Integrin function: molecular hierarchies of cytoskeletal and signaling molecules.
Integrin function: molecular hierarchies of cytoskeletal and signaling molecules.
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DOI：
10.1083/jcb.131.3.791
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发表时间：
1995-11
期刊：
影响因子：
--
通讯作者：
Yamada KM
中科院分区：
文献类型：
--
作者：
Miyamoto S;Teramoto H;Coso OA;Gutkind JS;Burbelo PD;Akiyama SK;Yamada KM
整合素受体在组织含肌动蛋白的细胞骨架和细胞外基质的信号转导中起重要作用。整合素功能的初始步骤可以使用包被有配体或抗整合素抗体的珠粒来实验性分析，以触发快速局灶性跨膜应答。在这项研究中确定了跨膜作用的层次结构。简单的整合素聚集触发了20种信号转导分子的局部跨膜积聚，包括RhoA、Rac 1、Ras、Raf、MEK、ERK和JNK。相比之下，在八个细胞骨架分子的测试，只有张力共积累。单独的整合素聚集也足以诱导JNK途径的快速活化，活化动力学不同于ERK。酪氨酸激酶抑制剂除莠霉素A或染料木黄酮阻断了20种信号转导分子中19种的积累以及JNK和ERK介导的信号传导。细胞松弛素D具有相同的作用，而其他三种酪氨酸激酶抑制剂则没有。信号分子中唯一的例外是激酶pp 125 FAK，即使在存在这些抑制剂的情况下，其也继续与α 5 β 1整联蛋白共聚集。酪氨酸激酶抑制也未能阻断配体占用加上整合素聚集触发三种细胞骨架分子talin、α-辅肌动蛋白和黏着斑蛋白跨膜积累的能力;这些分子即使在细胞松弛素D存在下也会积累。然而，必须满足所有四个条件，即，整联蛋白聚集、整联蛋白占据、酪氨酸激酶活性和肌动蛋白细胞骨架完整性，以实现整联蛋白介导的其他细胞骨架分子（包括F-肌动蛋白和桩蛋白）的局部积聚。因此，整合素介导分子反应的跨膜层次。
Integrin receptors play important roles in organizing the actin- containing cytoskeleton and in signal transduction from the extracellular matrix. The initial steps in integrin function can be analyzed experimentally using beads coated with ligands or anti- integrin antibodies to trigger rapid focal transmembrane responses. A hierarchy of transmembrane actions was identified in this study. Simple integrin aggregation triggered localized transmembrane accumulation of 20 signal transduction molecules, including RhoA, Rac1, Ras, Raf, MEK, ERK, and JNK. In contrast, out of eight cytoskeletal molecules tested, only tensin coaccumulated. Integrin aggregation alone was also sufficient to induce rapid activation of the JNK pathway, with kinetics of activation different from those of ERK. The tyrosine kinase inhibitors herbimycin A or genistein blocked both the accumulation of 19 out of 20 signal transduction molecules and JNK- and ERK-mediated signaling. Cytochalasin D had identical effects, whereas three other tyrosine kinase inhibitors did not. The sole exception among signaling molecules was the kinase pp125FAK which continued to coaggregate with alpha 5 beta 1 integrins even in the presence of these inhibitors. Tyrosine kinase inhibition also failed to block the ability of ligand occupancy plus integrin aggregation to trigger transmembrane accumulation of the three cytoskeletal molecules talin, alpha-actinin, and vinculin; these molecules accumulated even in the presence of cytochalasin D. However, it was necessary to fulfill all four conditions, i.e., integrin aggregation, integrin occupancy, tyrosine kinase activity, and actin cytoskeletal integrity, to achieve integrin- mediated focal accumulation of other cytoskeletal molecules including F- actin and paxillin. Integrins therefore mediate a transmembrane hierarchy of molecular responses.