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

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 CTG F plays a key role in the pathogenesis of different fibrotic disorders incl uding diabetic nephropathy. However. the molecular mechanisms by which CTGF exerts its effects are not known. Here we provide the first evidence for t he existence of an intracellular transport pathway for the growth factor in human mesangial cells. Our results demonstrate that CTGF is internalized f rom the cell surface in endosomes and accumulates in a juxtanuclear organel le from which the growth factor is then translocated into the cytosol. In t he cytosol CTGF is phosphorylated by protein kinase C and PMA treatment can enhance this phosphorylation. Phosphorylated CTGF may have an important ro le in the cytosol, but it is also translocated into the nucleus where it ma y directly affect transcription.