Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
J Neurosci. 2010 Jan 6;30(1):93-8. doi: 10.1523/JNEUROSCI.3974-09.2010.
Death-associated protein kinase (DAPK) is a key player in multiple cell death signaling pathways. We report that DAPK is regulated by DANGER, a partial MAB-21 domain-containing protein. DANGER binds directly to DAPK and inhibits DAPK catalytic activity. DANGER-deficient mouse embryonic fibroblasts and neurons exhibit greater DAPK activity and increased sensitivity to cell death stimuli than do wild-type control cells. In addition, DANGER-deficient mice manifest more severe brain damage after acute excitotoxicity and transient cerebral ischemia than do control mice. Accordingly, DANGER may physiologically regulate the viability of neurons and represent a potential therapeutic target for stroke and neurodegenerative diseases.
死亡相关蛋白激酶（DAPK）是多种细胞死亡信号通路中的关键分子。我们发现 DAPK 受到 DANGER 的调控，后者是一个含有 MAB-21 结构域的部分蛋白。DANGER 可以直接与 DAPK 结合并抑制其酶活性。DAPK 活性在 DANGER 缺陷型鼠胚胎成纤维细胞和神经元中升高，对细胞死亡刺激的敏感性也增强。此外，DANGER 缺陷型小鼠在急性兴奋性毒性和短暂性脑缺血后表现出更严重的脑损伤，比对照组小鼠更为明显。因此，DANGER 可能在生理水平上调控神经元的存活，成为卒中及神经退行性疾病的潜在治疗靶点。
