Death-Associated Protein Kinase
The death-associated protein kinase (DAPK) family contains three closely-related members: DAPK (also known as DAPK1), DAPK-related protein 1 (DRP-1) and ZIP kinase (ZIPK), all of which are serine/threonine kinases involved in apoptotic and autophagic cell death. Recent research has suggested that these three kinases interact to form complexes which transmit cell death signals in response to stresses such as detachment from the extracellular membrane, and stimuli including TNF-α, IFN-γ and TGF-β.
DAPK is the most-studied member of the family. It is a calmodulin (CaM)-regulated kinase that has been implicated in a variety of diverse signaling pathways involved in cell death, immune and inflammatory responses. DAPK contains several domains, including eight ankyrin repeats and a C-terminal death domain. Many of these domains contain protein-binding regions, and interactions with a variety of different proteins have been confirmed. For example, the DAPK death domain has been shown to interact with ERK and TSC2 proteins, thus placing it within growth factor signaling cascades. Growth factor regulation of DAPK is complex; ERK phosphorylation of DAPK promotes its proapoptotic activity, but DAPK phosphorylation of S6, in conjunction with RSK, promotes cell growth. DAPK is also a central mediator of ER stress signals in the context of both apoptosis and autophagy.
Like many proteins, DAPK is degraded by the ubiquitin-proteasome pathway. Two E3 ubiquitin ligases regulate DAPK activity: DIP-1; and the carboxyl terminus of Hsc70-interacting protein (CHIP), which interacts with DAPK via Hsp90. Epigenetic changes - in particular DAPK promoter hypermethylation - are a common inactivating modification in human cancers, and are often used as a marker of malignancy for various cancer types. DAPK activity has been linked to tumor and metastasis suppression, making it a target of interest in cancer research.
Concerning other members of the DAPK family, DRP-1 is homologous to DAPK with respect to its catalytic domain and calmodulin-regulatory domain; however, its C-terminal is different. ZIPK also contains a homologous kinase domain, but lacks a CaM-regulatory region. The closely related kinases DRAK1 and DRAK2 share approximately 50% sequence homology with the DAPK kinase domain, but also lack a calmodulin-regulatory region. Further research into the cross-talk between these kinases may yield greater understanding of the complex signaling pathways involved in cell death and survival.View all products for Death-Associated Protein Kinase »
|Gene||Species||Gene Symbol||Gene Accession No.||Protein Accession No.|
|Death-associated Protein Kinase (DAPK)||Human||DAPK1||NM_004938||P53355|
|DAPK-related Protein 1 (DRP-1)||Human||DAPK2||NM_014326||Q9UIK4|
|View all Death-Associated Protein Kinase Gene Data »|
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