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Review
. 2017 Aug;54(6):4716-4722.
doi: 10.1007/s12035-016-0008-y. Epub 2016 Jul 22.

DAPK1 Signaling Pathways in Stroke: from Mechanisms to Therapies

Shan Wang  1 , Xiangde Shi  2 , Hao Li  3   4 , Pei Pang  3   4 , Lei Pei  4   5 , Huiyong Shen  6 , Youming Lu  7   8
Affiliations
Review

DAPK1 Signaling Pathways in Stroke: from Mechanisms to Therapies

Shan Wang et al. Mol Neurobiol. 2017 Aug.

Abstract

Death-associated protein kinase 1 (DAPK1), a Ca2+/calmodulin (CaM)-dependent serine/threonine protein kinase, plays important roles in diverse apoptosis pathways not only in tumor suppression but also in neuronal cell death. The requirement of DAPK1 catalytic activity for its proposed cell functions and the elevation of catalytic activity of DAPK1 in injured neurons in models of neurological diseases, such as ischemia and epilepsy, validate that DAPK1 can be taken as a potential therapeutic target in these diseases. Recent studies show that DAPK1-NR2B, DAPK1-DANGER, DAPK1-p53, and DAPK1-Tau are currently known pathways in stroke-induced cell death, and blocking these cascades in an acute treatment effectively reduces neuronal loss. In this review, we focus on the role of DAPK1 in neuronal cell death after stroke. We hope to provide exhaustive summaries of relevant studies on DAPK1 signals involved in stroke damage. Therefore, disrupting DAPK1-relevant cell death pathway could be considered as a promising therapeutic approach in stroke.

Keywords: Cell death; DAPK1; Mechanism; Stroke; Therapeutics.

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Conflict of interest statement

Competing Interests

The authors declare that they have no competing interests.

Funding

This work was supported by the National Natural Science Foundation of China (Grants 81130079 and 91232302 to Y.M. L), the Key Project of United Fund of National Natural and Guangdong Province (U1301223 to H.Y. S), and the Medical Scientific Research Foundation of Guangdong Province, China (A2016304 to S. W).

Figures

Fig. 1
Fig. 1
Schematic diagram of human-derived DAPK1 protein structure. Shown are the known functional domains of human DAPK1. See text for details
Fig. 2
Fig. 2
Illustration for DAPK1-NR2B. DAPK1 is inactive in physiological state. After cerebral ischemic stroke, DAPK1 is activated (cDAPK1, constitutively active DAPK1) and combines with the extrasynaptic NMDARs, phosphorylating the serine 1303 in the NR2B C-terminal (CT) tail and mediating cell death. Blocking DAPK1-NMDARs interaction with an NR2BCT-interfering peptide resists ischemic stroke damage
Fig. 3
Fig. 3
Illustration for DAPK1-p53. The interaction of DAPK1–p53 activates both necrotic and apoptotic signaling through transcription- and mitochondria-dependent pathways. DAPK1 binds to p53DM and phosphorylates p53 at serine 23 (pS23), which on one hand translocates into the nucleus and activates the proapoptotic gene expression and apoptosis. On the other hand, the pS23 also enters into the mitochondrial matrix and interacts with CypD and induces necrosis. A peptide Tat-p53DM blocks the interaction of DAPK1 and p53 effectively (modified from Pei et al., The Journal of Neuroscience, 2014. 34(19): p. 6546–56 )
Fig. 4
Fig. 4
Illustration for DAPK1-Tau. DAPK1 is activated after cerebral ischemia and phosphorylates Tau Ser262, inducing spine loss and the following cell death. Blocking DAPK1-Tau interaction with a Tat-R1D peptide protects spine loss and ischemic stroke damage
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