Mirouse Vincent, Swick Lance L, Kazgan Nevzat, St Johnston Daniel, Brenman Jay E
The Gurdon Institute, Department of Genetics, University of Cambridge, Cambridge, England, UK.
J Cell Biol. 2007 May 7;177(3):387-92. doi: 10.1083/jcb.200702053. Epub 2007 Apr 30.
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 AMPKalpha. Surprisingly, ampkalpha 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 ampkalpha mutations. Furthermore, lkb1 phenotypes are rescued by a phosphomimetic version of AMPKalpha. 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.
LKB1在家族性肿瘤和自发性肿瘤中均发生突变，并作为一种主激酶发挥作用，可激活PAR-1极性激酶和5'-单磷酸腺苷激活的蛋白激酶（AMPK）。这引发了一种假说，即LKB1作为肿瘤抑制因子，分别通过PAR-1和AMPK来维持细胞极性和生长控制。然而，脊椎动物中LKB1-AMPK信号传导的遗传分析因存在多个冗余的AMPK亚基而变得复杂。我们描述了在单一的果蝇AMPK催化亚基AMPKalpha中突变的鉴定。令人惊讶的是，ampkalpha突变的上皮细胞在能量应激下失去极性并过度增殖。LKB1在体内是AMPK激活所必需的，而lkb1突变会导致与ampkalpha突变类似的能量应激依赖性表型。此外，lkb1表型可被AMPKalpha的磷酸模拟形式挽救。因此，LKB1通过AMPK发出信号，以协调上皮极性和增殖与细胞能量状态，这可能是LKB1肿瘤抑制功能的基础。
