c-Cbl facilitates fibronectin matrix production by v-Abl-transformed NIH3T3 cells via activation of small GTPases.
c-Cbl facilitates fibronectin matrix production by v-Abl-transformed NIH3T3 cells via activation of small GTPases.
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c-Cbl 通过激活小 GTP 酶促进 v-Abl 转化的 NIH3T3 细胞产生纤连蛋白基质。
DOI：
10.1038/sj.onc.1204246
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发表时间：
2001
期刊：
影响因子：
8
通讯作者：
Tsygankov,AY
中科院分区：
文献类型：
--
作者：
Teckchandani,AM;Feshchenko,EA;Tsygankov,AY
原癌基因蛋白c-Cbl已被证明作为一个多价的衔接子和蛋白酪氨酸激酶介导的信号转导的负调节剂。最近的研究表明它参与了细胞粘附相关事件的调节。我们以前已经表明，c-Cbl促进粘附和传播的v-Abl转化的成纤维细胞，这些影响是依赖于其酪氨酸磷酸化。然而，c-Cbl对成纤维细胞粘附的介导作用的机制仍然知之甚少。在这项研究中，我们表明，酪氨酸磷酸化依赖的c-Cbl对粘附的v-Abl转化成纤维细胞的影响主要是介导的增加，这些细胞的纤连蛋白基质沉积。这种增加纤连蛋白基质沉积，因此，在细胞粘附是依赖于细胞骨架重排诱导RhoA，Rac 1，并可能，Rap 1激活引起的c-Cbl。观察到的这些GTP酶的激活是通过将磷脂酰肌醇-3 ′激酶、CrkL和Vav 2募集至c-Cbl的C-末端酪氨酸残基介导的。本研究的结果还表明，泛素化是必不可少的c-Cbl对纤连蛋白基质的生产和细胞粘附的影响。
The protooncogenic protein c-Cbl has been shown to act as a multivalent adaptor and a negative regulator of protein tyrosine kinase-mediated signaling. Recent studies have implicated it in the regulation of cell adhesion-related events. We have previously shown that c-Cbl facilitates adhesion and spreading of v-Abl-transformed fibroblasts, and that these effects are dependent on its tyrosine phosphorylation. However, the mechanisms mediating effects of c-Cbl on fibroblast adhesion remain poorly understood. In this study we demonstrate that the tyrosine phosphorylation-dependent effect of c-Cbl on adhesion of v-Abl-transformed fibroblasts is primarily mediated by an increase in fibronectin matrix deposition by these cells. This increase in fibronectin matrix deposition and, hence, in cell adhesion is dependent on cytoskeletal rearrangements induced by RhoA, Rac1 and, possibly, Rap1 activation caused by c-Cbl. The observed activation of these GTPases is mediated by the recruitment of phosphatidylinositol-3′ kinase, CrkL and Vav2 to the C-terminal tyrosine residues of c-Cbl. The results of this study also demonstrate that ubiquitination is essential for the observed effects of c-Cbl on fibronectin matrix production and cell adhesion.