Báo cáo khoa học: Death-associated protein kinase (DAPK) and signal transduction pptx

MINIREVIEW SERIES Death-associated protein kinase (DAPK) and signal transduction Ted R. Hupp CRUK p53 Signal Transduction Laboratories, Institute of Genetics and Molecular Medicine, University of Edinburgh, UK Death-associated protein kinase-1 (DAPK) is the prototypic member of a family of death-related kinases that was originally identified as a factor that regulates apoptosis in response to the death-inducing cytokine signal interferon-c. DAPK has since been shown to play a specialized role as a kinase that can regulate diverse biological signals, including membrane blebbing, autophagy, growth factor-induced survival, tumour necrosis factor-mediated cell death, cancer development and ischaemic-induced neuronal cell death. Relatively little is known about how DAPK orches- trates these diverse cellular events. There is a great deal of knowledge on the genetic pathways that are integrated into highly conserved eukaryotic signalling kinases, such as ataxia telangiectasia mutated (ATM), CDC2 and MAPK. This is mainly due to the fact that these enzymes occur in genetically tractable organisms, such as yeast, which makes pathway mapping relatively rapid. However, many disease-causing genes in humans are not present in yeast and have only evolved in metazoans; DAPK is a case in point and this precludes rapid genetic screens for epistatic pathway mapping. This minireview series highlights some recent advances in DAPK signal transduction biology. The first minireview by Lin et al. highlights the use of combinatorial peptide linear domain screens to identify novel DAPK protein–protein interactions involved in membrane blebbing and mammalian target of rapamy- cin-containing complex signalling. The intriguing and relatively ill-defined role of DAPK in membrane blebbing is put into context in the second minireview by Bovellan et al., which highlights fundamental func- tions of membrane blebbing, not only in cell death, but also in cytokinesis and autophagy. These latter activities have critical implications for the role of DAPK in growth control, especially as DAPK can regulate the extent of membrane blebbing via interac- tions with microtubule-associated protein 1B. This pro- tein in turn interacts with the autophagy protein family member ATG8, thus forming a novel link between autophagy and membrane blebbing pathways. The third minireview by Kang and Avery discusses the use of the first genetic model (Caenorhabditis ele- gans) for DAPK, which is driving fundamental insight into the role of DAPK gene dosage in regulating the extent of autophagic signalling. Autophagy is an evo- lutionarily conserved lysosomal system used to degrade abnormal or long-lived proteins and can be induced by physiological stresses, including amino acid starvation and pathogen infection. The genetic role of DAPK in autophagy cannot be solved using yeast genetics and the continued use of the C. elegans model will proba- bly provide unique genetic insights into the role of DAPK and its death domain in autophagy. The final minireview in the series by Michie et al. reviews the difficult task of acquiring clinically relevant knowledge on any gene in medicine and in particular the role DAPK gene is proving to have in cancer development. The combined insights acquired using genetics, clin- ical screens and signal transduction biology indicates that the specific activity of DAPK is a pivotal feature in explaining its diverse functions. How many dynamic protein–protein interactions will integrate with and regulate the DAPK signal? A recent study attempting to define the ‘interactome’ of the DNA- damage activatable kinase ATM indicated that over 700 substrates exist for this enzyme. This was far more substrates than expected. Whether DAPK occu- pies as complex a ‘hub’ as ATM will require further cross-disciplinary research in this field to shed addi- tional light on the role of the DAPK pathway in biology and medicine. Ted Hupp is Professor of Experimental Cancer Biochemistry at the Institute of Genetics and Molecular Medicine at the University of Edinburgh. He received his PhD in Biochemistry in the laboratory of Jon Kaguni at Michigan State University, MI, USA, studying the initiation of chromosomal DNA replication in Escherichia coli and worked as a post- doctoral researcher with David Lane at the University of Dundee, UK, on the p53 tumour suppressor. The research in the Hupp laboratory aims to define the role of phosphorylation in the control of the p53 tumour suppressor pathway and to uncover the role of novel pro-oncogenic pathways, like anterior gradient-2, that inhibit the p53 pathway in human cancer. doi:10.1111/j.1742-4658.2009.07410.x FEBS Journal 277 (2010) 47 ª 2009 The Author Journal compilation ª 2009 FEBS 47 . MINIREVIEW SERIES Death-associated protein kinase (DAPK) and signal transduction Ted R. Hupp CRUK p53 Signal Transduction Laboratories, Institute of Genetics and Molecular Medicine, University. Molecular Medicine, University of Edinburgh, UK Death-associated protein kinase- 1 (DAPK) is the prototypic member of a family of death-related kinases that was originally identified as a factor. clin- ical screens and signal transduction biology indicates that the specific activity of DAPK is a pivotal feature in explaining its diverse functions. How many dynamic protein protein interactions