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.

Abbreviations used: aFGF, acidic fibroblast growth factor; CREB, cAMP-response element binding protein; CTGF, connective tissue growth factor; CCN family, CTGF, Cyr61/Cef10 and nephroblastoma overexpressed gene family; HMC, human mesangial cell; IGF, insulin-like growth factor; MBP, myelin basic protein; PAI-1, plasminogen activator inhibitor-1; PKC, protein kinase C; REP-1, Rab escort protein 1; rCTGF, recombinant CTGF.

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