Department of Pathology, Otto-von-Guericke University, Leipziger Strasse 44, 39120 Magdeburg, Germany
Migration DAPK is involved in stabilization of stress fibers through phosphorylation of MLC which occurs prior the onset of apoptosis (Kuo et al., 2003).
Signal transduction DAP kinase is up-regulated by hyperproliferative signals, and operates upstream of p19-ARF and p53 to induce apoptosis. Whereas the inactivation or loss of DAP kinase significantly reduces the p53 responses to c-Myc or E2F-1, it does not completely eliminate them, indicating that DAP kinase is not an exclusive player upstream of p19ARF/p53 (Raveh et al., 2001). Recent studies showed several mechanisms influencing DAPK activity. These include RSK dependent inactivation of DAPK1 (Anjum et al., 2005) and ERK-dependent activation of the proapoptotic function of DAPK (Chen et al., 2005). Death-promoting effects of DAPK are counteracted by Bcl2 (Cohen et al., 1997). It was shown that the apoptosis regulatory activities mediated by DAPK are controlled both by phosphorylation status and protein stability.
Phosphorylation sites There are three well characterized phosphorylation sites on DAPK protein; 1) the phosphorylation by RSK at Ser289, which triggers a suppression of DAPK pro-apoptotic function (Anjum et al., 2005), 2) the autophosphorylation site, which was mapped to Ser308 within the CaM-regulatory domain (Shohat et al., 2002), and 3) ERK-phosphorylation of DAPK at Ser735, which stimulates DAPK-mediated apoptosis by switching off the ERK-C/EBP-beta pathway (Chen et al., 2005). Src phosphorylates DAPK at Y491/492, which induces DAPK intra-/intermolecular interaction and inactivation (Wang et al., 2007).
Interaction partners Cathepsin B can directly interact with DAPK, forming a stable immune complex (Lin et al., 2007). It has been found that inhibition of HSP90 results in degradation of active dephosphorylated DAPK via the ubiquitin proteasome pathway. DAPK can also form heterocomplexes composed of HSP90 and CHIP or DIP1/Mib1, indicating that the heightened surveillance and modulation of DAPK activities is critical to accurate regulation of apoptosis and cellular homeostasis (Zhang et al., 2007). An interaction between UNC5C (UNC5H3) and DAPK1 was demonstrated (Llambi et al., 2005), whereby this interaction was shown to be dependent on both UNC5H2 lipid raft localization and palmitoylation (Maisse et al., 2008). An interaction between DAPK1 promoter and transcription factors ATF2 and c-jun was demonstrated in cisplatin-treated human breast cancer cells (Hayakawa et al., 2004). Amino acid starvation of cells induced a stable immune complex between microtubule-associated protein MAP1B and DAPK-1 (Harrison et al., 2008) highlighting a new mechanism for authophagy and membrane blebbing. There was found an interaction between DAPK and TSC2 proteins in response to growth factor stimulation that links the DAPK and mTORC1 signaling pathways affecting cell survival, autophagy, and apoptosis (Stevens et al., 2009).
Known substrates DAPK phosphorylates the myosin II regulatory light chain (Jin et al., 2001) and tropomyosin in response to ERK activation by hydrogen peroxide leading to stress fiber formation (Houle et al., 2007). Furthermore, Syntaxin is a DAP kinase substrate and provides a novel signal transduction pathway by which syntaxin function could be regulated in response to intracellular [Ca2+] and synaptic activity (Tian et al., 2003). Also one of the common DAPK substrate is p19ARF (Raveh et al., 2001). Shani el al. (2004) and Mukhopadhyay et al. (2008) showed that ZIPK serves as a substrate for DAPK. It has been reported that the mammalian 40S ribosomal protein S6 is a DAPK substrate (Schumacher et al., 2006).
NCBI: 1612 MIM: 600831 HGNC: 2674 Ensembl: ENSG00000196730
dbSNP: 1612 ClinVar: 1612 TCGA: ENSG00000196730 COSMIC: DAPK1
Regine Schneider-Stock ; Albert Roessner ; Khouloud Bajbouj
DAPK1 (death-associated protein kinase 1)
Atlas Genet Cytogenet Oncol Haematol. 2009-02-01
Online version: http://atlasgeneticsoncology.org/gene/417/js/lib/gene-explorer/teaching-explorer/