Death Associated Protein Kinase (DAPk, DAPK1) is a Ca2+/calmodulin regulated Ser/Thr kinase that functions in several cell death programs. It has numerous cellular substrates that mediate its various cellular functions, which include apoptosis, autophagy, programmed necrosis, as well as other substrates whose functional significance have not yet been identified. DAPk localizes to the cytoskeleton, and can phosphorylate and/or regulate several cytoskeletal proteins, thereby influencing membrane blebbing, cellular adhesion and motility, events which can accompany cell death or occur independently. DAPk in turn is regulated post-transcriptionally by phosphorylation and dephosphorylation events, including a critical inhibitory autophosphorylation on Ser308, and under certain circumstances, at the level of transcription and protein stability. Significantly, DAPk is a tumor suppressor gene whose expression is lost in numerous human malignancies, mostly through promoter hypermethylation, and has been used as a diagnostic and prognostic tool to evaluate disease severity, progression, metastatic rate and recurrence. DAPk is the founding member of a family of highly related kinases, which include DRP-1 (DAPK2) and ZIPk (DAPK3), which share several of DAPk’s functions and substrates. The human ZIPk sequence has significantly diverged from its mouse orthologue, Dlk, which is reflected in different subcellular localizations and functions; only those shown for the human protein are represented by this map.
