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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Wang, Won-jing Yao, Chung-chen Kuo, Jean-cheng Chen, Ruey-hwa |
| Description | Author Affiliation: Wang WJ ( Institute of Molecular Medicine, College of Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.) |
| Abstract | Death-associated protein kinase (DAP-kinase) is a calcium/calmodulin-dependent serine/threonine kinase, and participates in various apoptosis systems. However, its apoptosis-promoting mechanism is poorly understood. Here, we demonstrate that DAP-kinase suppresses integrin-mediated cell adhesion and signal transduction, whereas dominant-negative interference of this kinase promotes adhesion. This effect of DAP-kinase is neither a consequence of apoptosis nor a result of decreased expression of integrins. Rather, DAP-kinase downregulates integrin activity through an inside-out mechanism. We present evidence indicating that this adhesion-inhibitory effect accounts for a major mechanism of the apoptosis induced by DAP-kinase. First, in growth-arrested fibroblasts, DAP-kinase triggers apoptosis in cells plated on fibronectin, but does not affect the death of cells on poly-l-lysine. Second, in epithelial cells, DAP-kinase induces apoptosis in the anoikis-sensitive MCF10A cells, but not in the anoikis-resistant BT474 cells. Most importantly, the apoptosis-promoting effect of DAP-kinase is completely abolished by enforced activation of integrin-mediated signaling pathways from either integrin itself or its downstream effector, FAK. Finally, we show that integrin or FAK activation blocks the ability of DAP-kinase to upregulate p53. Our results indicate that DAP-kinase exerts apoptotic effects by suppressing integrin functions and integrin-mediated survival signals, thereby activating a p53-dependent apoptotic pathway. |
| ISSN | 00219525 |
| e-ISSN | 15408140 |
| Journal | The Journal of Cell Biology |
| Issue Number | 1 |
| Volume Number | 159 |
| Language | English |
| Publisher | Rockefeller University Press (United States) |
| Publisher Date | 2002-10-14 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Apoptosis Physiology Calcium-Calmodulin-Dependent Protein Kinases Metabolism Cell Adhesion Extracellular Matrix Integrins Signal Transduction Amino Acid Chloromethyl Ketones Animals Apoptosis Regulatory Proteins Breast Neoplasms Carcinoma Caspase 3 Caspase Inhibitors Caspases Cell Line Cell Size Cell Survival Cysteine Proteinase Inhibitors Death-Associated Protein Kinases Epithelial Cells Cytology Genes, Reporter Mice Tumor Suppressor Protein P53 Genetics Research Support, Non-U.S. Gov't Cell Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Medicine |
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