A tumor-associated beta 1 integrin mutation that abrogates epithelial differentiation control.
A tumor-associated beta 1 integrin mutation that abrogates epithelial differentiation control.
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DOI：
10.1083/jcb.200209016
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发表时间：
2003-02-17
期刊：
影响因子：
--
通讯作者：
Watt FM
中科院分区：
文献类型：
--
作者：
Evans RD;Perkins VC;Henry A;Stephens PE;Robinson MK;Watt FM
SCC4 人角质形成细胞源自舌鳞状细胞癌，并且几乎不发生自发分化。将野生型β1整合素亚基引入SCC4细胞会刺激分化，这表明细胞控制分化的整合素信号通路存在缺陷，或者β1亚基本身有缺陷。在这里，我们描述了 SCC4 β1 亚基的杂合突变。突变 T188I 映射到 I 样结构域。在重组蛋白固相检测和活细胞中，它会导致配体结合的组成型激活，而与配偶体 α 亚基无关。该突变促进细胞扩散，但不促进增殖、运动或侵袭。它导致 Erk MAPK 持续激活，与细胞扩散无关。当引入 SCC4 角质形成细胞时，野生型 β1 整合素会刺激分化，而突变型则无活性。正常角质形成细胞中 β1 整合素的激活也会抑制分化。这些结果首次确立了突变作为整合素促进肿瘤形成的机制，因为上皮癌的分化程度与预后呈负相关。他们还提供了关于整合素如何调节角质形成细胞分化的新见解。
SCC4 human keratinocytes are derived from a squamous cell carcinoma of the tongue and undergo very little spontaneous differentiation. Introduction of a wild-type β1 integrin subunit into SCC4 cells stimulates differentiation, suggesting either that the cells have a defect in the integrin signaling pathways that control differentiation or that the β1 subunit itself is defective. Here we describe a heterozygous mutation in the SCC4 β1 subunit. The mutation, T188I, maps to the I-like domain. It results in constitutive activation of ligand binding, irrespective of the partner α subunit, in solid phase assays with recombinant protein and in living cells. The mutation promotes cell spreading, but not proliferation, motility, or invasiveness. It results in sustained activation of Erk MAPK independent of cell spreading. When introduced into SCC4 keratinocytes, the wild-type β1 integrin stimulates differentiation, whereas the mutant is inactive. Activation of β1 integrins in normal keratinocytes also suppresses differentiation. These results establish, for the first time, mutation as a mechanism by which integrins can contribute to neoplasia, because the degree of differentiation in epithelial cancers is inversely correlated with prognosis. They also provide new insights into how integrins regulate keratinocyte differentiation.
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