R-Ras signals through specific integrin alpha cytoplasmic domains to promote migration and invasion of breast epithelial cells.
R-Ras signals through specific integrin alpha cytoplasmic domains to promote migration and invasion of breast epithelial cells.
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DOI：
10.1083/jcb.145.5.1077
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发表时间：
1999-05-31
期刊：
影响因子：
--
通讯作者：
Parise LV
中科院分区：
文献类型：
--
作者：
Keely PJ;Rusyn EV;Cox AD;Parise LV
整合素功能的特异性和调节对于细胞对细胞外基质的反应（包括分化和转化）具有重要影响。Ras相关的GTP酶R-Ras调节整合素的亲和力，但R-Ras下游的信号通路和生物学功能知之甚少。在这里，我们表明，稳定表达的激活R-Ras或密切相关的TC 21（R-Ras 2）诱导整合素介导的迁移和乳腺上皮细胞通过胶原蛋白和破坏分化成小管结构的入侵，而显性负R-Ras有相反的效果。这些结果意味着R-Ras和TC 21在促进转化表型和这些细胞的基底迁移和极化中的新作用。重要的是，R-Ras诱导胶原蛋白而不是纤连蛋白上的细胞粘附和迁移增加，表明R-Ras向特异性整合素发出信号。R-Ras增强表达含有α2而非α5胞质结构域的整合素嵌合体的细胞迁移的实验进一步支持了这一点。此外，对于α2胞质结构域，观察到先前仅在整联蛋白β胞质结构域之间观察到的反式显性抑制; α2β1介导的迁移受到过量α2而非α5胞质结构域含嵌合体表达的抑制，表明存在结合整联蛋白α亚基的限制因子。使用药理学抑制剂，我们发现R-Ras通过磷脂酰肌醇3-激酶和蛋白激酶C的组合诱导胶原迁移，但不是MAPK，这与其他Ras家族成员Rac，Cdc 42，N-和K-Ras不同。因此，R-Ras通过信号通路的独特组合与特定的整合素α胞质结构域通信，以促进细胞迁移和侵袭。
Specificity and modulation of integrin function have important consequences for cellular responses to the extracellular matrix, including differentiation and transformation. The Ras-related GTPase, R-Ras, modulates integrin affinity, but little is known of the signaling pathways and biological functions downstream of R-Ras. Here we show that stable expression of activated R-Ras or the closely related TC21 (R-Ras 2) induced integrin-mediated migration and invasion of breast epithelial cells through collagen and disrupted differentiation into tubule structures, whereas dominant negative R-Ras had opposite effects. These results imply novel roles for R-Ras and TC21 in promoting a transformed phenotype and in the basal migration and polarization of these cells. Importantly, R-Ras induced an increase in cellular adhesion and migration on collagen but not fibronectin, suggesting that R-Ras signals to specific integrins. This was further supported by experiments in which R-Ras enhanced the migration of cells expressing integrin chimeras containing the α2, but not the α5, cytoplasmic domain. In addition, a transdominant inhibition previously noted only between integrin β cytoplasmic domains was observed for the α2 cytoplasmic domain; α2β1-mediated migration was inhibited by the expression of excess α2 but not α5 cytoplasmic domain-containing chimeras, suggesting the existence of limiting factors that bind the integrin α subunit. Using pharmacological inhibitors, we found that R-Ras induced migration on collagen through a combination of phosphatidylinositol 3-kinase and protein kinase C, but not MAPK, which is distinct from the other Ras family members, Rac, Cdc42, and N- and K-Ras. Thus, R-Ras communicates with specific integrin α cytoplasmic domains through a unique combination of signaling pathways to promote cell migration and invasion.
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DOI：
10.1073/pnas.92.17.7686
发表时间：
1995-08-15
影响因子：
11.1
作者：
DUDLEY, DT;PANG, L;SALTIEL, AR
通讯作者：
SALTIEL, AR
影响因子：
4.8
作者：
Howe, AK;Juliano, RL
通讯作者：
Juliano, RL
影响因子：
8
作者：
Huff, SY;Quilliam, LA;Der, CJ
通讯作者：
Der, CJ
影响因子：
4.8
作者：
Herrmann, C;Horn, G;Wittinghofer, A
通讯作者：
Wittinghofer, A
影响因子：
7.5
作者：
Howe, A;Aplin, AE;Juliano, RL
通讯作者：
Juliano, RL