CCN2

Summary

CCN2 (cellular communication network factor 2, HGNC:2500) is a protein-coding gene on chromosome 6q23.2, encoding CCN family member 2 (P29279). Major connective tissue mitoattractant secreted by vascular endothelial cells.

The protein encoded by this gene is a mitogen that is secreted by vascular endothelial cells. The encoded protein plays a role in chondrocyte proliferation and differentiation, cell adhesion in many cell types, and is related to platelet-derived growth factor. Certain polymorphisms in this gene have been linked with a higher incidence of systemic sclerosis.

Source: NCBI Gene 1490 — RefSeq curated summary.

At a glance

• Gene–disease (curated): kyphomelic dysplasia (Limited, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 67 total — 3 pathogenic
• Phenotypes (HPO): 81
• Druggable target: yes
• MANE Select transcript: NM_001901

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2500
Approved symbol	CCN2
Name	cellular communication network factor 2
Location	6q23.2
Locus type	gene with protein product
Status	Approved
Aliases	IGFBP8
Ensembl gene	ENSG00000118523
Ensembl biotype	protein_coding
OMIM	121009
Entrez	1490

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000367976, ENST00000873798, ENST00000918594, ENST00000918595, ENST00000918596

RefSeq mRNA: 1 — MANE Select: NM_001901 NM_001901

CCDS: CCDS5151

Canonical transcript exons

ENST00000367976 — 5 exons

Exon	Start	End
ENSE00000763948	131949949	131950160
ENSE00000763949	131950292	131950543
ENSE00000798731	131950770	131950992
ENSE00001148038	131948176	131949560
ENSE00001446056	131951107	131951372

Expression profiles

Bgee: expression breadth ubiquitous, 270 present calls, max score 99.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 511.2960 / max 36006.2759, expressed in 1460 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
75588	508.1172	1459
75587	1.2715	547
75585	0.7040	358
75582	0.6516	359
204207	0.2726	147
75586	0.1661	81
75584	0.0707	24
75583	0.0424	6

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	99.91	gold quality
ascending aorta	UBERON:0001496	99.54	gold quality
thoracic aorta	UBERON:0001515	99.54	gold quality
smooth muscle tissue	UBERON:0001135	99.52	gold quality
mucosa of stomach	UBERON:0001199	99.49	gold quality
blood vessel layer	UBERON:0004797	99.49	gold quality
right coronary artery	UBERON:0001625	99.37	gold quality
gall bladder	UBERON:0002110	99.36	gold quality
descending thoracic aorta	UBERON:0002345	99.33	gold quality
left coronary artery	UBERON:0001626	99.30	gold quality
tendon of biceps brachii	UBERON:0008188	99.30	gold quality
saphenous vein	UBERON:0007318	99.25	gold quality
synovial joint	UBERON:0002217	99.18	gold quality
trachea	UBERON:0003126	99.18	gold quality
lower lobe of lung	UBERON:0008949	99.18	gold quality
calcaneal tendon	UBERON:0003701	99.15	gold quality
right lung	UBERON:0002167	99.14	gold quality
left uterine tube	UBERON:0001303	99.12	gold quality
aorta	UBERON:0000947	99.10	gold quality
tendon	UBERON:0000043	98.99	gold quality
stromal cell of endometrium	CL:0002255	98.91	gold quality
body of uterus	UBERON:0009853	98.90	gold quality
coronary artery	UBERON:0001621	98.89	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.89	gold quality
popliteal artery	UBERON:0002250	98.80	gold quality
tibial artery	UBERON:0007610	98.80	gold quality
upper lobe of left lung	UBERON:0008952	98.67	gold quality
tibial nerve	UBERON:0001323	98.66	gold quality
upper lobe of lung	UBERON:0008948	98.60	gold quality
layer of synovial tissue	UBERON:0007616	98.45	gold quality

Single-cell (SCXA)

Detected in 21 experiment(s), a significant marker in 19.

