Roles of PINCH-2 in regulation of glomerular cell shape change and fibronectin matrix deposition.
The PINCH-1-integrin-linked kinase (ILK)-alpha-parvin (PIP) complex plays important roles in the regulation of glomerular cell behavior, including podocyte shape change, apoptosis, and mesangial fibronectin matrix deposition. In this study, we show that PINCH-2, a protein that is structurally related to PINCH-1 but encoded by a different gene, is coexpressed with PINCH-1 in podocytes. Treatment of podocytes with transforming growth factor (TGF)-beta1 elevated the level of PINCH-2, resulting in increased association of PINCH-2 with ILK and alpha-parvin and concomitant displacement of PINCH-1 from the PIP complex. To gain insights into the functional consequences of elevated PINCH-2 expression, we overexpressed PINCH-2 in podocytes by infection with an adenovirus encoding PINCH-2. Overexpression of PINCH-2 resulted in displacement of PINCH-1 from the PIP complex and compromised podocyte spreading. The PINCH-2-mediated displacement of PINCH-1, however, did not prompt apoptosis. Interestingly, the effect of PINCH-2 on podocyte spreading depends on differentiation status, as overexpression of PINCH-2 in podocytes that were not fully differentiated did not alter cell spreading. Finally, we show that overexpression of PINCH-2 in mesangial cells resulted in displacement of PINCH-1 from the PIP complex but impaired neither mesangial cell spreading nor fibronectin matrix deposition. These studies suggest that PINCH-2 can substitute for PINCH-1 in at least certain processes in glomerular cells (e.g., podocyte survival signaling and mesangial fibronectin matrix deposition), albeit that an aberrantly high level of PINCH-2 may contribute to TGF-beta1-induced alteration in podocyte shape modulation.
Shi
Xiaohua
X
Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Qu
Hong
H
Kretzler
Matthias
M
Wu
Chuanyue
C
D000185:Actinin / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D007678:Kidney Glomerulus / Q000166:cytology*; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D051379:Mice; D008840:Microfilament Proteins; D050199:Podocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D000099200:Scaffold Protein ILK; D000096985:Calponins
D000185:Actinin; D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D005353:Fibronectins; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D017346:Protein Serine-Threonine Kinases; D053773:Transforming Growth Factor beta1; D000099200:Scaffold Protein ILK; C088088:LIMS1 protein, human; C490235:LIMS2 protein, human; C486590:PARVA protein, human; D000096985:Calponins