Uptake and intracellular transport of the connective tissue growth factor: a potential mode of action

Abstract

Connective tissue growth factor (CTGF) is a secreted cysteine-rich protein now considered as an important effector molecule in both physiological and pathological processes. An increasing amount of evidence indicates that CTGF plays a key role in the pathogenesis of different fibrotic disorders including diabetic nephropathy. However, the molecular mechanisms by which CTGF exerts its effects are not known. Here we provide the first evidence for the existence of an intracellular transport pathway for the growth factor in human mesangial cells. Our results demonstrate that CTGF is internalized from the cell surface in endosomes and accumulates in a juxtanuclear organelle from which the growth factor is then translocated into the cytosol. In the cytosol CTGF is phosphorylated by protein kinase C and PMA treatment can enhance this phosphorylation. Phosphorylated CTGF may have an important role in the cytosol, but it is also translocated into the nucleus where it may directly affect transcription.

Fell‐Muir lecture: connective tissue growth factor (CCN2) – a pernicious and pleiotropic player in the development of kidney fibrosis

“…Some CTGF then translocates to the cytosolic compartment where it is phosphorylated by protein kinase C before translocating to the nucleus (Wahab et al . ). In unstimulated cells, TrkA is distributed in a punctate pattern over the whole cell and also in a ring‐like structure around the nucleus.…”

“…Treatment of isolated nuclei with CTGF markedly increased their RNA pool size, but no specific mRNAs encoding collagens, fibronectin, etc., were detected, leading us to conclude that the increased transcription may be attributed to ribosomal RNA (Wahab et al . ).…”

“…The stimulatory effect of the latter is mediated through CTGF (Wahab et al . ,b). Both factors also increase the incorporation of the newly synthesized fibronectin into an insoluble extracellular matrix around the cells.…”

Protective effect of statin therapy on connective tissue growth factor induction by diabetesin vivoand high glucosein vitro

“…Increased CTGF levels induced by HG is quickly secreted into the intercellular spaces where it plays a role in signal transduction of downstream targets such as fibronectin which is increased, this may explain some of our observations. CTGF may also be translocated to the nucleus under HG conditions (Wahab et al, 2001). Ito et al (1998) showed by immunohistochemistry staining that only resident cells of the kidney overexpress CTGF mRNA, not migrated monocytes or macrophages.…”

A structural approach to the role of CCN (CYR61/CTGF/NOV) proteins in tumourigenesis

“…Whether the intracellular expression of these proteins accounts for the various roles of the CCN3 protein in signalling remains to be established. Along the same line, it is worth noting that, extracellular CCN2 was reported to be transported to the nucleus of endothelial cells [62] where it was proposed to modulate transcription.…”