Recombinant Human CCN family member 1 (CCN1) (Active)
Description
Molecular Structure and Production
Protein Characteristics:
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Domains: Contains four modular domains: IGFBP-like (Domain I), VWC (Domain II), TSP1-like (Domain III), and CT (Domain IV) .
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Post-Translational Modifications: Heparin-binding motifs in the CT domain enable ECM interactions .
Production Systems:
Functional Roles and Mechanisms
Key Biological Activities:
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Angiogenesis:
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Cell Adhesion and Migration:
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Wound Healing:
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Immune Modulation:
Research Findings and Applications
Table 1: Select Preclinical Studies
Therapeutic Potential:
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Inflammatory Diseases: Attenuates myocarditis and ischemic injury by blocking immune cell migration .
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Cancer: Dual role (pro-angiogenic in tumors vs. metastasis suppressor) .
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Regenerative Medicine: Accelerates wound closure via transient EMT induction .
Challenges and Future Directions
Product Specs
Target Background
- CCN1 has been identified as a potential biomarker associated with the inflammatory activity of Graves' orbitopathy (GO). PMID: 28548552
- Serum CCN1 concentrations in patients with Acute Heart Failure were significantly elevated compared to individuals without Acute Heart Failure (237 pg/ml vs. 124.8 pg/ml, p< 0.001). PMID: 30045012
- Research suggests that mRNA and serum expression levels of Cyr61, CTGF, and VEGF are elevated in muscle tissues of patients with polymyositis (PM)/dermatomyositis (DM). These findings indicate a potential role of these genes in the pathogenesis of these diseases, primarily by affecting blood vessel formation and promoting inflammatory responses. PMID: 30142763
- Genetic studies have revealed an association between specific genotypes of the CYR61 gene and an increased risk of acute myeloid leukemia (AML) in the Han Chinese population. The CC genotype of CYR61 significantly increased the risk of AML in both dominant and recessive inheritance models. Additionally, specific genotypes (rs2297141 and rs6576776) were associated with AML-M5 and AML-M2, respectively. These findings suggest that genetic polymorphisms in the CYR61 gene may be considered potential risk factors for AML in this population. PMID: 30142822
- CCN1 has been implicated in the pathogenesis of rheumatoid arthritis (RA) by promoting monocyte migration. It achieves this by upregulating the expression of monocyte chemoattractant protein-1 (CCL2) in osteoblasts. This finding suggests that CCN1 may be a potential target for RA treatment. PMID: 28341837
- MiR-365 has been identified as a tumor suppressor in osteosarcoma (OS), partially by targeting CYR61 expression. PMID: 29287201
- CCN1 may play a role in the progression of hepatic cirrhosis to hepatocellular carcinoma by regulating hepatic stellate cells. PMID: 29286082
- Research has demonstrated that Cyr61 is elevated in acute lymphoblastic leukemia (ALL) and promotes cell survival through the AKT/NF-kappaB pathway by upregulating Bcl-2. PMID: 27725691
- PPARgamma agonists may have therapeutic potential in rheumatoid arthritis by inhibiting the migration and invasion of rheumatoid arthritis-fibroblast-like synoviocytes through the downregulation of Cyr61. PMID: 27456070
- CCN1 stimulates CCL20 production in vitro and in vivo. This suggests that overexpression of CCN1 in hyperproliferating keratinocytes may contribute to the recruitment of inflammatory cells to skin lesions affected by psoriasis. PMID: 28602508
- Plasma Cyr61 concentration is significantly elevated in patients with pulmonary arterial hypertension (PAH). Cyr61 promotes pulmonary arterial smooth muscle cells proliferation via the AKT pathway, suggesting a potential role in the pathogenesis of PAH. PMID: 28824319
- Cyr61 and VEGF expressions have been identified as independent prognostic indicators of overall survival in patients with osteosarcoma. These factors may serve as important prognostic predictors in this disease. PMID: 28647210
- Research indicates that suppression of Cyr61 in cancer stem cell-like cells in pancreatic ductal adenocarcinoma (PDAC) may inhibit tumor cell metastasis after resection of the primary tumor. PMID: 27705906