Experiment	Marker?	Max mean expression
E-GEOD-124472	yes	14297.15
E-GEOD-114530	yes	10539.16
E-CURD-126	yes	6500.15
E-MTAB-8322	yes	5094.23
E-MTAB-8410	yes	54.54
E-GEOD-134144	yes	49.75
E-MTAB-10287	yes	43.79
E-HCAD-1	yes	30.72
E-CURD-46	yes	22.53
E-CURD-119	yes	20.63
E-HCAD-4	yes	18.74
E-HCAD-10	yes	17.53
E-HCAD-9	yes	15.31
E-HCAD-5	yes	15.07
E-GEOD-84465	yes	9.64

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AGT, AP1, AR, CEBPD, CILP, CREB1, CTNNB1, ESR1, ETS1, F3, FEZF2, FLI1, FOS, FOSB, FOXC1, FOXO1, HIF1A, HNF4A, IL4, IRF6, JUN, KLF10, KLF15, LRP1, MAF, MUC1, MZF1, NFKB, NME1, NR3C1, NR3C2, ONECUT1, POU5F1, PPARG, RELA, ROCK1, ROCK2, RUNX2, SMAD1, SMAD2

miRNA regulators (miRDB)

103 targeting CCN2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-379-3P	99.69	69.60	1524

Literature-anchored findings (GeneRIF, showing 40)

