducible conditional KO with meningeal lymphatic imaging; Co-IP of CCBE1-CAVIN1 with endothelial signaling assays

    PMID:36781122 PMID:36849082 PMID:38092144 PMID:38141283

    Open questions at the time
    • The TGFβR2-DRP1 axis has not been validated outside hepatocellular carcinoma cells
    • Whether meningeal lymphatic maintenance requires VEGF-C processing or another CCBE1 function is unknown
    • CAVIN1-dependent secretion mechanism needs independent confirmation
    • Structural basis for CCBE1-TGFβR2 interaction is not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the CCBE1-ADAMTS3-VEGF-C ternary complex, whether CCBE1's non-lymphangiogenic roles (erythropoiesis, cardiac development, mitochondrial dynamics) proceed through VEGF-C-dependent or independent mechanisms, and the physiological significance of CCBE1's metabolic effects on endothelial cells.
  • No crystal or cryo-EM structure of CCBE1 or its complexes exists
  • VEGF-C dependence of erythropoietic and cardiac phenotypes is untested
  • Endothelial metabolic effects are only from a single preprint

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4
Localization
GO:0005576 extracellular region 3 GO:0031012 extracellular matrix 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-1474244 Extracellular matrix organization 1
Partners
ADAMTS3CAVIN1TGFBR2VEGFC

