β4 integrin is a transforming molecule that unleashes met tyrosine kinase tumorigenesis
β4 integrin is a transforming molecule that unleashes met tyrosine kinase tumorigenesis
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DOI：
10.1158/0008-5472.can-05-2827
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发表时间：
2005-12-01
期刊：
影响因子：
11.2
通讯作者：
Trusolino, L
中科院分区：
文献类型：
--
作者：
Bertotti, A;Comoglio, PM;Trusolino, L
在缺乏整联蛋白衍生的粘附信号的情况下的细胞增殖（锚定非依赖性生长）是肿瘤转化的表型标志。因此，在肿瘤中经常观察到的一些整合素的上调被解释为一种附带现象，而不是致癌转化的致病因素。β（4）整联蛋白刺激上皮细胞的增殖和存活，并且在人癌中过表达，通常伴随肝细胞生长因子的Met酪氨酸激酶受体的上调。Met不具有转化能力，但可以利用β（4）胞质尾区作为底物/接头，用于扩增促有丝分裂和抗凋亡反应，而不依赖于细胞粘附。在这里，我们表明，β（4）的过度表达足以转化啮齿类动物成纤维细胞，增强乳腺癌细胞的锚定非依赖性生长，并诱导裸鼠肿瘤发生;相反，RNA干扰介导的耗竭废除肿瘤细胞的转化表型。这些自主致癌特性在Met共表达后显著加剧，表明整合素可以激发激酶的潜在致瘤潜力。β（4）非粘附变体仍与Met合作进行细胞转化，证实β（4）在放大Met生物学效应方面的粘附非依赖性功能。相反，不能被Met有效地酪氨酸磷酸化并且显示出降低的激活磷脂酰肌醇3-激酶依赖性和Ras依赖性途径的能力的β（4）信号传导缺陷突变体中止转化。我们的研究结果将β 4定义为原发性癌发生中酪氨酸激酶原癌基因的信号传导帮凶（“伺服癌基因”），在锚定非依赖性生长的正调控中引起原型粘附分子的非正统功能，并建议使用04作为抗癌治疗的靶点。（癌症研究2005; 65（23）：10674-9）。
Cell multiplication in the absence of integrin-derived adhesive signals (anchorage-independent growth) is the phenotypic hallmark of neoplastic transformation. Therefore, the frequently observed up-regulation of some integrins in tumors has been interpreted as an epiphenomenon and not as a causative factor of oncogenic conversion. beta(4) integrin stimulates proliferation and survival of epithelial cells and is overexpressed in human carcinomas, often in concomitance with up-regulation of the Met tyrosine kinase receptor for hepatocyte growth factor. Met is not endowed with transforming ability but can exploit the beta(4) cytoplasmic tail as a substrate/adaptor for amplification of mitogenic and antiapoptotic responses, independently of cell adhesion. Here, we show that overexpression of beta(4) is sufficient to transform rodent fibroblasts, enhances anchorage-independent growth of breast carcinoma cells, and induces tumorigenesis in nude mice; conversely, RNA interference-mediated depletion abrogates the transformed phenotype of neoplastic cells. These autonomous oncogenic properties are dramatically exacerbated upon Met coexpression, suggesting that the integrin can instigate the latent tumorigenic potential of the kinase. A beta(4) nonadhesive variant still cooperates with Met for cellular transformation, confirming the adhesion-independent function of beta(4) in magnification of Met biological effects. Conversely, a beta(4) signaling-incompetent mutant that cannot be efficiently tyrosine phosphorylated by Met and displays reduced ability to activate phosphatidylinositol 3-kinase-dependent and Ras-dependent pathways aborts transformation. Our findings define beta(4) as a signaling accomplice (a "servo-oncogene") of tyrosine kinase proto-oncogenes in primary carcinogenesis, evoke an unorthodox function for a prototypic adhesion molecule in the positive regulation of anchorage-independent growth, and suggest the use of 04 as a target for anticancer therapy. (Cancer Res 2005; 65(23): 10674-9).