- CYR61 has been implicated in promoting breast cancer lung metastasis by facilitating tumor cell extravasation and protecting cells from anoikis during initial seeding to the lung. PMID: 27911269
- Knockdown of CYR61 in gastric cancer AGS cells impairs cancer cell migration and invasion, suggesting a driver role of CYR61 in metastasis. PMID: 27105510
- Research suggests that CCN1 promotes VEGF expression in osteoblasts and increases endothelial progenitor cells angiogenesis in rheumatoid arthritis. This highlights a potential role of CCN1 in the vascular component of RA. PMID: 27465842
- Two interacting partners of urokinase-type plasminogen activator (uPA) receptor, the cysteine-rich angiogenic inducer 61 (Cyr61) and the Y-box-binding protein 1 (YB-1), have been identified and their differential expression demonstrated in triple-negative breast cancer (TNBC) cells and tumors. These findings may have implications for understanding the biology of TNBC. PMID: 27286449
- Collagen II-activated phosphorylated-DDR2 induces CYR61 through activation of transcription factor activator protein 1 (AP-1). The elevated CYR61, in turn, accelerates MMP1 production via ETS1 (ETS proto-oncogene 1). This pathway may be involved in the pathogenesis of cartilage degradation in osteoarthritis. PMID: 27653023
- Cyr61 has been shown to stimulate MMP-3 production in fibroblast-like synoviocytes of rheumatoid arthritis patients, contributing to the joint destruction associated with this disease. PMID: 27585710
- Low CCN1 expression is associated with esophageal cancer, suggesting a potential role in tumor suppression. PMID: 29055676
- Research has shown that Cyr61 expression is higher in ectopic endometrium compared to eutopic endometrium. Furthermore, Cyr61 expression in the endometrium has been correlated with various factors such as age, number of natural labors, blood loss, uterine volume, adenomyosis type, and concurrent endometriosis. These findings suggest a potential role of Cyr61 in the development of endometriosis and adenomyosis. PMID: 27644084
- The role of CYR61 in aromatase inhibitors resistance in estrogen receptor-positive breast cancer patients has been investigated, highlighting its potential as a therapeutic target to overcome this resistance. PMID: 27113745
- CYR61 has been identified as a TGF-beta-induced stromal-derived factor that regulates gemcitabine sensitivity in pancreatic ductal adenocarcinoma. This finding suggests a potential target for improving the effectiveness of gemcitabine treatment in pancreatic cancer. PMID: 27604902
- Studies support a previously unrecognized, cooperative interaction between the CCN1 matricellular protein and canonical TGF-beta1/SMAD3 signaling in promoting lung fibrosis. This finding provides insights into the complex mechanisms involved in lung fibrosis and may lead to novel therapeutic strategies. PMID: 26884454
- Research indicates a potential functional impact of Cyr61 in the development and progression of cervical cancer. PMID: 28476813
- Research highlights both CYR61 and TAZ genes as potential predictive biomarkers for stratifying the risk of developing adenocarcinoma in Barrett's esophagus. These findings suggest a potential mechanistic route for neoplastic progression in Barrett's esophagus. PMID: 27583562
- Reduced levels of CCN1 and CCN3, as observed in early-onset preeclampsia, may contribute to a shift from invasive to proliferative extravillous trophoblasts, explaining their shallow invasion properties in this disease. PMID: 26744771
- Studies have investigated the promoter activity and expression of CYR61 mRNA and protein. PMID: 28322825
- Research provides evidence that CCN1 can stimulate the proliferation and differentiation of osteoblasts in vitro and contribute to bone remodeling in vivo in myeloma bone disease. This suggests a potential role of CCN1 in the pathogenesis of myeloma bone disease. PMID: 28035364
- Research suggests that the WNT/beta-catenin signaling pathway enhances pancreatic cancer development and malignancy in part via upregulation of CYR61. This finding highlights a potential target for inhibiting pancreatic cancer progression. PMID: 27889647
- CCN1 RNAi reduced the mRNA and protein expression levels of CCN1, Akt, and VEGF in HUVECs. Furthermore, LY294002 reduced the mRNA and protein expression levels of CCN1 in hypoxic cells. These findings suggest that CCN1 RNAi may offer a novel therapeutic strategy for treating pathological angiogenesis by inhibiting the PI3K/AktVEGF pathway. PMID: 27666419
- High CYR61 expression is associated with colorectal cancer, suggesting a potential role in tumor development and progression. PMID: 27743169
