Integrin signaling through FAK in the regulation of mammary stem cells and breast cancer.
Integrin signaling through FAK in the regulation of mammary stem cells and breast cancer.
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DOI：
10.1002/iub.303
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发表时间：
2010-04
期刊：
影响因子：
4.6
通讯作者：
Guan, Jun-Lin
中科院分区：
文献类型：
--
作者：
Guan, Jun-Lin
局灶黏附激酶（Focal adhesion kinase， FAK）是一种细胞质酪氨酸激酶，被认为是整合素介导细胞内信号传导的关键媒介，整合素是细胞外基质细胞表面受体的主要家族，在多种细胞中调节不同的细胞功能。当整合素通过破坏自身抑制机制激活FAK时，FAK经历自磷酸化，并与Src和其他细胞蛋白形成复合物，通过其激酶活性或支架功能触发下游信号。许多整合素被鉴定为乳腺干细胞（MaSCs）的表面标记物，在小鼠模型研究中发现整合素和FAK在MaSCs的维持中发挥关键作用，这表明通过FAK的整合素信号传导可能作为MaSCs的功能标记物。与先前将FAK的表达和激活增加与人类乳腺癌联系起来的研究一致，这些发现表明FAK通过维持MaSCs池作为致癌转化的靶点来促进乳腺肿瘤发生的一种新的细胞机制。此外，在乳腺癌小鼠模型中，FAK失活也减少了乳腺癌干细胞（MaCSCs）的数量，降低了它们在体外的自我更新，并损害了它们在体内的致瘤性和维持能力，这表明FAK通过整合素信号传导通过其在MaCSCs中的功能在乳腺癌的生长和进展中发挥了潜在的作用。本文综述了这些最新进展和未来的研究，探讨了通过FAK通过调节MaCSCs在乳腺癌中整合素信号传导的机制，这可能会导致这种致命疾病的新疗法的发展。
Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase identified as a key mediator of intracellular signaling by integrins, a major family of cell surface receptors for extracellular matrix, in the regulation of different cellular functions in a variety of cells. Upon activation by integrins through disruption of an auto-inhibitory mechanism, FAK undergoes autophosphorylation and forms a complex with Src and other cellular proteins to trigger downstream signaling through its kinase activity or scaffolding function. A number of integrins are identified as surface markers for mammary stem cells (MaSCs) and both integrins and FAK are found to play crucial roles in the maintenance of MaSCs in studies using mouse models, suggesting that integrin signaling through FAK may serve as a functional marker for MaSCs. Consistent with previous studies linking increased expression and activation of FAK to human breast cancer, these findings suggest a novel cellular mechanism of FAK promotion of mammary tumorigenesis by maintaining the pools of MaSCs as targets of oncogenic transformation. Furthermore, FAK inactivation in mouse models of breast cancer also reduced the pool of mammary cancer stem cells (MaCSCs), decreased their self-renewal in vitro, and compromised their tumorigenicity and maintenance in vivo, suggesting a potential role of integrin signaling through FAK in breast cancer growth and progression through its functions in MaCSCs. This review discusses these recent advances and future studies into the mechanism of integrin signaling through FAK in breast cancer through regulation of MaCSCs that may lead to development of novel therapies for this deadly disease.
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作者：
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DOI：
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发表时间：
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期刊：
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影响因子：
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作者：
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通讯作者：
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