EGFR signals to mTOR through PKC and independently of Akt in glioma.
EGFR signals to mTOR through PKC and independently of Akt in glioma.
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DOI：
10.1126/scisignal.2000014
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发表时间：
2009-01-27
影响因子：
7.3
通讯作者：
Weiss WA
中科院分区：
文献类型：
--
作者：
Fan QW;Cheng C;Knight ZA;Haas-Kogan D;Stokoe D;James CD;McCormick F;Shokat KM;Weiss WA
编码表皮生长因子（EGF）受体（EGFR）的基因扩增通常发生在胶质母细胞瘤中，导致下游激酶（包括磷脂酰肌醇3′-激酶（PI 3 K）、Akt和哺乳动物雷帕霉素靶蛋白（mTOR））活化。在这里，我们表明mTOR及其下游底物rpS 6（核糖体蛋白S6）的磷酸化是EGFR抑制剂抗增殖作用的稳健生物标志物。EGFR信号传导的抑制与细胞中磷酸化mTOR（p-mTOR）和rpS 6（p-rpS 6）的丰度降低相关，所述细胞为编码PTEN（10号染色体上的磷酸酶和张力蛋白同源物）的基因的野生型，所述PTEN是PI 3 K的负调节剂。相比之下，EGFR信号传导的抑制未能影响对EGFR抑制剂具有抗性的PTEN突变体细胞中的p-mTOR或p-rpS 6。尽管磷酸化Akt（p-Akt）的丰度响应于EGFR信号传导的抑制而降低，但Akt对于EGFR和mTOR之间的信号传导是不稳定的。我们确定了一个Akt非依赖性途径连接EGFR和mTOR，这是严重依赖于蛋白激酶C（PKC）。与这些观察结果一致，EGFR的丰度通常与原发性人胶质母细胞瘤肿瘤中rpS 6和PKC的磷酸化相关，与Akt的磷酸化相关性较差。PKC抑制剂导致胶质瘤细胞活力下降，无论PTEN或EGFR状态如何，这表明PKC抑制剂应在胶质瘤中进行测试。这些发现强调了胶质瘤中EGFR和mTOR之间信号传导的重要性，确定PKCα对该网络至关重要，并质疑Akt作为胶质瘤中EGFR和mTOR偶联的关键中间体的必要性。
Amplification of the gene encoding the epidermal growth factor (EGF) receptor (EGFR) occurs commonly in glioblastoma, leading to activation of downstream kinases including phosphatidylinositol 3′-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR). Here, we show that phosphorylation of mTOR and its downstream substrate rpS6 (ribosomal protein S6) are robust biomarkers for the antiproliferative effect of EGFR inhibitors. Inhibition of EGFR signaling correlated with decreased abundance of phosphorylated mTOR (p-mTOR) and rpS6 (p-rpS6) in cells wild type for the gene encoding PTEN (phosphatase and tensin homolog on chromosome 10), a negative regulator of PI3K. In contrast, inhibition of EGFR signaling failed to affect p-mTOR or p-rpS6 in cells mutant for PTEN, which are resistant to EGFR inhibitors. Although the abundance of phosphorylated Akt (p-Akt) decreased in response to inhibition of EGFR signaling, Akt was dispensable for signaling between EGFR and mTOR. We identified an Akt-independent pathway linking EGFR to mTOR that was critically dependent on protein kinase C (PKC). Consistent with these observations, the abundance of EGFR generally correlated with phosphorylation of rpS6 and PKC in primary human glioblastoma tumors, and correlated poorly with phosphorylation of Akt. Inhibition of PKC led to decreased viability of glioma cells regardless of PTEN or EGFR status, suggesting that PKC inhibitors should be tested in glioma. These findings underline the importance of signaling between EGFR and mTOR in glioma, identify PKCα as essential to this network, and question the necessity of Akt as a critical intermediate coupling EGFR and mTOR in glioma.
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雷帕霉素在I期试验中针对复发性PTEN缺陷型胶质母细胞瘤患者的抗肿瘤活性。
影响因子：
15.8
作者：
Cloughesy, Tim F.;Yoshimoto, Koji;Nghiemphu, Phioanh;Brown, Kevin;Dang, Julie;Zhu, Shaojun;Hsueh, Teli;Chen, Yinan;Wang, Wei;Youngkin, David;Liau, Linda;Martin, Neil;Becker, Don;Bergsneider, Marvin;Lai, Albert;Green, Richard;Oglesby, Tom;Koleto, Michael;Trent, Jeff;Horvath, Steve;Mischel, Paul S.;Mellinghoff, Ingo K.;Sawyers, Charles L.
通讯作者：
Sawyers, Charles L.
影响因子：
10.3
作者：
Haas-Kogan, DA;Prados, MD;Stokoe, D
通讯作者：
Stokoe, D
影响因子：
5.7
作者：
Maira, Sauveur-Michel;Stauffer, Frederic;Garcia-Echeverria, Carlos
通讯作者：
Garcia-Echeverria, Carlos
影响因子：
5.7
作者：
Shi, YJ;Yan, HJ;Lichtenstein, A
通讯作者：
Lichtenstein, A
影响因子：
50.3
作者：
Fan, Qi-Wen;Knight, Zachary A.;Weiss, William A.
通讯作者：
Weiss, William A.