Regulation of fibronectin matrix deposition and cell proliferation by the PINCH-ILK-CH-ILKBP complex.
Alteration in renal glomerular mesangial cell growth and fibronectin matrix deposition is a hallmark of glomerulosclerosis, which ultimately leads to end-stage renal failure. We have previously shown that the expression of integrin-linked kinase (ILK), a cytoplasmic component of the cell-extracellular matrix contacts, is increased in mesangial cells in human patients with diabetic nephropathy. We show here that ILK forms a complex with PINCH and CH-ILKBP in primary mesangial cells, which are co-clustered at fibrillar adhesions, sites that are involved in fibronectin matrix deposition. To investigate functional significance of the PINCH-ILK-CH-ILKBP complex formation, we expressed the PINCH-binding N-terminal fragment and the CH-ILKBP-binding C-terminal fragment of ILK, respectively, in mesangial cells by using an adenoviral expression system. Overexpression of either the N-terminal fragment or the C-terminal fragment of ILK effectively inhibited the PINCH-ILK-CH-ILKBP complex formation. Inhibition of the PINCH-ILK-CH-ILKBP complex formation significantly reduced fibronectin matrix deposition and inhibited cell proliferation. These results indicate that the PINCH-ILK-CH-ILKBP complex is critically involved in the regulation of mesangial fibronectin matrix deposition and cell proliferation, and suggest that it may potentially serve as a useful target in the therapeutic control of progressive renal failure and other pathological processes involving abnormal cell proliferation and fibronectin matrix deposition.
Guo
Lida
L
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Wu
Chuanyue
C
D000185:Actinin; D000818:Animals; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism*; D002448:Cell Adhesion; D002455:Cell Division; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism*; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D046911:Macromolecular Substances; D008840:Microfilament Proteins; D008954:Models, Biological; D010446:Peptide Fragments / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D014162:Transfection; D000099200:Scaffold Protein ILK; D000096985:Calponins
D000185:Actinin; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D005353:Fibronectins; D046911:Macromolecular Substances; D008840:Microfilament Proteins; D010446:Peptide Fragments; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK; C486590:PARVA protein, human; D000096985:Calponins; C486591:PARVB protein, human