• Elevated levels of connective tissue growth factor, WISP-1, and CYR61 in primary breast cancers associated with more advanced features. (PMID:11751417)
• gene is expressed in granulosa-luteal cells (insulin-like growth factor binding protein-related protein-2; IGFBP-rP2) (PMID:11818516)
• Mechanical stress is required for high-level expression of connective tissue growth factor in fibroblasts. (PMID:11855859)
• the induction of FN by AGE is partly mediated by the AGE-induced up-regulation of cell-derived CTGF and is dependent on PKC activity (PMID:11897682)
• IL-4 interfered with the TGF-beta-induced transcriptional activation of the CTGF gene. (PMID:11967989)
• role in initiating angiogenesis in collaboration with matrix metalloproteinases (PMID:12016149)
• Identification of integrin alpha(M)beta(2) as an adhesion receptor on human peripheral blood monocytes for Cyr61 and connective tissue growth factor: immediate-early gene products expressed in atherosclerotic lesions. (PMID:12036876)
• CTGF has a role in binding to MMPs and VEGF-induced physiological or pathologic angiogenesis (PMID:12114504)
• enhancement of expression on chondrocytes by a novel cis-element (PMID:12150969)
• role in epithelial-mesenchymal transdifferentiation (PMID:12217862)
• CTGF mediates a number of its biological effects by the induction of signaling processes via beta(3) integrin (PMID:12218048)
• CTGF is a hypertrophic factor for human mesangial cells. molecular mechanisms underlying this G(1) phase arrest appear to be due to the induction of the cyclin-dependent kinase inhibitors (CDKI) p15(INK4), p21(Cip1), and p27(Kip1). (PMID:12239232)
• localization and expression during fracture healing (PMID:12398938)
• CTGF interacts with the cytoskeletal protein actin in chondrocytes. (PMID:12470643)
• In contrast to CD4+ alpha beta-T cells, gamma delta-T cells are capable of expressing CTGF mRNA and synthesizing its corresponding protein, which supports the concept that gamma delta-T cells contribute to wound healing or tissue fibrotic processes. (PMID:12496395)
• In brains from Alzheimer’s patients, a strong tangle-associated CTGF immunoreactivity was observed in entorhinal cortex, hippocampus and temporal cortex. (PMID:12535930)
• Gene expression regulation requires tgf-beta2 in fibroblasts. (PMID:12571253)
• Alterations in alpha5beta1 levels induced by TGF-beta are mediated at least in part through the induction of CTGF in glomerular mesangium (PMID:12595495)
• CTGF acts as a negative regulator of the cell growth in oral squamous cell carcinoma possibly through its interaction with growth modifiers inside the cell (PMID:12668285)
• These results suggest that TGF-beta1-induced CTGF mRNA expression is mediated through the JNK-dependent pathway, whereas p38 MAP kinase and ERK pathways minimally contribute (PMID:12760970)
• Production of CTGF by peritoneal mesothelial cells and its presence in peritoneal cavity in peritoneal dialysis. Increase in CTGF in peritoneal membrane fibrosis suggests involvement in underlying pathophysiologic mechanism(s). (PMID:12787426)
• CTGF/Hcs24 produced in the hypertrophic region may act on chondrocytes in the proliferative and maturative zone via some heparan sulfate proteoglycan, such as perlecan. (PMID:12811819)
• Regulates angiogenesis and endothelial cell function. (review) (PMID:12831056)
• the constitutive overexpression of CTGF in SSc fibroblasts seems to be independent of TGFbeta signaling but dependent at least in part on Sp1 (PMID:12888575)
• Magnitude of Urinary CTGF NH(2)-terminal fragment excretion is related to the severity of diabetic nephropathy (PMID:12941731)
• data link alterations in the microtubule and actin cytoskeleton to the expression of connective tissue growth factor (PMID:12951326)
• Postmortem brain tissue analysis demonstrates CTGF localized occasionally in astrocytes but not in macrophages/microglial cells of patients with cerebral malaria. (PMID:14512169)
• Cooperation between CTGF and IGF-I might be involved in glucose-induced matrix accumulation in tubulointerstitial fibrosis and might contribute to pathogenesis of diabetic nephropathy. (PMID:14633859)
• the sequence IRTPKISKPIKFELSG within CCN2is a unique binding domain for integrin alpha(v)beta(3) that is sufficient to mediate hepatic stellate cell adhesion (PMID:14684735)
• results suggest that connective tissue growth factor(CTGF) is involved in extracellular matrix production in parietal epithelial cells and that it is one of the mediators promoting the scarring process in glomerular crescents (PMID:14758550)
• The NH2-terminal CTGF fragment content is increased in the vitreous of patients with proliferative diabetic retinopathy. (PMID:14988298)
• CTGF inhibits metastasis and invasion of human lung adenocarcinoma by a CRMP-1-dependent mechanism. (PMID:14996858)
• Fibroblast proliferation, differentiation into myofibroblasts, & increased collagen synthesis are regulated via a CTGF-dependent pathway. CTGF serves to control a pivotal switch point in the cascade for connective tissue formation. (PMID:15003992)
• CYR61 and CTGF may play a role in the progression of gliomas; their levels at diagnosis may have prognostic significance. (PMID:15041728)
• unstimulated platelets contain considerable amounts of CTGF; CTGF presence in platelets is a result of endocytosis from extracellular environment in bone marrow; agonist-stimulation of platelets resulted in release of CTGF from the storage granules (PMID:15045137)
• evidence that adenylate cyclase as well as one or several protein kinases might be involved in the mechanoregulation of Cyr61, CTGF and Nov genes (PMID:15053922)
• connective tissue growth factor seems to be an attractive alternative therapeutic target for combating renal fibrosis–REVIEW (PMID:15090860)
• Levels are elevated in type 1 diabetic patients with nephropathy and appear to be correlated with proteinuria and creatinine clearance. (PMID:15111539)
• Generated antibodies for functional analysis of CTGF. Showed antibody bound to the CT module neutralizes efficiently the stimulatory effect of CTGF on chondrocytic cell proliferation (PMID:15113833)
• CTGF may play a crucial role in the renal tubular epithelial-transdifferentiation and the following deposition/degradation process of extracellular matrix during tubulointerstitial fibrosis (PMID:15135656)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ccn2a	ENSDARG00000042934
mus_musculus	Ccn2	ENSMUSG00000019997
rattus_norvegicus	Ccn2	ENSRNOG00000015036

Paralogs (5): CCN5 (ENSG00000064205), CCN4 (ENSG00000104415), CCN6 (ENSG00000112761), CCN3 (ENSG00000136999), CCN1 (ENSG00000142871)

Protein

Protein identifiers

CCN family member 2 — P29279 (reviewed: P29279)

Alternative names: Cellular communication network factor 2, Connective tissue growth factor, Hypertrophic chondrocyte-specific protein 24, Insulin-like growth factor-binding protein 8

All UniProt accessions (1): P29279

UniProt curated annotations — full annotation on UniProt →

Function. Major connective tissue mitoattractant secreted by vascular endothelial cells. Promotes proliferation and differentiation of chondrocytes. Is involved in the stimulation of osteoblast differentiation and has a critical role in osteogenesis. Mediates heparin- and divalent cation-dependent cell adhesion in many cell types including fibroblasts, myofibroblasts, endothelial and epithelial cells. Enhances fibroblast growth factor-induced DNA synthesis.

