The Beatson Institute for Cancer Research, Glasgow, UK.
Dev Cell. 2010 Aug 17;19(2):259-69. doi: 10.1016/j.devcel.2010.07.015.
The intestinal epithelium has a remarkable capacity to regenerate after injury and DNA damage. Here, we show that the integrin effector protein Focal Adhesion Kinase (FAK) is dispensable for normal intestinal homeostasis and DNA damage signaling, but is essential for intestinal regeneration following DNA damage. Given Wnt/c-Myc signaling is activated following intestinal regeneration, we investigated the functional importance of FAK following deletion of the Apc tumor suppressor protein within the intestinal epithelium. Following Apc loss, FAK expression increased in a c-Myc-dependent manner. Codeletion of Apc and Fak strongly reduced proliferation normally induced following Apc loss, and this was associated with reduced levels of phospho-Akt and suppression of intestinal tumorigenesis in Apc heterozygous mice. Thus, FAK is required downstream of Wnt Signaling, for Akt/mTOR activation, intestinal regeneration, and tumorigenesis. Importantly, this work suggests that FAK inhibitors may suppress tumorigenesis in patients at high risk of developing colorectal cancer.
肠上皮细胞在受伤和 DNA 损伤后具有很强的再生能力。在这里，我们表明整合素效应蛋白粘着斑激酶（FAK）对于正常的肠道内稳态和 DNA 损伤信号传导是不必要的，但对于 DNA 损伤后的肠道再生是必需的。鉴于 Wnt/c-Myc 信号在肠道再生后被激活，我们研究了在肠上皮细胞中缺失 APC 肿瘤抑制蛋白后 FAK 的功能重要性。APC 缺失后，FAK 的表达以 c-Myc 依赖性的方式增加。APC 和 Fak 的共缺失强烈降低了 APC 缺失通常诱导的增殖，这与磷酸化 Akt 的水平降低以及 APC 杂合子小鼠中肠道肿瘤发生的抑制有关。因此，FAK 是 Wnt 信号下游所必需的，用于 Akt/mTOR 的激活、肠道再生和肿瘤发生。重要的是，这项工作表明，FAK 抑制剂可能会抑制患有结直肠癌高风险的患者的肿瘤发生。
