Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade.
Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade.
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DOI：
10.1186/1475-4924-2-28
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发表时间：
2003
影响因子：
--
通讯作者：
Hardie DG
中科院分区：
文献类型：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
AMP激活的蛋白激酶（AMPK）级联是细胞能量电荷的传感器，其充当“代谢总开关”并抑制细胞增殖。激活需要上游激酶（AMPKKs）尚未确定的激活环内AMPK的Thr 172磷酸化。最近，我们确定了三个相关的蛋白激酶上游的酵母同源物的AMPK。虽然它们没有明显的哺乳动物同源物，但它们与LKB 1有关，LKB 1是一种在人类Peutz-Jeghers癌症综合征中突变的肿瘤抑制因子。我们最近发现LKB 1与两个辅助亚基STRADα/β和MO 25 α/β形成复合物。我们报告以下观察结果。首先，从大鼠肝脏中纯化的两种AMPKK活性包含LKB 1、STRADα和MO 25 α，并且可以使用抗LKB 1抗体进行免疫沉淀。其次，LKB 1、STRADα/β和MO 25 α/β的内源性和重组复合物通过Thr 172的磷酸化激活AMPK。第三，完全活性需要催化活性LKB 1、STRADα或STRADβ和MO 25 α或MO 25 β。第四，AMPK激活药物AICA核苷和苯丙氨酸不能激活HeLa细胞（缺乏LKB 1）中的AMPK，但可以通过稳定表达野生型但不具有催化活性的LKB 1来恢复激活。第五，AICA核苷和苯丙氨酸不能激活来自LKB 1敲除小鼠胚胎的永生化成纤维细胞中的AMPK。这些结果首次描述了LKB 1肿瘤抑制因子的生理底物，并表明它作为AMPK的上游调节因子发挥作用。我们的研究结果表明，Peutz-Jeghers综合征的肿瘤可能是由于LKB 1失活导致AMPK活化不足所致。
The AMP-activated protein kinase (AMPK) cascade is a sensor of cellular energy charge that acts as a 'metabolic master switch' and inhibits cell proliferation. Activation requires phosphorylation of Thr172 of AMPK within the activation loop by upstream kinases (AMPKKs) that have not been identified. Recently, we identified three related protein kinases acting upstream of the yeast homolog of AMPK. Although they do not have obvious mammalian homologs, they are related to LKB1, a tumor suppressor that is mutated in the human Peutz-Jeghers cancer syndrome. We recently showed that LKB1 exists as a complex with two accessory subunits, STRADα/β and MO25α/β. We report the following observations. First, two AMPKK activities purified from rat liver contain LKB1, STRADα and MO25α, and can be immunoprecipitated using anti-LKB1 antibodies. Second, both endogenous and recombinant complexes of LKB1, STRADα/β and MO25α/β activate AMPK via phosphorylation of Thr172. Third, catalytically active LKB1, STRADα or STRADβ and MO25α or MO25β are required for full activity. Fourth, the AMPK-activating drugs AICA riboside and phenformin do not activate AMPK in HeLa cells (which lack LKB1), but activation can be restored by stably expressing wild-type, but not catalytically inactive, LKB1. Fifth, AICA riboside and phenformin fail to activate AMPK in immortalized fibroblasts from LKB1-knockout mouse embryos. These results provide the first description of a physiological substrate for the LKB1 tumor suppressor and suggest that it functions as an upstream regulator of AMPK. Our findings indicate that the tumors in Peutz-Jeghers syndrome could result from deficient activation of AMPK as a consequence of LKB1 inactivation.