Matrix metalloproteinase 1 interacts with neuronal integrins and stimulates dephosphorylation of Akt
Matrix metalloproteinase 1 interacts with neuronal integrins and stimulates dephosphorylation of Akt
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DOI：
10.1074/jbc.m307051200
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发表时间：
2004-02-27
影响因子：
4.8
通讯作者：
Nath, A
中科院分区：
文献类型：
--
作者：
Conant, K;St Hillaire, C;Nath, A
多项研究表明基质金属蛋白酶 (MMP) 具有细胞毒性。然而，其负责机制尚不清楚。 MMP 可以通过破坏或降解支持细胞存活的基质蛋白的能力来促进细胞毒性，并且 MMP 还可以切割底物以产生刺激细胞死亡的分子。此外，MMP 本身可能作用于影响细胞存活的细胞表面受体。 α(2)β(1) 整合素就是此类受体之一，这是一种先前被认为与白细胞死亡有关的复合物。在本研究中，我们表明人类神经元表达 alpha(2)beta(1)，并且 pro-MMP-1 与该整联蛋白复合物相互作用。我们还表明，用 MMP-1 刺激神经元培养物与 Akt 磷酸化的快速减少有关，Akt 是一种可以影响 caspase 活性和细胞存活的激酶。此外，MMP-1 相关的 Akt 去磷酸化可被 α(2) 整联蛋白阻断抗体抑制，但不能被 MMP-1 酶活性抑制剂巴马司他抑制。 pro-MMP-1 的催化突变体也会刺激这种去磷酸化。其他研究表明，MMP-1 会导致神经元死亡，一般 caspase 抑制剂和抗 (2) 均可显着减少这种死亡，但巴马司他则不能。总之，这些结果表明 MMP-1 可以通过涉及整合素信号传导变化的非蛋白水解机制刺激 Akt 去磷酸化和神经元死亡。
Several studies have demonstrated that matrix metalloproteinases (MMPs) are cytotoxic. The responsible mechanisms, however, are not well understood. MMPs may promote cytotoxicity through their ability to disrupt or degrade matrix proteins that support cell survival, and MMPs may also cleave substrates to generate molecules that stimulate cell death. In addition, MMPs may themselves act on cell surface receptors that affect cell survival. Among such receptors is the alpha(2)beta(1) integrin, a complex that has previously been linked to leukocyte death. In the present study we show that human neurons express alpha(2)beta(1) and that pro-MMP-1 interacts with this integrin complex. We also show that stimulation of neuronal cultures with MMP-1 is associated with a rapid reduction in the phosphorylation of Akt, a kinase that can influence caspase activity and cell survival. Moreover, MMP-1-associated dephosphorylation of Akt is inhibited by a blocking antibody to the alpha(2) integrin, but not by batimastat, an inhibitor of MMP-1 enzymatic activity. Such dephosphorylation is also stimulated by a catalytic mutant of pro-MMP-1. Additional studies show that MMP-1 causes neuronal death, which is significantly diminished by both a general caspase inhibitor and anti-(2) but not by batimastat. Together, these results suggest that MMP-1 can stimulate dephosphorylation of Akt and neuronal death through a non-proteolytic mechanism that involves changes in integrin signaling.