Subunit / interactions. Monomer. Interacts with TSKU.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Expressed in bone marrow and thymic cells. Also expressed one of two Wilms tumors tested.

Disease relevance. Kyphomelic dysplasia (KMD) [MIM:211350] An autosomal recessive skeletal dysplasia characterized by bowing of the limbs primarily affecting the femora, along with short stature, short and wide iliac wings, horizontal acetabular roof, platyspondyly, metaphyseal flaring and distinctive facial features that include prominent forehead, micrognathia, microstomia, cleft palate and low set ears. The disease may be caused by variants affecting the gene represented in this entry. Spondyloepimetaphyseal dysplasia, Li-Shao-Li type (SEMDLSL) [MIM:621099] A form of spondyloepimetaphyseal dysplasia, a clinically and genetically heterogeneous group of skeletal disorders marked by vertebral, epiphyseal, and metaphyseal abnormalities. SEMDLSL is an autosomal dominant form characterized by childhood onset of defective skeletal development. Affected individuals exhibit disproportionate short stature, short lower limbs, limited joint flexion, premature osteoarthritis-like changes in weight-bearing joints, and low bone mass. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the CCN family.

Isoforms (2)

UniProt ID	Names	Canonical?
P29279-1	1, Long	yes
P29279-2	2, Short

RefSeq proteins (1): NP_001892* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000867	IGFBP-like	Domain
IPR000884	TSP1_rpt	Repeat
IPR001007	VWF_dom	Domain
IPR006207	Cys_knot_C	Domain
IPR006208	Glyco_hormone_CN	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR012395	IGFBP_CNN	Family
IPR017891	Insulin_GF-bd_Cys-rich_CS	Conserved_site
IPR036383	TSP1_rpt_sf	Homologous_superfamily
IPR043973	TSP1_CCN	Domain
IPR050941	CCN	Family

Pfam: PF00007, PF00093, PF00219, PF19035

UniProt features (25 total): disulfide bond 11, domain 4, sequence variant 3, glycosylation site 2, signal peptide 1, chain 1, splice variant 1, sequence conflict 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P29279-F1	78.43	0.32

Functional residue map

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

Disulfide bonds (11): 33–56, 35–57, 43–60, 68–82, 74–95, 256–293, 273–307, 284–323, 287–325, 292–329, 29–54

Glycosylation sites (2): 28, 225

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-2032785	YAP1- and WWTR1 (TAZ)-stimulated gene expression
R-HSA-8951671	RUNX3 regulates YAP1-mediated transcription
R-HSA-212436	Generic Transcription Pathway
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878159	Transcriptional regulation by RUNX3

MSigDB gene sets: 687 (showing top): AHRARNT_01, GCACCTT_MIR18A_MIR18B, CREL_01, TSUNODA_CISPLATIN_RESISTANCE_UP, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, CHIBA_RESPONSE_TO_TSA_UP, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, GOBP_CARTILAGE_DEVELOPMENT, BOYAULT_LIVER_CANCER_SUBCLASS_G56_DN, LU_IL4_SIGNALING, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, FISCHER_G1_S_CELL_CYCLE, LFA1_Q6

GO Biological Process (26): cartilage condensation (GO:0001502), angiogenesis (GO:0001525), osteoblast differentiation (GO:0001649), tissue homeostasis (GO:0001894), chondrocyte differentiation (GO:0002062), cell adhesion (GO:0007155), cell-matrix adhesion (GO:0007160), signal transduction (GO:0007165), integrin-mediated signaling pathway (GO:0007229), fibroblast growth factor receptor signaling pathway (GO:0008543), epidermis development (GO:0008544), response to wounding (GO:0009611), negative regulation of gene expression (GO:0010629), cell migration (GO:0016477), lung development (GO:0030324), regulation of chondrocyte differentiation (GO:0032330), chondrocyte proliferation (GO:0035988), positive regulation of cell differentiation (GO:0045597), positive regulation of JNK cascade (GO:0046330), positive regulation of stress fiber assembly (GO:0051496), positive regulation of ERK1 and ERK2 cascade (GO:0070374), DNA biosynthetic process (GO:0071897), reactive oxygen species metabolic process (GO:0072593), ossification (GO:0001503), regulation of developmental process (GO:0050793), connective tissue development (GO:0061448)

