Sebbagh Michael, Santoni Marie-Josée, Hall Brian, Borg Jean-Paul, Schwartz Martin A
Cardiovascular Research Center and Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA.
Curr Biol. 2009 Jan 13;19(1):37-42. doi: 10.1016/j.cub.2008.11.033. Epub 2008 Dec 24.
LKB1 kinase is a tumor suppressor that is causally linked to Peutz-Jeghers syndrome. In complex with the pseudokinase STRAD and the scaffolding protein MO25, LKB1 phosphorylates and activates AMPK family kinases, which mediate many cellular processes. The prototypical family member AMPK regulates cell energy metabolism and epithelial apicobasal polarity. This latter event is also dependent on E-cadherin-mediated adherens junctions (AJs) at lateral borders. Strikingly, overexpression of LKB1/STRAD can also trigger establishment of epithelial polarity in the absence of cell-cell or cell-matrix contacts. However, the upstream factors that normally govern LKB1/STRAD function are unknown. Here we show by immunostaining and fluorescence resonance energy transfer that active LKB1/STRAD kinase complex colocalizes with E-cadherin at AJs. LKB1/STRAD localization and AMPK phosphorylation require E-cadherin-dependent maturation of AJs. However, LKB1/STRAD complex kinase activity is E-cadherin independent. These data suggest that in polarized epithelial cells, E-cadherin regulates AMPK phosphorylation by controlling the localization of the LKB1 complex. The LKB1 complex therefore appears to function downstream of E-cadherin in tumor suppression.
LKB1激酶是一种肿瘤抑制因子，与黑斑息肉综合征存在因果关联。LKB1与假激酶STRAD及支架蛋白MO25形成复合物，使AMPK家族激酶磷酸化并激活，后者介导多种细胞过程。该家族的典型成员AMPK调节细胞能量代谢及上皮细胞的顶-基极性。后一过程还依赖于位于细胞侧面边界处的E-钙黏蛋白介导的黏附连接（AJs）。引人注目的是，在不存在细胞-细胞或细胞-基质接触的情况下，LKB1/STRAD的过表达也能触发上皮极性的建立。然而，正常调控LKB1/STRAD功能的上游因子尚不清楚。在此，我们通过免疫染色和荧光共振能量转移表明，活性LKB1/STRAD激酶复合物与E-钙黏蛋白在AJs处共定位。LKB1/STRAD的定位及AMPK的磷酸化需要AJs依赖E-钙黏蛋白的成熟。然而，LKB1/STRAD复合物的激酶活性不依赖E-钙黏蛋白。这些数据表明，在极化上皮细胞中，E-钙黏蛋白通过控制LKB1复合物的定位来调节AMPK的磷酸化。因此，LKB1复合物在肿瘤抑制中似乎发挥着E-钙黏蛋白下游的作用。