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 CCBE1 promotes proteolytic cleavage of the poorly active 29/31-kDa pro-VEGF-C by ADAMTS3, generating the mature 21/23-kDa VEGF-C that induces increased VEGFR signaling. CCBE1 itself does not process VEGF-C but enhances ADAMTS3-mediated cleavage. Cell-based VEGF-C processing assay (CCBE1-transfected cells), in vivo AAV-mediated co-transduction in mouse muscle, receptor signaling readouts Circulation High 24552833
2014 Genetic epistasis in zebrafish shows ccbe1 acts within the Vegfc/Vegfr3 pathway: Vegfc-driven phenotypes are suppressed in ccbe1 mutants, Vegfc-driven sprouting is enhanced by local Ccbe1 overexpression, Vegfc/Vegfr3-dependent ERK signaling is impaired without Ccbe1, and overexpression of mature VEGFC rescues ccbe1 loss-of-function phenotypes. Zebrafish genetic epistasis (double mutants, overexpression rescue), ERK signaling assays, in vitro VEGFC processing assay Development (Cambridge, England) High 24523457
2011 CCBE1 is required for budding and migration of Prox1+ lymphatic endothelial cells from the cardinal vein in mice; CCBE1 protein binds extracellular matrix components in vitro and strongly enhances VEGF-C-mediated lymphangiogenesis in a corneal micropocket assay, but has little lymphangiogenic effect alone. Ccbe1 knockout mouse phenotypic analysis, in vitro ECM binding assay, corneal micropocket lymphangiogenesis assay, proximity ligation assay for VEGFR3 activation Circulation research High 21778431
2015 The collagen repeat domain of CCBE1 is essential for VEGF-C processing and lymphangiogenesis: CCBE1ΔCollagen mice fully phenocopy CCBE1 knockout and fail to activate VEGFC in vitro, whereas CCBE1ΔEGF retains ability to activate VEGFC processing in vitro and partially supports lymphangiogenesis in vivo. Knock-in mice expressing domain deletion mutants, in vivo zebrafish rescue assays, in vitro VEGFC processing assay Circulation research High 25814692
2017 The N-terminal EGF-like domain of CCBE1 colocalizes pro-VEGF-C with ADAMTS3 at the lymphatic endothelial cell surface, facilitating proteolytic activation; when ADAMTS3 is limiting, only the N-terminal domain (not the C-terminal collagen domain) supports VEGF-C processing. A disease-associated ADAMTS3 mutation causes abnormal CCBE1 localization. Domain-deletion recombinant proteins in cell-based VEGFC processing assay, colocalization microscopy, transgenic mouse model for VEGF-C C-terminal domain requirement Scientific reports High 28687807
2013 E2F7 and E2F8 directly bind and transcriptionally activate the CCBE1 promoter; inactivation of e2f7/8 in zebrafish impairs venous sprouting and lymphangiogenesis with reduced ccbe1 expression, and overexpression of e2f7/8 rescues Ccbe1-dependent phenotypes. Genome-wide E2F binding (ChIP), promoter reporter assays, zebrafish e2f7/8 loss-of-function and rescue experiments PloS one Medium 24069224
2013 CCBE1 is required cell-nonautonomously for fetal liver definitive erythropoiesis; loss of CCBE1 reduces erythroblastic island formation due to abnormal macrophage function, without affecting erythropoietin or stem cell factor expression. Postnatal CCBE1 deletion does not impair erythropoiesis. Ccbe1 null mouse embryo analysis, conditional hematopoietic cell-specific deletion, colony-forming assays, hematopoietic reconstitution, erythroblastic island formation assay Blood High 23426945
2020 TGFβ signaling downregulates CCBE1 transcription in cancer-associated fibroblasts and CRC cells through direct binding of SMADs to the CCBE1 gene locus, reducing VEGF-C maturation and lymphangiogenesis. Chromatin immunoprecipitation (ChIP) for SMAD binding to CCBE1 locus, qPCR, western blot, in vitro HLEC tube formation and migration, in vivo hindfoot lymphatic metastasis model Theranostics Medium 32089745
2023 YAP/TAZ-TEAD4 complexes transcriptionally upregulate CCBE1 by directly binding to the enhancer region of CCBE1 in CRC cells and cancer-associated fibroblasts, resulting in enhanced VEGFC proteolysis and lymphangiogenesis. BET inhibitor JQ1 inhibits CCBE1 transcription and suppresses VEGFC proteolysis. ChIP for TEAD4 binding at CCBE1 enhancer, in vitro HLEC tube formation, in vivo xenograft lymphangiogenesis model, JQ1 pharmacological inhibition The Journal of biological chemistry Medium 36781122
2023 CCBE1 inhibits mitochondrial fission by preventing DRP1 phosphorylation at Ser616 through direct binding to TGFβR2 to inhibit TGFβ signaling, thereby promoting mitochondrial fusion in HCC cells. Recombinant CCBE1 protein treatment, CCBE1 overexpression, co-immunoprecipitation (binding to TGFβR2), DRP1 phosphorylation assay, mitochondrial morphology analysis, in vitro and in vivo tumor models Matrix biology : journal of the International Society for Matrix Biology Medium 36849082
2023 SP1 phosphorylation at Ser101 drives CCBE1 transcription in TMZ-resistant GBM; CCBE1 secretion depends on binding to CAVIN1. CCBE1 promotes VEGFC maturation and activates VEGFR2/VEGFR3/Rho signaling in vascular endothelial cells to induce hyper-angiogenesis in TMZ-resistant tumors. In vivo and in vitro gain/loss of function, co-immunoprecipitation (CAVIN1-CCBE1 binding), signaling pathway analysis, HCMEC/d3 endothelial cell functional assays Cancer letters Medium 38092144
2022 Copper stress epigenetically suppresses ccbe1 expression via hypermethylation of E2F7/8 binding sites on the ccbe1 promoter, reducing E2F7/8 binding enrichment and contributing to lymphangiogenesis defects in zebrafish embryos. ChIP for E2F7/8 binding at ccbe1 promoter, methylation analysis, zebrafish embryo model, mammalian cell assays Angiogenesis Medium 35034208
2022 Loss of CCBE1 in the epicardium leads to congenital heart defects including thinner and hyper-trabeculated ventricular myocardium, reduced cardiomyocyte and epicardial cell proliferation, reduced epicardial-derived cell migration, and deregulation of EMT-related genes. Ccbe1 knockout mouse model, epicardial explant outgrowth assay, RNA-seq, immunostaining, qRT-PCR International journal of molecular sciences Medium 36293499
2023 Inducible deletion of CCBE1 in adult mice impairs postnatal development of meningeal lymphatics and decreases macromolecule drainage to deep cervical lymph nodes; adult CCBE1 deletion causes regression of established meningeal lymphatic structures. Inducible conditional CCBE1 knockout mouse, meningeal lymphatic structural analysis, macromolecule drainage assay Biomedicine & pharmacotherapy Medium 38141283
2018 CCBE1 knockdown by shRNA or blockade with a neutralizing antibody impairs differentiation of mouse embryonic stem cells along the cardiac mesoderm lineage, resulting in decreased mature cardiomyocyte marker expression and smaller embryoid bodies. shRNA knockdown, neutralizing antibody blockade in mouse ESC differentiation, cardiomyocyte marker expression analysis PloS one Medium 30281646
2025 CCBE1 knockdown in HUVECs reduces mitochondrial reactive oxygen species and mitochondrial mass, and shifts cells into a metabolically elevated state with increased ATP production, respiration, and glycolysis, without affecting proliferation or permeability. siRNA knockdown in HUVECs, multi-colour flow cytometry for mROS and mitochondrial mass, Seahorse metabolic assay bioRxivpreprint Low bio_10.1101_2025.08.18.670989