GO Molecular Function (4): integrin binding (GO:0005178), insulin-like growth factor binding (GO:0005520), heparin binding (GO:0008201), protein binding (GO:0005515)

GO Cellular Component (6): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), extracellular matrix (GO:0031012), cell periphery (GO:0071944)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Generic Transcription Pathway	2
Transcriptional regulation by RUNX3	1
RNA Polymerase II Transcription	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell differentiation	3
cartilage development	2
cellular process	2
regulation of cell differentiation	2
cellular anatomical structure	2
skeletal system morphogenesis	1
cell aggregation	1
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
ossification	1
multicellular organismal-level homeostasis	1
anatomical structure homeostasis	1
cell-substrate adhesion	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell surface receptor signaling pathway	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to fibroblast growth factor stimulus	1
tissue development	1
response to stress	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
cell motility	1
respiratory tube development	1
animal organ development	1
respiratory system development	1
chondrocyte differentiation	1
regulation of cartilage development	1
cell population proliferation	1
positive regulation of cellular process	1
positive regulation of developmental process	1
JNK cascade	1
positive regulation of MAPK cascade	1
regulation of JNK cascade	1
positive regulation of actin filament bundle assembly	1
stress fiber assembly	1
regulation of stress fiber assembly	1

Protein interactions and networks

STRING

3780 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CCN2	TGFB1	P01137	967
CCN2	NTRK1	P04629	945
CCN2	FN1	P02751	939
CCN2	DCN	P07585	928
CCN2	IGFBP7	Q16270	904
CCN2	HSPG2	P98160	892
CCN2	VWF	P04275	883
CCN2	COL1A1	P02452	849
CCN2	SMAD2	Q15796	842
CCN2	BMP2	P12643	839
CCN2	IGF1	P01343	829
CCN2	MMP3	P08254	824
CCN2	MMP2	P08253	813
CCN2	MMP9	P14780	810
CCN2	AKT1	P31749	803

IntAct

66 interactions, top by confidence:

A	B	Type	Score
ESR1	CCN2	psi-mi:“MI:0915”(physical association)	0.680
ESR1	CCN2	psi-mi:“MI:0403”(colocalization)	0.680
ESR1	CCN2	psi-mi:“MI:0407”(direct interaction)	0.680
CCN2	ESR1	psi-mi:“MI:0914”(association)	0.680
FN1	CCN2	psi-mi:“MI:0403”(colocalization)	0.650
FN1	CCN2	psi-mi:“MI:0915”(physical association)	0.650
CCN2	FN1	psi-mi:“MI:0407”(direct interaction)	0.650
CCN2	FN1	psi-mi:“MI:0915”(physical association)	0.650
FN1	CCN2	psi-mi:“MI:0407”(direct interaction)	0.650
CDA	LIN7A	psi-mi:“MI:0914”(association)	0.640
VWCE	HSPA5	psi-mi:“MI:0914”(association)	0.640
ESR2	CCN2	psi-mi:“MI:0915”(physical association)	0.630
ESR2	CCN2	psi-mi:“MI:0407”(direct interaction)	0.630
CCN2	LRP2	psi-mi:“MI:0914”(association)	0.530
EGFL8	MPO	psi-mi:“MI:0914”(association)	0.530
EDN3	MGRN1	psi-mi:“MI:0914”(association)	0.530
NOTCH2	ZNF316	psi-mi:“MI:0914”(association)	0.530
PIP	TBKBP1	psi-mi:“MI:0914”(association)	0.530
SLC31A1	PRORP	psi-mi:“MI:0914”(association)	0.530
CCN2	CEP43	psi-mi:“MI:0407”(direct interaction)	0.440
CCN2	FGFR2	psi-mi:“MI:0407”(direct interaction)	0.440
CCN2	FGFR3	psi-mi:“MI:0407”(direct interaction)	0.440
C4orf17	CCN2	psi-mi:“MI:0915”(physical association)	0.400
CCN2		psi-mi:“MI:0915”(physical association)	0.370
	CCN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (41): EP300 (Affinity Capture-MS), CREBBP (Affinity Capture-MS), TRIM68 (Affinity Capture-MS), FZR1 (Affinity Capture-MS), KLHL23 (Affinity Capture-MS), COA7 (Affinity Capture-MS), LRP2 (Affinity Capture-MS), ARIH1 (Affinity Capture-MS), CTGF (Protein-RNA), VEGFA (Affinity Capture-Western), CTGF (Reconstituted Complex), CTGF (Two-hybrid), CTGF (Affinity Capture-MS), CTGF (Affinity Capture-MS), TRIM68 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5PUP4, A5YT95, O18739, O19113, O19116, O62650, O75077, O75882, O95980, P10669, P19883, P21674, P28686, P29268, P29279, P31514, P42642, P47931, P48745, P50291, P70701, P97401, Q28893, Q4V7F2, Q5EA46, Q5RF67, Q6NW40, Q6PFE7, Q8C4U3, Q8IYR6, Q8N474, Q8R4F1, Q91XD7, Q92765, Q95117, Q96CW9, Q96HD1, Q99J86, Q9DEQ4, Q9GM01

