Connective tissue growth factor: Role in trabecular meshwork remodeling and intraocular pressure lowering

(A) TGF-β signaling via SMAD-dependent and SMAD-independent pathways to regulate CTGF-mediated ECM production. TGF-β signaling is initiated by binding of the ligand with the receptors. In SMAD pathway, the activated receptors phosphorylate SMAD 2 and SMAD 3 together with SMAD 4 to promote CTGF expression. SMAD 7 acts as inhibitory mediator for further stimulation of SMAD signaling. In SMAD-independent pathway, TGF-β activates MAP3K at scaffold protein, JNK-interacting protein-1, which facilitates the activation of MAP2K and JNK MAPK. JNK can also be activated by TAK1 upon polyubiquitylation with TRAF6 at the ligand-bound TGF-βR. Binding of the TGF-βR causing autophosphorylation of tyrosine residues recruits Shc and Grb2. The Shc-Grb2 complex binds to SOS that activates Rac1 and Ras GTPases. Rac1 activates Raf to phosphorylate MKK3/6 and stimulate p38. Ras activates Raf to phosphorylate MEK1 which stimulates ERK1/2. TGF-βR also activates ROCK signaling leading to phosphorylation of JNK and p38. The activation of these MAPK signaling molecules JNK, p38, and ERK1/2 induces the expression of CTGF for ECM synthesis. YAP/TAZ involves binding with the SMAD 2/3/4 complex and directly translocates into the nucleus. The siRNA inhibits the transcription of CTGF gene. The transcription of CTGF gene promotes the CTGF protein synthesis and secretes extracellularly. TGF-β: transforming growth factor β; TGF-βR: TGF-c receptor; SMAD: suppressor of mothers against decapentaplegic; MAP: mitogen-activated protein; MAPK: mitogen-activated protein kinase; JNK: c-Jun amino terminal kinase; TRAF6: tumor necrosis factor: TNF receptor–associated factor 6; TAK1: TGF-β-associated kinase 1; Shc: Src homology domain 2–containing protein; Grb2: growth factor receptor–binding protein 2; SOS: son of sevenless; GTP: guanosine triphosphate; MKK3/6: MAP kinase kinase 3/6; ERK: extracellular signal–regulated kinases; MEK1: MAP/ERK kinase 1; ROCK: RhoA/Rho-associated protein kinase; YAP/TAZ: yes-associated protein 1/transcriptional co-activator with PDZ-binding motif; siRNA: short-interfering RNA; CTGF: connective tissue growth factor. (B) Schematic representation of CTGF protein structure showing four structurally distinct domains and the proteins or growth factors that interact with specific domain. IGFBP: insulin-like growth factor–binding protein; vWC: von Willebrand factor type C; TSP: thrombospondin-1; CT: C-terminal cystine knot; IGF: insulin-like growth factor; TGF-β: transforming growth factor-β; BMP: bone morphogenetic protein; VEGF: vascular endothelial growth factor; LRP: lipoprotein receptor–related protein; HSPGs: heparan sulfate proteoglycans; EGF: epidermal growth factor; ET1: endothelin 1; LPA: lysophosphatidic acid; FN: fibronectin. Created with BioRender.com.Pointed black arrows refer to stimulatory and red blunt arrows refer to inhibitory.

Publication

Connective tissue growth factor: Role in trabecular meshwork remodeling and intraocular pressure lowering. (2023) Mohammad Daniel Shafiq Hassan, et al. Exp Biol Med (Maywood). 2023 Aug;248(16):1425-1436. Figure: F1.

Disease mentions