LKB1 and AMPK maintain epithelial cell polarity under energetic stress.
LKB1 and AMPK maintain epithelial cell polarity under energetic stress.
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DOI：
10.1083/jcb.200702053
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发表时间：
2007-05-07
期刊：
影响因子：
--
通讯作者：
Brenman JE
中科院分区：
文献类型：
--
作者：
Mirouse V;Swick LL;Kazgan N;St Johnston D;Brenman JE
LKB1在家族性和自发性肿瘤中都发生突变，并作为激活PAR-1极性激酶和腺苷5 '单磷酸活化激酶（AMPK）的主激酶。这导致了LKB1作为肿瘤抑制因子的假设，因为它需要分别通过PAR-1和AMPK维持细胞极性和生长控制。然而，由于存在多个冗余的AMPK亚基，脊椎动物中LKB1-AMPK信号传导的遗传分析变得复杂。我们描述了单个果蝇AMPK催化亚基AMPKα的突变鉴定。令人惊讶的是，ampkα突变的上皮细胞在能量应激下失去极性并过度增殖。AMPK在体内激活需要LKB1， LKB1突变导致与AMPK α突变相似的能量应激依赖性表型。此外，lkb1表型被AMPKα的拟磷版本拯救。因此，LKB1通过AMPK发出信号，协调上皮极性和细胞能量状态的增殖，这可能是LKB1肿瘤抑制功能的基础。
LKB1 is mutated in both familial and spontaneous tumors, and acts as a master kinase that activates the PAR-1 polarity kinase and the adenosine 5′monophosphate–activated kinase (AMPK). This has led to the hypothesis that LKB1 acts as a tumor suppressor because it is required to maintain cell polarity and growth control through PAR-1 and AMPK, respectively. However, the genetic analysis of LKB1–AMPK signaling in vertebrates has been complicated by the existence of multiple redundant AMPK subunits. We describe the identification of mutations in the single Drosophila melanogaster AMPK catalytic subunit AMPKα. Surprisingly, ampkα mutant epithelial cells lose their polarity and overproliferate under energetic stress. LKB1 is required in vivo for AMPK activation, and lkb1 mutations cause similar energetic stress–dependent phenotypes to ampkα mutations. Furthermore, lkb1 phenotypes are rescued by a phosphomimetic version of AMPKα. Thus, LKB1 signals through AMPK to coordinate epithelial polarity and proliferation with cellular energy status, and this might underlie the tumor suppressor function of LKB1.
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