Phosphorylation of FADD by the kinase CK1α promotes KRASG12D-induced lung cancer.
Phosphorylation of FADD by the kinase CK1α promotes KRASG12D-induced lung cancer.
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DOI：
10.1126/scisignal.2005607
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发表时间：
2015-01-27
影响因子：
7.3
通讯作者：
Galbán S
中科院分区：
文献类型：
--
作者：
Bowman BM;Sebolt KA;Hoff BA;Boes JL;Daniels DL;Heist KA;Galbán CJ;Patel RM;Zhang J;Beer DG;Ross BD;Rehemtulla A;Galbán S
基因编码的基因组扩增和FADD蛋白（fas相关死亡结构域）的磷酸化与肺癌和头颈癌的不良临床结果相关。激活鸟苷三磷酸酶RAS的突变可促进多种癌症中的细胞增殖。我们发现，在肺癌患者组织中，磷酸化FADD的丰度与突变KRAS的丰度相关。通过krasg12d驱动肺癌条件小鼠模型的免疫组织化学分析和体内成像，我们发现FADD编码基因的缺失抑制了肿瘤的生长，降低了细胞的增殖指数，并降低了促进细胞周期的RAS-MAPK（丝裂原活化蛋白激酶）通路下游效应物的激活，包括视网膜母细胞瘤（RB）和细胞周期蛋白D1。在小鼠胚胎成纤维细胞中，KRAS激活诱导有丝分裂需要FADD和CK1α（酪蛋白激酶1α）磷酸化FADD。在kras突变小鼠中删除编码CK1α的基因，消除了FADD的磷酸化，抑制了肺癌的发展。磷酸化的FADD在细胞周期的G2/M期最为丰富，质谱分析显示，磷酸化的FADD与介导G2/M过渡的激酶相互作用，包括PLK1 （polo样激酶1）、AURKA（极光激酶A）和BUB1（不受苯并咪唑1抑制的出芽）。在用CK1α抑制剂CKI-7处理的细胞中，这种相互作用减弱。因此，作为磷酸化RAS下游FADD的激酶，CK1α可能是kras驱动的肺癌的治疗靶点。
Genomic amplification of the gene encoding and phosphorylation of the protein FADD (Fas-associated death domain) is associated with poor clinical outcome in lung cancer and in head and neck cancer. Activating mutations in the guanosine triphosphatase RAS promotes cell proliferation in various cancers. We found that the abundance of phosphorylated FADD correlated with that of mutant KRAS in patient lung cancer tissues. Using immunohistochemistry analysis and in vivo imaging of conditional mouse models of KRASG12D-driven lung cancer, we found that the deletion of the gene encoding FADD suppressed tumor growth, reduced the proliferative index of cells, and decreased the activation of downstream effectors of the RAS–MAPK (mitogen-activated protein kinase) pathway that promote the cell cycle, including retinoblastoma (RB) and cyclin D1. In mouse embryonic fibroblasts, the induction of mitosis upon activation of KRAS required FADD and the phosphorylation of FADD by CK1α (casein kinase 1α). Deleting the gene encoding CK1α in KRAS-mutant mice abrogated the phosphorylation of FADD and suppressed lung cancer development. Phosphorylated FADD was most abundant during the G2/M phase of the cell cycle, and mass spectrometry revealed that phosphorylated FADD interacted with kinases that mediate the G2/M transition, including PLK1 (Polo-like kinase 1), AURKA (Aurora kinase A) and BUB1 (budding uninhibited by benzimidazoles 1). This interaction was decreased in cells treated with a CKI-7, a CK1α inhibitor. Therefore, as the kinase that phosphorylates FADD downstream of RAS, CK1α may be a therapeutic target for KRAS-driven lung cancer.
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影响因子：
16.6
作者：
Kim, Hyunjoo;Lee, Ho-June;Oh, Yumin;Choi, Seon-Guk;Hong, Se-Hoon;Kim, Hyo-Jin;Lee, Song-Yi;Choi, Ji-Woo;Hwang, Deog Su;Kim, Key-Sun;Kim, Hyo-Joon;Zhang, Jianke;Youn, Hyun-Jo;Noh, Dong-Young;Jung, Yong-Keun
通讯作者：
Jung, Yong-Keun
影响因子：
28.5
作者：
Akinleye A;Furqan M;Mukhi N;Ravella P;Liu D
通讯作者：
Liu D
影响因子：
11.5
作者：
Gibcus, Johan H.;Menkema, Lorian;Schuuring, Ed
通讯作者：
Schuuring, Ed
影响因子：
12.4
作者：
Gómez-Angelats, M;Cidlowski, JA
通讯作者：
Cidlowski, JA
影响因子：
2.5
作者：
Anger, M;Kues, WA;Niemann, H
通讯作者：
Niemann, H