title: Formation and phosphorylation of the PINCH-1-integrin linked kinase-alpha-parvin complex are important for regulation of renal glomerular podocyte adhesion, architecture, and survival.
abstract: Alterations in the cellular architecture, adhesion, and/or loss of glomerular podocytes are causal factors in the development of proteinuria and the progression to end-stage renal failure. With the use of an inducible podocyte differentiation system, it was found that the cellular levels of PINCH-1, integrin linked kinase (ILK), and alpha-parvin, cytoplasmic components of cell-extracellular matrix adhesions, were significantly increased during podocyte differentiation. Concomitantly, an increased amount of the PINCH-1-ILK-alpha-parvin complex was detected in the differentiated, foot process-containing podocytes. Overexpression of the PINCH-1-binding ankyrin repeat domain of ILK but not that of a PINCH-1-binding defective mutant form of the ankyrin domain effectively inhibited the formation of the PINCH-1-ILK-alpha-parvin complex. Disruption of the PINCH-1-ILK-alpha-parvin complex significantly reduced the podocyte-matrix adhesion and foot process formation. Furthermore, a marked increase of apoptosis in the podocytes in which the assembly of the PINCH-1-ILK-alpha-parvin complex was compromised was detected. Inhibition of ILK with a small compound inhibitor also altered podocyte cytoskeleton and increased apoptosis. Finally, it is shown that alpha-parvin is phosphorylated in podocytes. Mutations at the alpha-parvin N-terminal proline-directed serine phosphorylation sites reduced its complex formation with ILK and resulted in defects in podocyte adhesion, architecture, and survival. These results provide important evidence for a crucial role of the PINCH-1-ILK-alpha-parvin complex in the control of podocyte adhesion, morphology, and survival.
authors.affiliation: 707B Scaife Hall, Department of Pathology, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA 15261, USA.
authors.forename: Yanqiang
authors.initials: Y
authors.lastname: Yang
authors.forename: Lida
authors.initials: L
authors.lastname: Guo
authors.forename: Simone M
authors.initials: SM
authors.lastname: Blattner
authors.forename: Peter
authors.initials: P
authors.lastname: Mundel
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.forename: Chuanyue
authors.initials: C
authors.lastname: Wu
mesh_terms: D000185:Actinin / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D002454:Cell Differentiation; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000502:physiology*; D005109:Extracellular Matrix / Q000502:physiology; D007678:Kidney Glomerulus / Q000166:cytology / Q000502:physiology*; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D051379:Mice; D008840:Microfilament Proteins; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000099200:Scaffold Protein ILK; D000096985:Calponins
chemical_list: D000185:Actinin; D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK; C490232:Lims1 protein, mouse; C486590:PARVA protein, human; D000096985:Calponins