MAP4K4 is a novel MAPK/ERK pathway regulator required for lung adenocarcinoma maintenance.
MAP4K4 is a novel MAPK/ERK pathway regulator required for lung adenocarcinoma maintenance.
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MAP4K4 是肺腺癌维持所需的新型 MAPK/ERK 通路调节因子
DOI：
10.1002/1878-0261.12055
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发表时间：
2017-06
影响因子：
6.6
通讯作者：
Hu J
中科院分区：
文献类型：
--
作者：
Gao X;Chen G;Gao C;Zhang DH;Kuan SF;Stabile LP;Liu G;Hu J
约76%的肺腺癌患者在受体酪氨酸激酶（RTK）/RAS/RAF通路中存在激活突变，导致丝裂原活化蛋白激酶（MAPK）通路异常激活，特别是MAPK/ERK通路。然而，许多缺乏这些基因组突变的肺腺癌也显示出显着的MAPK通路激活，这表明其他MAPK通路的改变仍未被检测到。这项研究已经确定丝氨酸/苏氨酸激酶丝裂原活化蛋白4激酶4（MAP 4K 4）是肺腺癌中MAPK/ERK信号转导的一种新的正调控因子。结果显示，MAP 4K 4在肺腺癌中显著升高，与KRAS或EGFR突变状态无关。MAP 4K 4的敲低抑制肺腺癌细胞的增殖、锚定非依赖性生长和迁移，并且还抑制人肺腺癌异种移植物生长和转移。从机制上讲，我们发现MAP 4K 4通过抑制蛋白磷酸酶2活性来激活ERK。我们的结果进一步表明，MAP 4K 4的下调阻止了EGFR抑制剂厄洛替尼处理的肺腺癌细胞中ERK的再激活。总之，我们的研究结果确定MAP 4K 4作为一种新的MAPK/ERK通路调节剂在肺腺癌，肺腺癌的维持所需的。
About 76% of patients with lung adenocarcinoma harbor activating mutations in the receptor tyrosine kinase (RTK)/RAS/RAF pathways, leading to aberrant activation of the mitogen‐activated protein kinase (MAPK) pathways particularly the MAPK/ERK pathway. However, many lung adenocarcinomas lacking these genomic mutations also display significant MAPK pathway activation, suggesting that additional MAPK pathway alterations remain undetected. This study has identified serine/threonine kinase mitogen‐activated protein 4 kinase 4 (MAP4K4) as a novel positive regulator of MAPK/ERK signaling in lung adenocarcinoma. The results showed that MAP4K4 was drastically elevated in lung adenocarcinoma independently of KRAS or EGFR mutation status. Knockdown of MAP4K4 inhibited proliferation, anchorage‐independent growth and migration of lung adenocarcinoma cells, and also inhibited human lung adenocarcinoma xenograft growth and metastasis. Mechanistically, we found that MAP4K4 activated ERK through inhibiting protein phosphatase 2 activity. Our results further showed that downregulation of MAP4K4 prevented ERK reactivation in EGFR inhibitor erlotinib‐treated lung adenocarcinoma cells. Together, our findings identify MAP4K4 as a novel MAPK/ERK pathway regulator in lung adenocarcinoma that is required for lung adenocarcinoma maintenance.
DOI：
10.1016/j.bbrc.2009.05.082
发表时间：
2009-08-07
影响因子：
3.1
作者：
Bae, Dongsoon;Ceryak, Susan
通讯作者：
Ceryak, Susan