Molecular dissection of integrin signalling proteins in the control of mammary epithelial development and differentiation
Molecular dissection of integrin signalling proteins in the control of mammary epithelial development and differentiation
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DOI：
10.1242/dev.028423
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发表时间：
2009-03-15
期刊：
影响因子：
4.6
通讯作者：
Streuli, Charles H.
中科院分区：
文献类型：
--
作者：
Akhtar, Nasreen;Marlow, Rebecca;Streuli, Charles H.
细胞-基质黏附对上皮细胞的发育和组织特异性功能至关重要。例如，在乳腺中，β 1-整合素对于肺泡的正常发育和决定细胞分化的内分泌信号通路的激活是必需的。然而，连接整合素与激素信号通路下游效应器的粘附复合物蛋白尚不清楚。为了了解粘附与细胞表型相关的机制，我们研究了两种近端β - 1整合素信号中间体，整合素连接激酶（ILK）和局灶粘附激酶（FAK）的参与。通过使用Cre-LoxP系统进行遗传分析，我们提供了证据，证明ILK，而不是FAK，在体内乳生成和培养的腔上皮细胞分化中起关键作用。在体内和原代细胞培养中，ILK的条件缺失通过阻止STAT5的磷酸化和核易位导致分化缺陷，STAT5是哺乳所需的转录因子。激活的RAC （ras相关的C3肉毒杆菌底物）在ILK缺失的腺泡中的表达恢复了泌乳缺陷，表明RAC1在整合素/ILK粘附复合物和分化途径之间提供了机制联系。因此，我们已经确定ILK是整合素信号传导参与分化的重要下游组分，并且已经确定了整合素黏附体内部的高度特异性，该黏附体将细胞-基质相互作用与上皮组织特异性功能联系起来。
Cell-matrix adhesion is essential for the development and tissue-specific functions of epithelia. For example, in the mammary gland, beta 1-integrin is necessary for the normal development of alveoli and for the activation of endocrine signalling pathways that determine cellular differentiation. However, the adhesion complex proteins linking integrins with downstream effectors of hormonal signalling pathways are not known. To understand the mechanisms involved in connecting adhesion with this aspect of cell phenotype, we examined the involvement of two proximal beta 1-integrin signalling intermediates, integrin-linked kinase (ILK) and focal adhesion kinase (FAK). By employing genetic analysis using the Cre-LoxP system, we provide evidence that ILK, but not FAK, has a key role in lactogenesis in vivo and in the differentiation of cultured luminal epithelial cells. Conditional deletion of ILK both in vivo and in primary cell cultures resulted in defective differentiation, by preventing phosphorylation and nuclear translocation of STAT5, a transcription factor required for lactation. Expression of an activated RAC (RAS-related C3 botulinum substrate) in ILK-null acini restored the lactation defect, indicating that RAC1 provides a mechanistic link between the integrin/ILK adhesion complex and the differentiation pathway. Thus, we have determined that ILK is an essential downstream component of integrin signalling involved in differentiation, and have identified a high degree of specificity within the integrin-based adhesome that links cell-matrix interactions with the tissue-specific function of epithelia.