| CTGF, or connective tissue growth factor, belongs to the CCN family of matricellular proteins characterized by modular domains that enable diverse interactions in the extracellular matrix. It features an insulin-like growth factor-binding protein domain, von Willebrand factor type C repeat, thrombospondin type 1 repeat, and cysteine-rich C-terminal domain, which collectively facilitate binding to integrins, LRP receptors, HSPGs, VEGF, TGF-β superfamily members, fibronectin, and BMPs. Secreted into the matrix, CTGF binds cell surface integrins like αvβ3, α5β1, and α6β1 to activate FAK/Src/ERK, PI3K/Akt, and NF-κB pathways, promoting fibroblast adhesion, migration, myofibroblast transdifferentiation, and extracellular matrix deposition including collagen I and fibronectin. Through TSP1 domain interaction with VEGF, it modulates angiogenesis by sequestering VEGF or releasing it via RhoA inactivation, while VWC domain antagonizes BMP-2/7 signaling and chaperones TGF-β to enhance SMAD2/3-mediated transcription. YAP/TAZ from the Hippo pathway transactivate CTGF expression via TEAD binding, forming feedback loops that drive sustained matrix remodeling, and CTGF reciprocates by stabilizing YAP nuclear localization. CTGF supports skeletal development by regulating chondrocyte proliferation and osteoblast differentiation, wound repair through myofibroblast activation, and vascular integrity via barrier formation. TGF-β, angiotensin II, hypoxia, and mechanical stress induce CTGF via SMAD, MAPK, and ETS1 promoters, amplifying profibrotic responses in liver, lung, kidney, and heart fibrosis where it cooperates with TGF-β for persistent collagen accumulation. Elevated in desmoplastic tumors like pancreatic cancer, CTGF fosters EMT via integrin-linked kinase/ERK/PI3K, tumor stroma deposition, and metastasis, though context-dependent suppression occurs in some lung and colorectal cancers. |
