Shc mediates anoikis through RhoA
Shc mediates anoikis through RhoA
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发表时间：
2007
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通讯作者：
Zhenyi Ma;D. Myers;R. Wu;F. Nwariaku;L. Terada
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作者：
Zhenyi Ma;D. Myers;R. Wu;F. Nwariaku;L. Terada
实质细胞需要依赖整合素附着于实体结构才能存活。由于这种锚定依赖性，大多数组织细胞在被迫悬浮在液体环境中数小时内开始发生凋亡，这一过程被称为anoikis （Frisch和Francis， 1994）。生理性斑点发生在乳腺和前列腺的退化过程中，而病理性斑点的丧失被认为伴随着恶性细胞获得转移能力。目前，anoikis在很大程度上被理解为整合素相关的外向内生存信号的退出。因此，存活蛋白局灶黏附激酶（FAK）、Src、Akt和Ras的组成性激活都能绕过脱落诱导的死亡（Frisch和Francis, 1994； Frisch等人，1996；Martin等人，2006）。然而，在没有Ras、磷酸肌苷3-激酶或FAK激活的情况下，anoikis可以被规避（McFall等人，2001；Díaz-Montero等人，2006；Kang等人，2007），这表明除了使生存信号失能外，还需要激活特定的死亡途径。此外，没有结构矩阵刚性的整合素连接不足以防止anoikis，这表明整合素也通过感知环境的机械特性来控制anoikis。可溶基质片段或固相RGD肽与微珠结合，如结连素和簇整联素，但既不能防止圆融，也不能提高漂浮内皮细胞的存活率（Re等，1994），这与观察到的细胞圆融本身会迫使依赖于附着的细胞死亡（Chen等，1997）一致。单向外向内信号模型解释依恋感觉的缺点与细胞在“内-外-内”反馈回路中启动旨在测量基底刚度的过程的概念是一致的（Discher et al., 2005）。负责这种机械感觉的分子机制及其与锚定依赖的关系仍然是未知的；例如，造血细胞就缺乏这种机制，因为它们既不依赖于锚定，又对底物刚度不敏感（Discher et al., 2005）。有趣的是，造血细胞也抑制p66的表达，p66是整合素相关接头Shc的长亚型（Migliaccio et al., 1997）。p52在很大程度上通过Ras的募集和激活来促进存活和增殖信号，而p66则是一种促凋亡蛋白。在这里，我们发现p66允许RhoA的激活，从而导致漂浮细胞的张力依赖性死亡。因此，P66可能在报告脱离的机械感觉回路的传出肢中很重要。
Parenchymal cells require integrin-dependent attachment to solid structures to survive. As a consequence of such anchorage dependence, most tissue cells start to undergo apoptotic death within hours of being forced into suspension in a fl uid environment, a process termed anoikis (Frisch and Francis, 1994). Physiological anoikis occurs during the involution of mammary and prostate glands, whereas pathological loss of anoikis is thought to accompany the malignant cell’s acquisition of metastatic capabilities. Presently, anoikis is understood largely in terms of withdrawal of integrin-related outside-in survival signals. Thus, constitutive activation of the survival proteins focal adhesion kinase (FAK), Src, Akt, and Ras all bypass detachment-induced death (Frisch and Francis, 1994; Frisch et al., 1996; Martin et al., 2006). However, anoikis can be circumvented in the absence of Ras, phosphoinositide 3-kinase, or FAK activation (McFall et al., 2001; Díaz-Montero et al., 2006; Kang et al., 2007), suggesting that the activation of specifi c death pathways may be necessary in addition to the disabling of survival signals. Furthermore, integrin ligation without structural matrix rigidity is insuffi cient to prevent anoikis, indicating that integrins also control anoikis by sensing mechanical properties of the environment. Soluble matrix fragments or solid-phase RGD peptides bound to microbeads, e.g., ligate and cluster integrins, but neither prevent rounding nor increase the survival rate of fl oating endothelial cells (Re et al., 1994), which is consistent with observations that cell rounding by itself forces death upon attachmentdependent cells (Chen et al., 1997). The shortcomings of a unidirectional outside-in signaling model to explain attachment sensation is consistent with the concept that cells initiate processes designed to gauge substrate stiffness in an “inside-outside-in” feedback loop (Discher et al., 2005). The molecular machinery responsible for such mechanosensation and its relationship to anchorage dependence have remained recondite; hematopoietic cells, for instance, lack such machinery, as they are both anchorage independent and insensitive to substrate stiffness (Discher et al., 2005). Interestingly, hematopoietic cells also repress expression of p66, the long isoform of the integrin-associated adaptor Shc (Migliaccio et al., 1997). Whereas p52 is known to facilitate survival and proliferative signals, in large part through Ras recruitment and activation, p66 is best known as a proapoptotic protein. Here, we show that p66 permits activation of RhoA, which leads to tension-dependent death in fl oating cells. p66 may thus be important in the efferent limb of a mechanosensory loop reporting detachment.