Cipriano R, Bryson B L, Miskimen K L S, Bartel C A, Hernandez-Sanchez W, Bruntz R C, Scott S A, Lindsley C W, Brown H A, Jackson M W
Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
Department of Pharmacology, The Vanderbilt Institute of Chemical Biology, The Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Oncogene. 2014 Jun 19;33(25):3298-306. doi: 10.1038/onc.2013.293. Epub 2013 Aug 5.
Despite the progress made in targeted anticancer therapies in recent years, challenges remain. The identification of new potential targets will ensure that the arsenal of cancer therapies continues to expand. FAM83B was recently discovered in a forward genetic screen for novel oncogenes that drive human mammary epithelial cell (HMEC) transformation. We report here that elevated FAM83B expression increases Phospholipase D (PLD) activity, and that suppression of PLD1 activity prevents FAM83B-mediated transformation. The increased PLD activity is engaged by hyperactivation of epidermal growth factor receptor (EGFR), which is regulated by an interaction involving FAM83B and EGFR. Preventing the FAM83B/EGFR interaction by site-directed mutation of lysine 230 of FAM83B suppressed PLD activity and MAPK signaling. Furthermore, ablation of FAM83B expression from breast cancer cells inhibited EGFR phosphorylation and suppressed cell proliferation. We propose that understanding the mechanism of FAM83B-mediated transformation will provide a foundation for future therapies aimed at targeting its function as an intermediary in EGFR, MAPK and mTOR activation.
尽管近年来靶向抗癌疗法取得了进展，但挑战依然存在。确定新的潜在靶点将确保癌症治疗手段不断扩充。FAM83B最近在一项针对驱动人乳腺上皮细胞（HMEC）转化的新型癌基因的正向遗传学筛选中被发现。我们在此报告，FAM83B表达升高会增加磷脂酶D（PLD）活性，而抑制PLD1活性可阻止FAM83B介导的转化。PLD活性增加是由表皮生长因子受体（EGFR）的过度激活引起的，而EGFR的过度激活受FAM83B与EGFR之间相互作用的调控。通过对FAM83B的赖氨酸230进行定点突变来阻止FAM83B/EGFR相互作用，可抑制PLD活性和MAPK信号传导。此外，消除乳腺癌细胞中的FAM83B表达可抑制EGFR磷酸化并抑制细胞增殖。我们认为，了解FAM83B介导的转化机制将为未来旨在靶向其作为EGFR、MAPK和mTOR激活中介功能的治疗提供基础。