Diamond homologs: A5A6L1, D3Z5L9, D3ZKF5, O00622, O18739, O19113, O54775, O76076, O95388, O95389, P18406, P19336, P28686, P29268, P29279, P42642, P48745, P51609, Q64299, Q99PP0, Q9ES72, Q9JHC6, Q9QZQ5, Q9R1E9, Q9Z0G4, E1BJW1, A0JNK3, A2RNT9, A2RT60, A4IHA1, A4XSC0, A5PKD8, A5W8F5, A6VUA4, A6YFB5, A9JRB3, B0KV30, B1J4D7, B3LVG7, B3P3J9

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
CCN2	up-regulates	LRP6	binding
MZF1	“up-regulates quantity by expression”	CCN2	“transcriptional regulation”
NME1	“down-regulates quantity by repression”	CCN2	“transcriptional regulation”
CCN2	up-regulates	ECM_synthesis
TEAD4	“up-regulates quantity by expression”	CCN2	“transcriptional regulation”
CCN2	“up-regulates activity”	“A5/b1 integrin”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 65 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
integrin-mediated signaling pathway	5	15.4×	7e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	52
Likely benign	7
Benign	1

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
3629449	NM_001901.4(CCN2):c.65G>C (p.Arg22Pro)	Pathogenic
3630046	NM_001901.4(CCN2):c.443G>A (p.Cys148Tyr)	Pathogenic
3630047	NM_001901.4(CCN2):c.779_786del (p.Pro260fs)	Pathogenic

SpliceAI

309 predictions. Top by Δscore:

Variant	Effect	Δscore
6:131949556:CCCTT:C	acceptor_gain	1.0000
6:131949557:CCTTC:C	acceptor_gain	1.0000
6:131949558:CTT:C	acceptor_gain	1.0000
6:131949561:C:CC	acceptor_gain	1.0000
6:131949571:C:CT	acceptor_gain	1.0000
6:131949572:A:T	acceptor_gain	1.0000
6:131949945:GTAC:G	donor_loss	1.0000
6:131949948:C:CG	donor_loss	1.0000
6:131949962:T:TA	donor_gain	1.0000
6:131950156:GTAAG:G	acceptor_gain	1.0000
6:131950157:TAAG:T	acceptor_gain	1.0000
6:131950158:AAG:A	acceptor_gain	1.0000
6:131950159:AG:A	acceptor_gain	1.0000
6:131950160:GC:G	acceptor_loss	1.0000
6:131950161:C:CC	acceptor_gain	1.0000
6:131950161:C:CG	acceptor_loss	1.0000
6:131950162:T:G	acceptor_loss	1.0000
6:131950164:C:CT	acceptor_gain	1.0000
6:131950165:G:T	acceptor_gain	1.0000
6:131950170:C:CT	acceptor_gain	1.0000
6:131950290:AC:A	donor_gain	1.0000
6:131950291:CC:C	donor_gain	1.0000
6:131950989:CCGG:C	acceptor_gain	1.0000
6:131950990:CGG:C	acceptor_gain	1.0000
6:131950990:CGGC:C	acceptor_gain	1.0000
6:131950992:GC:G	acceptor_loss	1.0000
6:131950993:C:CA	acceptor_loss	1.0000
6:131951101:GCTT:G	donor_loss	1.0000
6:131951102:CTTAC:C	donor_loss	1.0000
6:131951103:TTAC:T	donor_loss	1.0000

