Integrin α2β1 inhibits Fas-mediated apoptosis in T lymphocytes by protein phosphatase 2A-dependent activation of the MAPK/ERK pathway
Integrin α2β1 inhibits Fas-mediated apoptosis in T lymphocytes by protein phosphatase 2A-dependent activation of the MAPK/ERK pathway
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DOI：
10.1074/jbc.m305169200
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发表时间：
2003-12-05
影响因子：
4.8
通讯作者：
Aoudjit, F
中科院分区：
文献类型：
--
作者：
Gendron, S;Couture, J;Aoudjit, F
T 淋巴细胞在激活过程中逃避凋亡的机制仍不清楚。在这项研究中，我们阐明了 β(1) 整合素调节 Fas 介导的 T 淋巴细胞凋亡的细胞内信号传导途径。在 Jurkat T 细胞和活化的外周血 T 淋巴细胞中进行的实验中，发现 α(2)β(1) 整合素与 I 型胶原 (Coll I) 的结合可显着减少 Fas 诱导的细胞凋亡和 caspase-8 激活；膜联蛋白 V 结合和 DNA 片段化分别减少了约 42% 和 38%。我们证明 Coll I 的保护作用不需要新的蛋白质合成，而是依赖于 MAPK/Erk 途径的激活。此外，我们发现 Coll I 激活蛋白磷酸酶 2A (PP2A) 是 Coll I 介导的 Erk 激活以及 Fas 诱导的 caspase-8 激活和细胞凋亡的抑制所必需的。 β(1) 整联蛋白的其他配体、纤连蛋白 (Fbn) 和层粘连蛋白 (Lam) 不维持显着的 Erk 激活，并且对 Fas 诱导的细胞凋亡没有影响。总而言之，这些结果提供了 α(2)β(1) 整合素下游 MAPK/Erk 通路的 PP2A 依赖性激活的第一个证据，该通路在调节 T 淋巴细胞中 Fas 介导的细胞凋亡中具有功能性作用。因此，这项研究强调了 Coll I 相互作用可能对 T 淋巴细胞稳态的控制及其在慢性炎症性疾病中的持续存在的潜在重要性。
The mechanisms by which T lymphocytes escape apoptosis during their activation are still poorly defined. In this study, we elucidated the intracellular signaling pathways through which beta(1) integrins modulate Fas-mediated apoptosis in T lymphocytes. In experiments done in Jurkat T cells and activated peripheral blood T lymphocytes, engagement of alpha(2)beta(1) integrin with collagen type I ( Coll I) was found to significantly reduce Fas-induced apoptosis and caspase-8 activation; Annexin V binding and DNA fragmentation were reduced by similar to42 and 38%, respectively. We demonstrated that the protective action of Coll I does not require new protein synthesis but was dependent on the activation of the MAPK/ Erk pathway. Furthermore, we found that activation of protein phosphatase 2A (PP2A) by Coll I was required for both Coll I-mediated activation of Erk, and inhibition of Fas-induced caspase-8 activation and apoptosis. Other ligands of beta(1) integrins, fibronectin (Fbn), and laminin ( Lam), did not sustain significant Erk activation and had no effect on Fas-induced apoptosis. Taken together, these results provide the first evidence of a PP2A-dependent activation of the MAPK/ Erk pathway downstream of alpha(2)beta(1) integrin, which has a functional role in regulating Fas-mediated apoptosis in T lymphocytes. As such, this study emphasizes the potential importance that Coll I interactions may have on the control of T lymphocyte homeostasis and their persistence in chronic inflammatory diseases.