TGF-beta1 regulates the PINCH-1-integrin-linked kinase-alpha-parvin complex in glomerular cells.
Glomerular damage is a major cause of renal failure. Recent studies suggest that a ternary protein complex that consists of PINCH-1, integrin-linked kinase, and alpha-parvin, cytoplasmic components of cell-extracellular matrix adhesions, plays pivotal roles in regulation of glomerular cell behavior. It is reported here that TGF-beta1, a key factor in the progression of glomerular failure, regulates the PINCH-1-integrin-linked kinase-alpha-parvin (PIP) complex formation in glomerular podocytes and mesangial cells. Treatment of podocytes with TGF-beta1 inhibited the PIP complex formation. Forced disruption of the PIP complex in podocytes activated p38 mitogen-activated protein kinase and promoted apoptosis. Importantly, inhibition of p38 mitogen-activated protein kinase, either with a chemical p38 inhibitor (SB202190) or with a dominant negative form of p38alpha, alleviates podocyte apoptosis that is induced by the disruption of the PIP complex. In contrast to an inhibitory role in podocytes, TGF-beta1 promotes the PIP complex formation in mesangial cells. Thus, TGF-beta1 regulates the PIP complex in a cell type-dependent manner. Because the PIP complex promotes glomerular mesangial matrix deposition and protects podocytes from apoptosis, the TGF-beta1-induced up- and downregulation of the PIP complex likely contribute to the pleiotropic effects of TGF-beta1 on different glomerular cell types and hence the progression of glomerular failure.
Jung
Kyu Yong
KY
Department of Pathology, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA 15261, USA.
Chen
Ka
K
Kretzler
Matthias
M
Wu
Chuanyue
C
D000185:Actinin / Q000737:chemistry / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007678:Kidney Glomerulus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D051379:Mice; D046912:Multiprotein Complexes; D050199:Podocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099200:Scaffold Protein ILK
D000185:Actinin; D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases; D000099200:Scaffold Protein ILK; C490232:Lims1 protein, mouse