Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways.
Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways.
复制标题
表皮生长因子受体细胞增殖信号通路。
DOI：
10.3390/cancers9050052
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发表时间：
2017-05-17
期刊：
影响因子：
5.2
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
Wee P;Wang Z
表皮生长因子受体（EGFR）是一种受体酪氨酸激酶，其通常在癌症如非小细胞肺癌、转移性结肠直肠癌、胶质母细胞瘤、头颈癌、胰腺癌和乳腺癌中上调。多种机制介导EGFR活性的上调，包括其细胞外结构域的常见突变和截短，如EGFRvIII截短，以及其激酶结构域的常见突变和截短，如L 858 R和T790 M突变，或外显子19截短。这些EGFR畸变过度激活下游促癌信号传导途径，包括RAS-RAF-MEK-ERK MAPK和AKT-PI 3 K-mTOR途径。然后，这些途径激活许多有利于癌细胞增殖的生物输出，包括它们在细胞周期中的慢性启动和进展。在这里，我们回顾了调节EGFR信号转导的分子机制，包括EGFR结构及其突变，配体结合和EGFR二聚化，以及导致G1细胞周期进展的信号通路。我们的重点是诱导细胞周期蛋白D的表达，CDK 4/6激活，并通过EGFR信号通路的细胞周期蛋白依赖性激酶抑制剂蛋白（CDKi）的抑制。我们还讨论了EGFR靶向治疗的成功和挑战，以及它们与CDK 4/6抑制剂联合使用的潜力。
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly upregulated in cancers such as in non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. Various mechanisms mediate the upregulation of EGFR activity, including common mutations and truncations to its extracellular domain, such as in the EGFRvIII truncations, as well as to its kinase domain, such as the L858R and T790M mutations, or the exon 19 truncation. These EGFR aberrations over-activate downstream pro-oncogenic signaling pathways, including the RAS-RAF-MEK-ERK MAPK and AKT-PI3K-mTOR pathways. These pathways then activate many biological outputs that are beneficial to cancer cell proliferation, including their chronic initiation and progression through the cell cycle. Here, we review the molecular mechanisms that regulate EGFR signal transduction, including the EGFR structure and its mutations, ligand binding and EGFR dimerization, as well as the signaling pathways that lead to G1 cell cycle progression. We focus on the induction of CYCLIN D expression, CDK4/6 activation, and the repression of cyclin-dependent kinase inhibitor proteins (CDKi) by EGFR signaling pathways. We also discuss the successes and challenges of EGFR-targeted therapies, and the potential for their use in combination with CDK4/6 inhibitors.