- Treatment of B16 cells with epirubicin and IFN-a increased CYR61 levels, inhibited cell growth, and decreased proliferating cell nuclear antigen expression. These findings suggest that CYR61 may become a therapeutic target for malignant melanoma patients with high CYR61 expression. PMID: 27665942
- Research has examined the clinical relevance of NOV, along with CYR61 and CTGF, in gastric cancer by analyzing their transcript levels. The expression of NOV and CYR61 was increased in gastric cancer, with elevated CYR61 expression associated with poorer survival. NOV promoted proliferation and invasion of gastric cancer cells. These findings suggest a complex role of these matricellular proteins in gastric cancer development and progression. PMID: 27633176
- Research has explored the protective role of 7,8-DHF in hypoxic HK-2 cells. Findings indicate that 7,8-DHF activates Cyr61 signaling and suppresses ER stress, providing potential clinical implications for treating acute kidney injury. PMID: 28116298
- CYR61 is upregulated in epithelial cells of salivary glands in patients with primary Sjogren's syndrome. PMID: 26630293
- RNA silencing of CCN family member 1 protein (CCN1) inhibits umbilical vein endothelial cell (HUVEC) proliferation under hypoxic conditions by inhibiting phosphoinositide 3-kinase (PI3K)/AKT protein signaling. PMID: 26459773
- Research indicates that the CYR61 CTGF NOV matricellular proteins (CCN family of proteins) comprises members CCN1, CCN2, CCN3, CCN4, CCN5, and CCN6. These proteins have been identified in various types of cancer and are known to play roles in cellular processes related to cancer development and progression. PMID: 26498181
- Research suggests that Cyr61 is induced by EGF through the ERK/CREB signal pathway and plays a crucial role in the migration and invasion of anaplastic thyroid cancer cells. PMID: 25773758
- CCN1 is an injury response protein that functions not only to restrict fibrosis in the liver but also to suppress hepatocarcinogenesis by inhibiting EGFR-dependent hepatocyte compensatory proliferation. PMID: 26028023
- Research demonstrates that NF2 negatively controls the invasiveness of Glioblastoma multiforme through YAP-dependent induction of CYR61/CCN1 and miR-296-3p. This finding provides insights into the molecular mechanisms underlying the tumor suppressor function of NF2 in glioblastoma. PMID: 26923924
- CCN1 promotes cell growth and angiogenesis in cancers through its interaction with several integrins. It has also been proven to be an independent prognostic factor for patient survival. PMID: 26201842
- c-Src regulates secreted proteins, including the exosomal Cyr61, which are involved in modulating the metastatic potential of triple-negative breast cancer cells. This finding suggests a potential target for inhibiting breast cancer metastasis. PMID: 25980494
- Research has shown evidence that CCN1 is O-fucosylated at Threonine 242, and that O-fucosylation of CCN1 regulates its secretion. This finding provides insights into the post-translational modifications that influence CCN1's biological activity. PMID: 26424659
- Reactive oxygen species increase c-Jun, a critical member of the transcription factor AP-1 complex, and increase c-Jun binding to the AP-1 site of the CCN1 promoter. This suggests that reactive oxygen species may play a role in regulating CCN1 expression. PMID: 25536346
- Overexpression of Cyr61 may induce epithelial-mesenchymal transition, leading to laryngeal squamous-cell carcinoma invasion and metastasis and poor prognosis. This suggests a potential target for inhibiting laryngeal squamous cell carcinoma progression. PMID: 25854342
- Cyr61 promotes CD204 expression and the migration of macrophages via the MEK/ERK pathway in esophageal squamous cell carcinoma. This finding highlights a potential role of Cyr61 in promoting tumor cell invasion and metastasis in this cancer type. PMID: 25620088
- Research is the first to suggest a relationship between a genetic variant p.R47W in CCN1 and atrial septal defects in humans. This finding warrants further investigation into the potential role of CCN1 in congenital heart defects. PMID: 25135600
- SYK is downstream of CYR61 and contributes to CYR61-mediated mitoxantrone resistance. The CYR61-SYK pathway represents a potential target for reducing stroma-induced chemoresistance in cancer. PMID: 25974135
Customer Reviews
Applications : Vascular permeability assay
Review: Mice with orthotopic tumors were intratumorally injected with recombinant Cyr61 reconstituted in HBSS every other day starting on day 21 after tumor cell injection (3× in total).
Q&A
What structural domains define Recombinant Human CCN1’s functional versatility?
