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
Trang 1M I N I R E V I E W S E R I E S
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 propro-tein 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