Source papers

Stage 0 corpus · 38 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans. Nature genetics 215 19935664
2014 CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation. Circulation 186 24552833
2011 CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo. Circulation research 168 21778431
2014 Ccbe1 regulates Vegfc-mediated induction of Vegfr3 signaling during embryonic lymphangiogenesis. Development (Cambridge, England) 139 24523457
2017 Targeting of CCBE1 by miR-330-3p in human breast cancer promotes metastasis. British journal of cancer 76 28419078
2017 Efficient activation of the lymphangiogenic growth factor VEGF-C requires the C-terminal domain of VEGF-C and the N-terminal domain of CCBE1. Scientific reports 72 28687807
2009 Linkage and sequence analysis indicate that CCBE1 is mutated in recessively inherited generalised lymphatic dysplasia. Human genetics 70 19911200
2020 CCBE1 promotes tumor lymphangiogenesis and is negatively regulated by TGFβ signaling in colorectal cancer. Theranostics 46 32089745
2015 Functional Dissection of the CCBE1 Protein: A Crucial Requirement for the Collagen Repeat Domain. Circulation research 41 25814692
2012 Evaluation of Clinical Manifestations in Patients with Severe Lymphedema with and without CCBE1 Mutations. Molecular syndromology 38 23653581
2013 Atypical E2fs control lymphangiogenesis through transcriptional regulation of Ccbe1 and Flt4. PloS one 32 24069224
2013 The secreted lymphangiogenic factor CCBE1 is essential for fetal liver erythropoiesis. Blood 30 23426945
2016 CCBE1 promotes GIST development through enhancing angiogenesis and mediating resistance to imatinib. Scientific reports 26 27506146
2013 CCBE1 mutation in two siblings, one manifesting lymphedema-cholestasis syndrome, and the other, fetal hydrops. PloS one 25 24086631
2022 Copper stress impairs angiogenesis and lymphangiogenesis during zebrafish embryogenesis by down-regulating pERK1/2-foxm1-MMP2/9 axis and epigenetically regulating ccbe1 expression. Angiogenesis 23 35034208
2011 Ccbe1 expression marks the cardiac and lymphatic progenitor lineages during early stages of mouse development. The International journal of developmental biology 19 22252499
2023 Neovascularization directed by CAVIN1/CCBE1/VEGFC confers TMZ-resistance in glioblastoma. Cancer letters 18 38092144
2023 The YAP-TEAD4 complex promotes tumor lymphangiogenesis by transcriptionally upregulating CCBE1 in colorectal cancer. The Journal of biological chemistry 15 36781122
2023 CCBE1 promotes mitochondrial fusion by inhibiting the TGFβ-DRP1 axis to prevent the progression of hepatocellular carcinoma. Matrix biology : journal of the International Society for Matrix Biology 13 36849082
2021 miR-942-5p Inhibits Proliferation, Metastasis, and Epithelial-Mesenchymal Transition in Colorectal Cancer by Targeting CCBE1. BioMed research international 13 33997050
2018 The clinical significance of CCBE1 expression in human colorectal cancer. Cancer management and research 12 30555263
2017 Clinical significance of CCBE1 expression in lung cancer. Molecular medicine reports 12 29207117
2015 A novel CCBE1 mutation leading to a mild form of hennekam syndrome: case report and review of the literature. BMC medical genetics 11 25925991
2022 Circ_0006174 promotes the malignancy of colorectal cancer cell via the miR‑1205/CCBE1/Wnt pathway. Molecular medicine reports 10 35674190
2014 Expression and function of Ccbe1 in the chick early cardiogenic regions are required for correct heart development. PloS one 9 25545279
2022 CCBE1 Is Essential for Epicardial Function during Myocardium Development. International journal of molecular sciences 7 36293499
2023 CCBE1 regulates the development and prevents the age-dependent regression of meningeal lymphatics. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 6 38141283
2022 CCBE1 in Cardiac Development and Disease. Frontiers in genetics 6 35222551
2021 Predicting the Most Deleterious Missense Nonsynonymous Single-Nucleotide Polymorphisms of Hennekam Syndrome-Causing CCBE1 Gene, In Silico Analysis. TheScientificWorldJournal 6 34234628
2018 Loss of Ccbe1 affects cardiac-specification and cardiomyocyte differentiation in mouse embryonic stem cells. PloS one 6 30281646
2017 CCBE1 mutation causing sclerosing cholangitis: Expanding the spectrum of lymphedema-cholestasis syndrome. Hepatology (Baltimore, Md.) 5 28073151
2022 The Lymphangiogenic Factor CCBE1 Promotes Angiogenesis and Tumor Growth in Colorectal Cancer. Current molecular medicine 4 34819004
2022 Hsa_circ_0076931 suppresses malignant biological properties, down-regulates miR-6760-3p through direct binding, and up-regulates CCBE1 in glioma. Bioscience reports 3 34931668
2022 LncRNA DNAJC3-AS1 promotes the biological functions of papillary thyroid carcinoma via regulating the microRNA-27a-3p/CCBE1 axis. Cell biology international 2 36583660
2018 Full-length human CCBE1 production and purification: leveraging bioprocess development for high quality glycosylation attributes and functionality. Journal of biotechnology 2 30165116
2022 [High expression of CCBE1 in adjacent tissues of tongue squamous cell carcinoma is correlated with pericancerous lymphatic vessel proliferation and poor 5-year survival outcomes]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 1 36329590
2020 Intestinal lymphangiectasia in a 3-month-old girl: A case report of Hennekam syndrome caused by CCBE1 mutation. Medicine 1 32629717
2020 [Variant analysis of CCBE1 gene in a case of Hennekam lymphangiectasia-lymphedema syndrome type 1]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 32472549