RIN1 is an ABL tyrosine kinase activator and a regulator of epithelial-cell adhesion and migration
RIN1 is an ABL tyrosine kinase activator and a regulator of epithelial-cell adhesion and migration
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DOI：
10.1016/j.cub.2005.03.049
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发表时间：
2005-05-10
期刊：
影响因子：
9.2
通讯作者：
Colicelli, J
中科院分区：
文献类型：
--
作者：
Hu, HL;Bliss, JM;Colicelli, J
背景：ABL酪氨酸激酶控制肌动蛋白在发育和对环境刺激的反应中的重塑。这些变化影响细胞粘附、细胞迁移和细胞-细胞接触。鲜为人知的是，然而，关于上游机制调节ABL蛋白activation.Results：我们报告，RAS效应RIN 1是ABL酪氨酸激酶的激活剂。RIN 1在成纤维细胞中的表达促进了膜尖峰的形成; ABL过表达也有类似的作用。RIN 1与ABL SH 3和SH 2结构域结合，这些相互作用刺激ABL 2催化活性。这导致CRK和CRKL的磷酸化增加，通过促进分子内而非分子间缔合来抑制这些细胞骨架调节剂。活化的RAS参与稳定的RAS-RIN 1-ABL 2复合物并刺激RIN 1的酪氨酸激酶活化功能。RAS结合结构域（RBD）的缺失强烈刺激了RIN 1的ABL 2激活功能，表明RAS激活是RIN 1自身抑制的缓解所致。RIN 1的ABL结合结构域（RIN 1-ABD）增加ABL 2免疫复合物的活性和纯化的RIN 1-ABD刺激的ABL 2激酶对CRK的活性。与野生型细胞相比，Rin 1（-/-）小鼠的乳腺上皮细胞（MEC）显示出细胞粘附加速和运动性增加。RIN 1在上皮细胞系中的敲低阻断了CRKL磷酸化的诱导，证实RIN 1通常作为细胞motility.Conclusions的抑制剂发挥作用：RIN 1是一种直接结合ABL酪氨酸激酶激活剂在细胞中，以及在一个确定的成分测定。在响应环境变化，这一新的信号通路介导与上皮细胞的粘附和迁移相关的肌动蛋白重塑。
Background: ABL tyrosine kinases control actin remodeling in development and in response to environmental stimuli. These changes affect cell adhesion, cell migration, and cell-cell contact. Little is known, however, about upstream mechanisms regulating ABL protein activation.Results: We report that the RAS effector RIN1 is an activator of ABL tyrosine kinases. RIN1 expression in fibroblasts promotes the formation of membrane spikes; similar effects have been reported for ABL overexpression. RIN1 binds to the ABL SH3 and SH2 domains, and these interactions stimulate ABL2 catalytic activity. This leads to increased phosphorylation of CRK and CRKL, inhibiting these cytoskeletal regulators by promoting intramolecular over intermolecular associations. Activated RAS participates in a stable RAS-RIN1-ABL2 complex and stimulates the tyrosine kinase-activation function of RIN1. Deletion of the RAS binding domain (RBD) strongly stimulated the ABL2 activation function of RIN1, suggesting that RAS activation results from the relief of RIN1 autoinhibition. The ABL binding domain of RIN1 (RIN1-ABD) increased the activity of ABL2 immune complexes and purified RIN1-ABD-stimulated ABL2 kinase activity toward CRK. Mammary epithelial cells (MECs) from Rin1(-/-) mice showed accelerated cell adhesion and increased motility in comparison to wild-type cells. Knockdown of RIN1 in epithelial-cell lines blocked the induction of CRKL phosphorylation, confirming that RIN1 normally functions as an inhibitor of cell motility.Conclusions: RIN1 is a directly binding ABL tyrosine kinase activator in cells as well as in a defined-component assay. In response to environmental changes, this novel signal pathway mediates actin remodeling associated with adhesion and migration of epithelial cells.