ERK kinase phosphorylates and destabilizes the tumor suppressor FBW7 in pancreatic cancer.
ERK kinase phosphorylates and destabilizes the tumor suppressor FBW7 in pancreatic cancer.
复制标题
ERK 激酶磷酸化胰腺癌中的肿瘤抑制因子 FBW7 并使其不稳定
作者：
F-box和WD重复结构域7 （FBW7）是Skp1-Cul1-F-box （SCF）泛素连接酶复合物的底物识别成分，通过靶向多种癌蛋白降解，作为主要的肿瘤抑制因子发挥作用。FBW7的基因组缺失或突变在许多人类癌症中经常被发现，但在胰腺导管腺癌中却没有发现。因此，了解FBW7的抑瘤功能如何在胰腺癌中受损是很重要的。在本研究中，我们首次观察到胰腺癌临床样本中FBW7的低表达与ERK激活显著相关，主要是由于胰腺癌中的KRAS突变。我们进一步发现，ERK直接与FBW7相互作用，并在Thr205位点磷酸化FBW7，从而促进FBW7泛素化和蛋白酶体降解。此外，磷酸化缺陷的T205A FBW7突变体对ERK活化具有抗性，可以显著抑制胰腺癌细胞的增殖和肿瘤发生。这些结果共同证明了致癌KRAS突变如何抑制肿瘤抑制因子FBW7，从而揭示了KRAS突变在促进胰腺癌进展中的重要功能。
F-box and WD repeat domain-containing 7 (FBW7) is the substrate recognition component of the Skp1-Cul1-F-box (SCF) ubiquitin ligase complex and functions as a major tumor suppressor by targeting various oncoproteins for degradation. Genomic deletion or mutation of FBW7 has frequently been identified in many human cancers but not in pancreatic ductal adenocarcinoma. Thus it is important to know how the tumor suppressive function of FBW7 is impaired in pancreatic cancer. In this study, we first observed that low FBW7 expression correlated significantly with ERK activation in pancreatic cancer clinical samples, primarily due to KRAS mutations in pancreatic cancer. We further showed that ERK directly interacted with FBW7 and phosphorylated FBW7 at Thr205, which sequentially promoted FBW7 ubiquitination and proteasomal degradation. Furthermore, the phospho-deficient T205A FBW7 mutant is resistant to ERK activation and could significantly suppress pancreatic cancer cell proliferation and tumorigenesis. These results collectively demonstrate how the oncogenic KRAS mutation inhibits the tumor suppressor FBW7, thus revealing an important function of KRAS mutations in promoting pancreatic cancer progression.
登录
查看更多内容
影响因子：
64.8
作者：
Inuzuka, Hiroyuki;Shaik, Shavali;Onoyama, Ichiro;Gao, Daming;Tseng, Alan;Maser, Richard S.;Zhai, Bo;Wan, Lixin;Gutierrez, Alejandro;Lau, Alan W.;Xiao, Yonghong;Christie, Amanda L.;Aster, Jon;Settleman, Jeffrey;Gygi, Steven P.;Kung, Andrew L.;Look, Thomas;Nakayama, Keiichi I.;DePinho, Ronald A.;Wei, Wenyi
通讯作者：
Wei, Wenyi
影响因子：
28.2
作者：
Collisson EA;Trejo CL;Silva JM;Gu S;Korkola JE;Heiser LM;Charles RP;Rabinovich BA;Hann B;Dankort D;Spellman PT;Phillips WA;Gray JW;McMahon M
通讯作者：
McMahon M
影响因子：
8.8
作者：
Eser, S.;Schnieke, A.;Schneider, G.;Saur, D.
通讯作者：
Saur, D.
DOI：
10.1158/1078-0432.ccr-12-0315
发表时间：
2012-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Iacobuzio-Donahue CA;Velculescu VE;Wolfgang CL;Hruban RH
通讯作者：
Hruban RH
影响因子：
5.7
作者：
Ibusuki, Mutsuko;Yamamoto, Yutaka;Iwase, Hirotaka
通讯作者：
Iwase, Hirotaka