AlphaMissense

2311 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:131949346:C:T	C323Y	1.000
6:131949453:A:C	C287W	1.000
6:131949454:C:G	C287S	1.000
6:131949454:C:T	C287Y	1.000
6:131949455:A:G	C287R	1.000
6:131949455:A:T	C287S	1.000
6:131949463:C:T	C284Y	1.000
6:131949991:G:C	C237W	1.000
6:131949993:A:G	C237R	1.000
6:131950043:C:G	R220P	1.000
6:131950084:C:A	W206C	1.000
6:131950084:C:G	W206C	1.000
6:131950086:A:G	W206R	1.000
6:131950086:A:T	W206R	1.000
6:131950341:C:A	W164C	1.000
6:131950341:C:G	W164C	1.000
6:131949339:G:C	C325W	0.999
6:131949340:C:A	C325F	0.999
6:131949340:C:G	C325S	0.999
6:131949340:C:T	C325Y	0.999
6:131949341:A:G	C325R	0.999
6:131949341:A:T	C325S	0.999
6:131949345:A:C	C323W	0.999
6:131949346:C:A	C323F	0.999
6:131949346:C:G	C323S	0.999
6:131949347:A:G	C323R	0.999
6:131949347:A:T	C323S	0.999
6:131949400:A:C	F305C	0.999
6:131949400:A:G	F305S	0.999
6:131949435:G:C	C293W	0.999

dbSNP variants (sampled 300 via entrez): RS1000198671 (6:131951420 C>A,T), RS1000248948 (6:131950303 G>A), RS1000250802 (6:131951821 C>A,G,T), RS1000584692 (6:131951347 C>T), RS1000734182 (6:131950891 G>A), RS1000741379 (6:131951203 G>A,C,T), RS1001523219 (6:131949621 T>G), RS1002477185 (6:131947861 A>C), RS1002741526 (6:131947797 T>A,C), RS1002811571 (6:131949384 G>A), RS1003473260 (6:131952214 G>A), RS1003495745 (6:131948505 G>A), RS1004772837 (6:131951768 C>A), RS1005102891 (6:131951927 C>T), RS1005429477 (6:131952675 A>G)

Disease associations

OMIM: gene MIM:121009 | disease phenotypes: MIM:621099, MIM:211350

GenCC curated gene-disease

Disease	Classification	Inheritance
kyphomelic dysplasia	Limited	Autosomal recessive
spondyloepimetaphyseal dysplasia	Limited	Autosomal dominant

Mondo (3): spondyloepimetaphyseal dysplasia, Li-Shao-Li type (MONDO:0976230), kyphomelic dysplasia (MONDO:0008881), spondyloepimetaphyseal dysplasia (MONDO:0100510)

Orphanet (1): Kyphomelic dysplasia (Orphanet:1801)

HPO phenotypes

81 total (30 of 81 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000175	Cleft palate
HP:0000204	Cleft upper lip
HP:0000217	Xerostomia
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000369	Low-set ears
HP:0000670	Carious teeth
HP:0000895	Lateral clavicle hook
HP:0000907	Anterior rib cupping
HP:0000926	Platyspondyly
HP:0000951	Abnormality of the skin
HP:0001000	Abnormality of skin pigmentation
HP:0001053	Hypopigmented skin patches
HP:0001059	Pterygium
HP:0001324	Muscle weakness
HP:0001369	Arthritis
HP:0001371	Flexion contracture
HP:0001376	Limitation of joint mobility
HP:0001386	Joint swelling
HP:0001387	Joint stiffness
HP:0001635	Congestive heart failure
HP:0001762	Talipes equinovarus
HP:0002015	Dysphagia
HP:0002017	Nausea and vomiting
HP:0002020	Gastroesophageal reflux
HP:0002024	Malabsorption
HP:0002092	Pulmonary arterial hypertension

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003094_8	Mitral valve prolapse	8.000000e-06
GCST006585_2621	Blood protein levels	9.000000e-32

