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  • Death associated protein kinase DAPK


    Death-associated protein kinase (DAPK), a known apoptosis regulator, is shown to be up-regulated in atherosclerotic lesions (Arab et al., 2008). DAPK up-regulation leads to increased cell turnover and arterial wall instability, which provides increase susceptibility to LDL BMS 299897 (Schumacher et al., 2002). In cancer pathology, DAPK expression is silenced in some forms of cancer (Cohen and Kimchi, 2001); and the tumor suppression ability of DAPK has been demonstrated: both as inhibitor of metastasis in vivo (Cohen et al., 1999) and as an apoptotic promoter in vitro (Pelled et al., 2002). Aside with its apoptosis activity, DAPK also binds to and regulates actin in the cytoskeleton (Bialik et al., 2004, Shohat et al., 2001). In endothelial cells, tropomyosin-1, another subject of DAPK phosphorylation, is important in maintaining cardiovascular homeostasis and its expression is lost in tumor cells (Bharadwaj et al., 2005). Understanding endothelial DAPK expression and function will help elucidate overlaps between the apoptotic and shear stress signaling pathways. This review will assess our current knowledge on the effect of shear stress on endothelial cell phenotype, apoptosis, and DAPK. Fluid shear stress may regulate DAPK signaling for both pro- and anti-apoptotic processes, and we evaluate the potential role of DAPK in endothelial mechanotransduction and apoptosis in the vasculature.
    Endothelial mechanotransduction
    Death associated protein kinase
    Conclusion DAPK is localized to the actin network, and promotes actomyosin contractility. DAPK stabilizes stress fibers by phosphorylation of MLC (Bialik et al., 2004, Kuo et al., 2003). In endothelial cells DAPK phosphorylates TM-1 at Ser283 in response to ERK activation under oxidative stress (Houle et al., 2007). TM-1 is important in maintaining BMS 299897 cardiovascular homeostasis, and its expression is lost in tumor cells (Bharadwaj et al., 2005). Furthermore, DAPK-regulated apoptosis pathway is suppressed during the angiogenic process. Netrin-1 is recently discovered to promote endothelial cell survival and angiogenesis by inhibiting its pro-apoptotic receptor UNC5B and its downstream regulator DAPK (Castets et al., 2009). Complete functions of DAPK are still being elucidated, which would further emphasize the importance of DAPK. The question remains, does fluid shear stress inhibits endothelial apoptosis by regulating DAPK expression? We begin to take a comprehensive look at DAPK as novel mechano-sensitive effectors of cellular responses through both functional and mechanistic analyses, by investigating the effects of shear stress on DAPK and TNFα induced apoptosis in endothelial cells (Rennier and Ji, 2012). We found a time-dependent effect of mechanical (shear stress) or biochemical (TNFα) induction on DAPK and apoptosis. DAPK could have other non-apoptotic functions in endothelial cells. The role of DAPK in apoptosis and its association with the actin cytoskeleton suggest it as a regulator of endothelial responses in mechanotransduction. DAPK can be potentially utilized by endothelial cells in affecting morphological changes in response to shear stress. The cytoskeleton effect of DAPK occurs before onset of apoptosis, and is independent of DAPK death domain. One potential model for this dual role of DAPK is that shear stresses regulate apoptotic function of DAPK in a time-dependent manner: the onset of shear stress will sequester DAPK to its cytoskeleton activities, and attenuate its ability to interact with subsequent stress-activated apoptotic binding partners. For example, shear stress increases binding of DAPK with cytoskeleton components TM-1 and MLC, while apoptotic cytokine will increase binding of DAPK with cytoplasmic partners to induce apoptosis.