Matrix-specific suppression of integrin activation in shear stress signaling
Matrix-specific suppression of integrin activation in shear stress signaling
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DOI：
10.1091/mbc.e06-04-0289
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发表时间：
2006-11-01
影响因子：
3.3
通讯作者：
Schwartz, M. A.
中科院分区：
文献类型：
--
作者：
Orr, A. W.;Ginsberg, M. H.;Schwartz, M. A.
动脉粥样硬化斑块形成于血流受扰部位。我们以前发现，Flow激活内皮细胞整合素，然后整合素与内皮下细胞外基质(ECM)结合，并在细胞中通过纤维连接蛋白或纤维蛋白原，触发核因子-kappa B的激活。此外，纤维连接蛋白和纤维蛋白原在早期易发生动脉粥样硬化的部位沉积到内皮下ECM中。我们现在表明，Flow激活了ECM特异的信号，从而建立了整合素优势模式。Flow可诱导细胞激活胶原，但不能激活纤维连接蛋白或纤维蛋白原。相反，α5β1和αvβ3在纤维连接蛋白和纤维蛋白原上被激活，而不是胶原。这些整合素未能在非许可的ECM上被激活，是因为被连接的整合素主动抑制。蛋白激酶A在胶原蛋白上被特异性激活，并抑制流动诱导的αvβ3激活。或者，蛋白激酶Cα在纤维连接蛋白上被激活，并介导α2β1抑制。因此，整合素通过特定的激酶途径主动交叉抑制。这些机制可能决定细胞对复杂的细胞外基质的反应。
Atherosclerotic plaque develops at sites of disturbed flow. We previously showed that flow activates endothelial cell integrins, which then bind to the subendothelial extracellular matrix (ECM), and, in cells on fibronectin or fibrinogen, trigger nuclear factor-kappa B activation. Additionally, fibronectin and fibrinogen are deposited into the subendothelial ECM at atherosclerosis-prone sites at early times. We now show that flow activates ECM-specific signals that establish patterns of integrin dominance. Flow induced alpha 2 beta 1 activation in cells on collagen, but not on fibronectin or fibrinogen. Conversely, alpha 5 beta 1 and alpha v beta 3 are activated on fibronectin and fibrinogen, but not collagen. Failure of these integrins to be activated on nonpermissive ECM is because of active suppression by the integrins that are ligated. Protein kinase A is activated specifically on collagen and suppresses flow-induced alpha v beta 3 activation. Alternatively, protein kinase C alpha is activated on fibronectin and mediates alpha 2 beta 1 suppression. Thus, integrins actively cross-inhibit through specific kinase pathways. These mechanisms may determine cellular responses to complex extracellular matrices.