Growth factor-dependent activation of alphavbeta3 integrin in normal epithelial cells: implications for tumor invasion.
Growth factor-dependent activation of alphavbeta3 integrin in normal epithelial cells: implications for tumor invasion.
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DOI：
10.1083/jcb.142.4.1145
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发表时间：
1998-08-24
期刊：
影响因子：
--
通讯作者：
De Filippi R
中科院分区：
文献类型：
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作者：
Trusolino L;Serini G;Cecchini G;Besati C;Ambesi-Impiombato FS;Marchisio PC;De Filippi R
整合素激活是一种多方面的现象，导致对基质配体的亲和力和亲和力增加。为了研究癌细胞基质浸润过程中产生的细胞因子是否激活无功能的上皮整合素，使用了源自正常腺体（HTU-5）和乳头状癌（HTU-34）的人甲状腺克隆细胞系统。在 HTU-5 细胞中，αvβ3 整合素遍布整个膜，与细胞骨架断开，无法介导粘附。相反，在 HTU-34 细胞中，αvβ3 聚集在焦点接触 (FC) 处并介导牢固附着和扩散。在用肝细胞生长因子/分散因子 (HGF/SF) 处理后，HTU-5 细胞中发生了 FC 上的 αvβ3 募集和配体结合活性，与 HTU-34 基本相同。 HTU-34 克隆分泌 HGF/SF，其受体被组成型酪氨酸磷酸化，表明自分泌环负责 αvβ3 激活状态。 HTU-34 细胞中抗体介导的 HGF/SF 功能抑制破坏了 FC 上的 αvβ3 富集并损害了粘附。因此，正常细胞中αvβ3的激活是由HTU-34条件培养基基于其HGF/SF含量产生的。这些结果提供了正常上皮细胞中生长因子驱动的整合素激活机制的第一个例子，并揭示了基于细胞因子的自分泌环对于整合素激活的生理控制的重要性。
Integrin activation is a multifaceted phenomenon leading to increased affinity and avidity for matrix ligands. To investigate whether cytokines produced during stromal infiltration of carcinoma cells activate nonfunctional epithelial integrins, a cellular system of human thyroid clones derived from normal glands (HTU-5) and papillary carcinomas (HTU-34) was employed. In HTU-5 cells, αvβ3 integrin was diffused all over the membrane, disconnected from the cytoskeleton, and unable to mediate adhesion. Conversely, in HTU-34 cells, αvβ3 was clustered at focal contacts (FCs) and mediated firm attachment and spreading. αvβ3 recruitment at FCs and ligand-binding activity, essentially identical to those of HTU-34, occurred in HTU-5 cells upon treatment with hepatocyte growth factor/scatter factor (HGF/SF). The HTU-34 clone secreted HGF/SF and its receptor was constitutively tyrosine phosphorylated suggesting an autocrine loop responsible for αvβ3 activated state. Antibody-mediated inhibition of HGF/SF function in HTU-34 cells disrupted αvβ3 enrichment at FCs and impaired adhesion. Accordingly, activation of αvβ3 in normal cells was produced by HTU-34 conditioned medium on the basis of its content of HGF/SF. These results provide the first example of a growth factor–driven integrin activation mechanism in normal epithelial cells and uncover the importance of cytokine-based autocrine loops for the physiological control of integrin activation.