Essential role for integrin linked kinase in Akt-mediated integrin survival signaling in hippocampal neurons
Essential role for integrin linked kinase in Akt-mediated integrin survival signaling in hippocampal neurons
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DOI：
10.1046/j.1471-4159.2003.01579.x
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发表时间：
2003-02-01
影响因子：
4.7
通讯作者：
Mattson, MP
中科院分区：
文献类型：
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作者：
Gary, DS;Milhavet, O;Mattson, MP
神经元中整合素受体的激活可以促进细胞存活和突触可塑性，但潜在的信号转导途径尚不清楚。我们报告说，整合素信号防止胚胎海马神经元凋亡的机制，涉及整合素连接激酶（ILK）激活Akt激酶。使用含有源自层粘连蛋白α链的氨基酸序列EIKLLIS的肽激活整联蛋白可保护海马神经元免受谷氨酸或星形孢菌素诱导的细胞凋亡，并以β 1整联蛋白依赖性方式增加Akt活性。用编码显性失活Akt的质粒转染神经元阻断了整合素激活肽的保护作用，Akt的化学抑制剂也是如此。虽然磷酸肌醇-3（PI 3）激酶的抑制剂阻断了肽的保护作用，但我们发现整合素刺激后PI 3激酶活性没有增加，这表明PI 3激酶对Akt活性是必需的，但不足以增加整合素活化后Akt活性。相反，我们显示了整合素受体诱导的Akt激活中ILK的需求。ILK在整合素刺激后被激活，并且显性阴性ILK阻断整合素介导的Akt激活和细胞存活。ILK和Akt的激活也是基质相关层粘连蛋白神经保护所必需的。这些结果建立了一个新的途径，信号细胞的生存在神经元中的整合素受体活化的反应。
Activation of integrin receptors in neurons can promote cell survival and synaptic plasticity, but the underlying signal transduction pathway(s) is unknown. We report that integrin signaling prevents apoptosis of embryonic hippocampal neurons by a mechanism involving integrin-linked kinase (ILK) that activates Akt kinase. Activation of integrins using a peptide containing the amino acid sequence EIKLLIS derived from the alpha chain of laminin protected hippocampal neurons from apoptosis induced by glutamate or staurosporine, and increased Akt activity in a beta(1) integrin-dependent manner. Transfection of neurons with a plasmid encoding dominant negative Akt blocked the protective effect of the integrin-activating peptide, as did a chemical inhibitor of Akt. Although inhibitors of phosphoinositide-3 (PI3) kinase blocked the protective effect of the peptide, we found no increase in PI3 kinase activity following integrin stimulation suggesting that PI3 kinase was necessary for Akt activity but was not sufficient for the increase in Akt activity following integrin activation. Instead, we show a requirement for ILK in integrin receptor-induced Akt activation. ILK was activated following integrin stimulation and dominant negative ILK blocked integrin-mediated Akt activation and cell survival. Activation of ILK and Akt were also required for neuroprotection by substrate-associated laminin. These results establish a novel pathway that signals cell survival in neurons in response to integrin receptor activation.