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538128	Kyphomelic dysplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3712901 (SINGLE PROTEIN), CHEMBL5465557 (PROTEIN-PROTEIN INTERACTION)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.51	Kd	3100	nM	CHEMBL5440500
5.41	Kd	3900	nM	CHEMBL5436107

PubChem BioAssay actives

2 with measured affinity, of 104 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[3-[(3S,6S,9S,12S,15S,18S,21S)-9-(4-aminobutyl)-12,15-bis[(1R)-1-hydroxyethyl]-6-(1H-imidazol-5-ylmethyl)-18-(1H-indol-3-ylmethyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazabicyclo[19.3.0]tetracosan-3-yl]propyl]guanidine	1991124: Binding affinity to His-tagged full length human CCN2 CT domain assessed as dissociation constant by isothermal titration calorimetry assay	kd	3.1000	uM
(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S,3R)-2-amino-3-hydroxybutanoyl]amino]hexanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]-N-[(2S)-1-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pyrrolidine-2-carboxamide	1991124: Binding affinity to His-tagged full length human CCN2 CT domain assessed as dissociation constant by isothermal titration calorimetry assay	kd	3.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	increases reaction, affects expression, affects cotreatment, decreases reaction, increases expression	8
Paraquat	increases reaction, affects cotreatment, affects expression, increases expression, decreases reaction	8
Valproic Acid	decreases expression, decreases methylation, increases expression, affects expression	8
bisphenol A	decreases expression, increases expression, affects reaction, affects expression, affects binding (+1 more)	7
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	7
sodium arsenite	affects cotreatment, increases abundance, increases expression, decreases expression	5
Troglitazone	affects cotreatment, decreases expression, decreases reaction, increases expression	5
Doxorubicin	affects expression, increases expression	5
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, affects expression	5
Cyclosporine	decreases expression, increases expression, affects expression, affects cotreatment	5
Cadmium Chloride	increases expression, decreases expression, increases abundance	5
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation, increases expression	4
Cisplatin	decreases expression, increases expression, affects expression, affects cotreatment	4
Glucose	increases expression, affects reaction, affects expression, decreases reaction	4
Hydrogen Peroxide	affects expression, increases expression	4
Particulate Matter	increases expression, decreases expression, increases abundance, affects cotreatment	4
methylmercuric chloride	increases expression	3
cobaltous chloride	increases expression, increases reaction, decreases expression	3
SB 203580	decreases reaction, increases expression, decreases expression	3
(+)-JQ1 compound	decreases expression, increases expression	3
Acetaminophen	affects expression, decreases expression, increases expression	3
Air Pollutants	decreases expression, increases abundance, increases expression	3
Cadmium	increases abundance, increases expression, decreases reaction, decreases expression	3
Ethinyl Estradiol	affects expression, decreases expression	3
Formaldehyde	increases expression	3
Lipopolysaccharides	decreases expression, decreases reaction, increases expression, affects expression, affects response to substance	3
Methotrexate	decreases response to substance, decreases expression, increases expression	3
Smoke	increases expression, increases abundance	3
XMU-MP-1	affects cotreatment, decreases expression, decreases reaction	2
honokiol	decreases reaction, increases expression	2

ChEMBL screening assays

16 unique, capped per target: 16 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5344028	Binding	Inhibition of recombinant human CCN2 FL domain expressed in human HK-1 cells assessed as reduction in COL1A1 synthesis at 20 uM incubated for 24 hrs by Western blotting assay	Discovery and Design of Novel Cyclic Peptides as Specific Inhibitors Targeting CCN2 and Disrupting CCN2/EGFR Interaction for Kidney Fibrosis Treatment. — J Med Chem

Cellosaurus cell lines

6 cell lines: 3 embryonic stem cell, 2 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A0U7	SEES3-1V human CTGF, clone1	Embryonic stem cell	Male
CVCL_A0U8	SEES3-1V human CTGF, clone2	Embryonic stem cell	Male
CVCL_A0U9	SEES3-1V human CTGF, clone3	Embryonic stem cell	Male
CVCL_B1MJ	Abcam HeLa CCN2 KO	Cancer cell line	Female
CVCL_D7LW	Ubigene A-549 CCN2 KO	Cancer cell line	Male
CVCL_D9BA	Ubigene HEK293 CCN2 KO	Transformed cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.