Involvement of cell-cell interactions in the rapid stimulation of Cas tyrosine phosphorylation and Src kinase activity by transforming growth factor-β1
Involvement of cell-cell interactions in the rapid stimulation of Cas tyrosine phosphorylation and Src kinase activity by transforming growth factor-β1
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DOI：
10.1074/jbc.m201178200
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发表时间：
2002-08-30
影响因子：
4.8
通讯作者：
Joo, CK
中科院分区：
文献类型：
--
作者：
Kim, JT;Joo, CK
转化生长因子-β（TGF-β）调节广泛的生理和病理细胞过程，包括细胞迁移、间充质转化、细胞外基质合成和细胞死亡。Cas（Crk相关底物，130 kDa）是一种定位于粘着斑和应力纤维的衔接蛋白，也已知在细胞迁移和诱导立即早期基因表达中具有重要功能。在这里，我们报告说，一个快速和短暂的酪氨酸磷酸化的Cas诱导的TGF-β 1和E-钙粘蛋白介导的细胞-细胞相互作用和Src激酶途径参与这个早期的TGF-β信号。加入TGF-β 1的上皮细胞迅速诱导Cas的酪氨酸磷酸化，并促进粘着斑分子之间形成复合物。Cas磷酸化需要肌动蛋白细胞骨架的完整性，但不依赖于细胞粘附，这意味着Cas依赖的信号可能不同于整合素信号。TGF-β 1也刺激Src激酶活性，Src的特异性抑制剂完全阻断TGF-β 1诱导的Cas磷酸化。在我们的研究结果中看到的Cas磷酸化和Src激酶激活是以上皮表型特异性方式诱导的。将E-cadherin稳定转染L929细胞和L细胞以及E-cadherin阻断试验表明，E-cadherin介导的细胞-细胞相互作用对于Cas磷酸化和Src激酶激活都是必需的。总之，我们的数据表明，快速Cas磷酸化和Src激酶激活可能在TGF-β信号转导中发挥新的作用。
Transforming growth factor-beta (TGF-beta) regulates a wide range of physiological and pathological cellular processes, including cell migration, mesenchymal transition, extracellular matrix synthesis, and cell death. Cas (Crk-associated substrate, 130 kDa), an adaptor protein localized at focal adhesions and stress fibers, is also known to have important functions in cell migration and the induction of immediate-early gene expression. Here, we report that a rapid and transient tyrosine phosphorylation of Cas is induced by TGF-beta1 and that E-cadherin-mediated cell-cell interaction and the Src kinase pathway are involved in this early TGF-beta signaling. The addition of TGF-beta1 to epithelial cells rapidly induced tyrosine phosphorylation of Cas and promoted the formation of complexes between focal adhesion molecules. Cas phosphorylation required the integrity of the actin cytoskeleton but was not dependent on cell adhesion, implying that Cas-dependent signaling may be distinct from integrin signaling. TGF-beta1 also stimulated Src kinase activity, and specific inhibitors of Src completely blocked the induction of Cas phosphorylation by TGF-beta1. The Cas phosphorylation and Src kinase activation seen in our results were induced in an epithelial phenotype-specific manner. Stable transfection of E-cadherin to L929 cells and L cells as well as E-cadherin blocking assay revealed that E-cadherin-mediated cell-cell interactions were essential for both Cas phosphorylation and Src kinase activation. Taken together, our data suggest that rapid Cas phosphorylation and Src kinase activation may play a novel role in TGF-beta signal transduction.