LFA-1-induced T cell migration on ICAM-1 involves regulation of MLCK-mediated attachment and ROCK-dependent detachment
LFA-1-induced T cell migration on ICAM-1 involves regulation of MLCK-mediated attachment and ROCK-dependent detachment
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DOI：
10.1242/jcs.00606
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发表时间：
2003-08-01
影响因子：
4
通讯作者：
Hogg, N
中科院分区：
文献类型：
--
作者：
Smith, A;Bracke, M;Hogg, N
这项研究分析了通过白细胞整合素LFA-1与ICAM-1结合而启动的信号事件，这导致T细胞附着、极化和随机迁移。这些事件在很大程度上依赖于肌球蛋白轻链激酶和ROCK(Rho激酶)调控下肌球蛋白细胞骨架的动态变化。一个关键的发现是，这两个激酶的活性在空间上是分开的。肌球蛋白轻链激酶(MLCK)必须在T细胞的前沿起作用，因为阻断它的活性会导致极化的T细胞从细胞的前部收缩。这些活性通过抑制MLCK的激活剂钙调蛋白而得到反映。相反，ROCK(和RhoA)的抑制具有防止T细胞后缘脱落的效果，表明该激酶在细胞的后部工作。这两种酶的这种区域化活性反映在它们在T细胞内的定位上。肌球蛋白轻链激酶集中在前缘，重叠的F-肌动蛋白，而ROCK更广泛地分布在T细胞的后缘。因此，这两种激酶在迁移的T细胞中发挥着两种不同的功能，肌球蛋白轻链激酶活性对前沿的附着和移动至关重要，而岩石活性则是脱离后缘所必需的。这两个依赖肌动球蛋白的过程协同工作，导致T细胞向前迁移。
This study analyzes signaling events initiated through binding of the leukocyte integrin LFA-1 to ICAM-1, which leads to T cell attachment, polarization and random migration. These events are critically dependent on dynamic changes in the acto-myosin cytoskeleton under the regulation of myosin light chain kinase and ROCK (Rho kinase). A key finding is that the activity of these two kinases is spatially segregated. Myosin light chain kinase (MLCK) must operate at the leading edge of the T cell because blocking its activity causes the polarized T cell to retract from the front of the cell. These activities are mirrored by inhibiting calmodulin, the activator of MLCK. In contrast inhibition of ROCK (and RhoA) has the effect of preventing detachment of the T cell trailing edge, showing that this kinase operates at the rear of the cell. This compartmentalized activity of the two kinases is reflected in their localization within the T cell. Myosin light chain kinase is concentrated at the leading edge, overlapping F-actin, whereas ROCK is more widely distributed in the trailing edge of the T cell. Thus these two kinases perform two different functions in the migrating T cell, with myosin light chain kinase activity important for attachment and movement at the leading edge and ROCK activity required for the detachment of the trailing edge. These two actomyosin-dependent processes operate coordinately to cause forward migration of a T cell.