Distinct roles of two structurally closely related focal adhesion proteins, alpha-parvins and beta-parvins, in regulation of cell morphology and survival.
Proteins at cell-extracellular matrix adhesions (e.g. focal adhesions) are crucially involved in regulation of cell morphology and survival. We show here that CH-ILKBP/actopaxin/alpha-parvin and affixin/beta-parvin (abbreviated as alpha- and beta-parvin, respectively), two structurally closely related integrin-linked kinase (ILK)-binding focal adhesion proteins, are co-expressed in human cells. Depletion of alpha-parvin dramatically increased the level of beta-parvin, suggesting that beta-parvin is negatively regulated by alpha-parvin in human cells. Loss of PINCH-1 or ILK, to which alpha- and beta-parvin bind, significantly reduced the activation of Rac, a key signaling event that controls lamellipodium formation and cell spreading. We were surprised to find that loss of alpha-parvin, but not that of beta-parvin, markedly stimulated Rac activation and enhanced lamellipodium formation. Overexpression of beta-parvin, however, was insufficient for stimulation of Rac activation or lamellipodium formation, although it was sufficient for promotion of apoptosis, another important cellular process that is regulated by PINCH-1, ILK, and alpha-parvin. In addition, we show that the interactions of ILK with alpha- and beta-parvin are mutually exclusive. Overexpression of beta-parvin or its CH(2) fragment, but not a CH(2) deletion mutant, inhibited the ILK-alpha-parvin complex formation. Finally, we provide evidence suggesting that inhibition of the ILK-alpha-parvin complex is sufficient, although not necessary, for promotion of apoptosis. These results identify Rac as a downstream target of PINCH-1, ILK, and parvin. Furthermore, they demonstrate that alpha- and beta-parvins play distinct roles in mammalian cells and suggest that the formation of the ILK-alpha-parvin complex is crucial for protection of cells from apoptosis.
Zhang
Yongjun
Y
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Chen
Ka
K
Tu
Yizeng
Y
Wu
Chuanyue
C
D000185:Actinin / Q000502:physiology*; D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis; D048429:Cell Size; D022081:Cell Surface Extensions; D002470:Cell Survival; D004268:DNA-Binding Proteins; D022001:Focal Adhesions / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D000099200:Scaffold Protein ILK; D000096985:Calponins
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; D020744:rac GTP-Binding Proteins; D000099200:Scaffold Protein ILK; C088088:LIMS1 protein, human; C486590:PARVA protein, human; D000096985:Calponins; C486591:PARVB protein, human