Recombinant Human CCN1 (275–381 aa fragment) retains the insulin-like growth factor-binding protein (IGFBP) and von Willebrand factor type C (vWC) domains, which mediate interactions with integrins α6β1, αvβ3, and αvβ5 . The absence of the thrombospondin type 1 (TSP1) and C-terminal (CT) domains in truncated variants impacts heparin-binding affinity and downstream signaling . For example, the IGFBP domain is indispensable for chemotaxis in wound-healing assays, while the vWC domain stabilizes integrin α6β1 binding in breast cancer models . Researchers should validate domain-specific activity using deletion mutants (e.g., CCN1 1–2 vs. 1–3 variants) in adhesion or proliferation assays .
How should researchers verify batch-to-batch consistency of Recombinant CCN1?
Quality control requires three orthogonal methods:
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SDS-PAGE: Confirm >90% purity and 12–14 kDa molecular weight under reducing conditions .
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Functional assays: Test angiogenic activity using endothelial tube formation assays (10–50 ng/mL optimal dose) .
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Integrin binding: Validate via solid-phase binding assays with immobilized α6β1 or αvβ3 integrins, comparing dissociation constants (Kd) between batches . Discrepancies in cell adhesion outcomes often trace to variations in heparin sulfate proteoglycan content across cell lines, necessitating parallel positive controls (e.g., HEK293T vs. primary fibroblasts) .
How does CCN1’s dual role in angiogenesis and senescence influence experimental design?
CCN1 exhibits context-dependent pro-angiogenic or pro-senescent activity dictated by integrin binding partners and proteolytic processing . In oxygen-induced retinopathy models, full-length CCN1 (40–50 kDa) promotes pathological neovascularization, whereas MMP-2/14-cleaved fragments (25–30 kDa) exacerbate inflammation via sustained VEGFA expression . To isolate mechanisms:
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Senescence studies: Use serum-starved breast cancer cells (MCF-7) with 100 nM 4-hydroxytamoxifen to induce endocrine resistance, monitoring p21/p16 expression post-CCN1 treatment (20 ng/mL, 48 hr) .
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Angiogenesis studies: Combine recombinant CCN1 (50 ng/mL) with VEGF-neutralizing antibodies in HUVEC tube formation assays to decouple direct vs. VEGF-mediated effects .
Table 1: Context-Dependent CCN1 Signaling Outcomes
How can researchers resolve contradictions in CCN1’s role across disease models?
Disparate findings often arise from differential post-translational modifications (PTMs) or species-specific isoform usage. For example:
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PTM Variability: Non-phosphorylated CCN1 (E. coli-derived) fails to activate αvβ3 in neuronal plasticity assays, unlike mammalian-expressed isoforms . Always confirm phosphorylation status via Pro-Q Diamond staining .
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Species Specificity: Mouse CCN1 (92% homology to human) shows reduced affinity for human α6β1 integrin . Use cross-species co-culture systems or humanized integrin knock-in models to bridge translational gaps.
What methodological pitfalls affect CCN1 stability in in vivo studies?
Recombinant CCN1 has a plasma half-life of <2 hr due to rapid MMP-2 cleavage . To prolong activity:
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Delivery Optimization: Use AAV2/5 vectors with GFAP promoters for astrocyte-specific expression in neural circuits (titer: 2–4×10¹² vg/mL) .
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Protease Inhibition: Co-administer batimastat (MMP inhibitor, 10 μM) in subcutaneous Matrigel plugs to preserve full-length protein .
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Dosage Titration: Biphasic responses occur; excessive CCN1 (>100 ng/mL) induces paradoxical apoptosis via FAS ligand upregulation .
Methodological Case Study: CCN1 in Neuroplasticity Research
A 2024 bioRxiv study highlights CCN1’s role in stabilizing adult visual cortex circuits . Key steps for replication:
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Viral Delivery: Inject AAV2/5-CCN1-HA (P14) into mouse visual cortex; validate HA-tag expression via immunohistochemistry (Fig. 2B–C) .
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Plasticity Assay: Perform monocular enucleation at P28, sacrifice after 4 days, and quantify Arc mRNA width via smFISH (16 μm sections, 4–6 mice/group) .
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Data Interpretation: CCN1 overexpression reduces Arc expansion by 37% (p<0.01), indicating stabilized ocular dominance columns . Control for circadian effects by standardizing light exposure pre-euthanasia .
